Stephen M. Stick

Lung Disease at Diagnosis in Infants with Cystic Fibrosis Detected by Newborn Screening

RATIONALE The promise of newborn screening (NBS) for cystic fibrosis (CF) has not been fully realized, and the extent of improvement in respiratory outcomes is unclear. We hypothesized that significant lung disease was present at diagnosis. OBJECTIVES To determine the extent of lung disease in a geographically defined population of infants with CF diagnosed after detection by NBS. METHODS Fifty-seven infants (median age, 3.6 mo) with CF underwent bronchoalveolar lavage and chest computed tomography (CT) using a three-slice inspiratory and expiratory protocol. MEASUREMENTS AND MAIN RESULTS Despite the absence of respiratory symptoms in 48 (84.2%) of infants, a substantial proportion had lung disease with bacterial infection detected in 12 (21.1%), including Staphylococcus aureus (n = 4) and Pseudomonas aeruginosa (n = 3); neutrophilic inflammation (41. 4 x 10(3) cells/ml representing 18.7% of total cell count); proinflammatory cytokines, with 44 (77.2%) having detectable IL-8; and 17 (29.8%) having detectable free neutrophil elastase activity. Inflammation was increased in those with infection and respiratory symptoms; however, the majority of those infected were asymptomatic. Radiologic evidence of structural lung disease was common, with 46 (80.7%) having an abnormal CT; 11 (18.6%) had bronchial dilatation, 27 (45.0%) had bronchial wall thickening, and 40 (66.7%) had gas trapping. On multivariate analysis, free neutrophil elastase activity was associated with structural lung disease. Most children with structural lung disease had no clinically apparent lung disease. CONCLUSIONS These data support the need for full evaluation in infancy and argue for new treatment strategies, especially those targeting neutrophilic inflammation, if the promise of NBS for CF is to be realized.

Association of domestic exposure to volatile organic compounds with asthma in young children

Aim: To investigate the association between domestic exposure to volatile organic compounds (VOCs) and asthma in young children. Methods: A population based case-control study was conducted in Perth, Western Australia in children aged between 6 months and 3 years. Cases (n = 88) were children recruited at Princess Margaret Hospital accident and emergency department and discharged with asthma as the primary diagnosis; 104 controls consisted of children from the same age group without an asthma diagnosis identified through the Health Department of Western Australia. Information regarding the health status of the study children and characteristics of the home was collected using a standardised questionnaire. Exposure to VOCs, average temperature and relative humidity were measured in winter and summer in the living room of each participating household. Results: Cases were exposed to significantly higher VOC levels (μg/m3) than controls (p<0.01). Most of the individual VOCs appeared to be significant risk factors for asthma with the highest odds ratios for benzene followed by ethylbenzene and toluene. For every 10 unit increase in the concentration of toluene and benzene (μg/m3) the risk of having asthma increased by almost two and three times, respectively. Conclusions: Domestic exposure to VOCs at levels below currently accepted recommendations may increase the risk of childhood asthma. Measurement of total VOCs may underestimate the risks associated with individual compounds.

Domestic exposure to formaldehyde significantly increases the risk of asthma in young children

Concern has arisen in recent years about indoor air pollution as a risk factor for asthma. Formaldehyde exposure was examined in relation to asthma among young children (between 6 months and 3 yrs old) in a population-based control study carried out in Perth, Western Australia, between 1997–1999. An association between exposure to formaldehyde and asthma in young children has been suggested. Cases (n=88), whose parents were recruited at Princess Margaret Hospital Accident and Emergency Dept (Perth, Western Australia), were children discharged with asthma as the primary diagnosis. Controls (n=104), who were children in the same age group without asthma diagnosed by a doctor, were identified from birth records through the Health Dept of Western Australia (Perth, Western Australia). Health outcomes for the children were studied using a respiratory questionnaire and skin-prick tests. Formaldehyde, average temperature and relative humidity were measured on two occasions, winter (July–September 1998) and summer (December 1998–March 1999) in the childs bedroom and in the living room. The study found seasonal differences in formaldehyde levels in the childrens bedrooms and living rooms with significantly greater formaldehyde exposure during the summer period for case and control subjects. The generalised estimating equation model showed that children exposed to formaldehyde levels of ≥60 µg·m−3 are at increased risk of having asthma. The results suggest that domestic exposure to formaldehyde increases the risk of childhood asthma.

Bronchiectasis in Infants and Preschool Children Diagnosed with Cystic Fibrosis after Newborn Screening

OBJECTIVES To determine the prevalence of bronchiectasis in young children with cystic fibrosis (CF) diagnosed after newborn screening (NBS) and the relationship of bronchiectasis to pulmonary inflammation and infection. STUDY DESIGN Children were diagnosed with CF after NBS. Computed tomography and bronchoalveolar lavage were performed with anesthesia (n = 96). Scans were analyzed for the presence and extent of abnormalities. RESULTS The prevalence of bronchiectasis was 22% and increased with age (P = .001). Factors associated with bronchiectasis included absolute neutrophil count (P = .03), neutrophil elastase concentration (P = .001), and Pseudomonas aeruginosa infection (P = .03). CONCLUSIONS Pulmonary abnormalities are common in infants and young children with CF and relate to neutrophilic inflammation and infection with P. aeruginosa. Current models of care for infants with CF fail to prevent respiratory sequelae. Bronchiectasis is a clinically relevant endpoint that could be used for intervention trials that commence soon after CF is diagnosed after NBS.

Induction of Epithelial–Mesenchymal Transition in Primary Airway Epithelial Cells from Patients with Asthma by Transforming Growth Factor-β1

RATIONALE Airway remodeling in asthma is associated with the accumulation of fibroblasts, the primary cell responsible for synthesis and secretion of extracellular matrix proteins. The process by which the number of fibroblasts increases in asthma is poorly understood, but epithelial-mesenchymal transition (EMT) may play a significant role. OBJECTIVES To evaluate whether EMT occurs in primary airway epithelial cells (AECs), the mechanisms involved, and if this process is altered in asthmatic AECs. METHODS AECs were obtained from subjects with asthma (n = 8) and normal subjects without asthma (n = 10). Monolayer and air-liquid interface-AEC (ALI-AEC) cultures were treated with transforming growth factor (TGF)-beta1 (10 ng/ml) for 72 hours and assayed for mesenchymal and epithelial markers using quantitative polymerase chain reaction, confocal microscopy, and immunoblot. The involvement of BMP-7, Smad3, and MAPK-mediated signaling were also evaluated. MEASUREMENTS AND MAIN RESULTS TGF-beta1-induced EMT in AEC monolayers derived from subjects with asthma and normal donors. EMT was characterized by changes in cell morphology, increased expression of mesenchymal markers EDA-fibronectin, vimentin, alpha-smooth muscle actin, and collagen-1, and loss of epithelial markers E-cadherin and zonular occludin-1. Inhibition of TGF-beta1-induced signaling with Smad3-inhibiting siRNA or TGF-beta1-neutralizing antibodies prevented and reversed EMT, respectively, whereas BMP-7 had no effect. In ALI-AEC cultures derived from normal subjects, EMT was confined to basally situated cells, whereas in asthmatic ALI-AEC cultures EMT was widespread throughout the epithelium. CONCLUSIONS TGF-beta1 induces EMT in a Smad3-dependent manner in primary AECs. However, in asthmatic-derived ALI-AEC cultures, the number of cells undergoing EMT is greater. These findings support the hypothesis that epithelial repair in asthmatic airways is dysregulated.

International consensus on (ICON) pediatric asthma

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re‐evaluate and fine‐tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype‐specific treatment choices; however, this goal has not yet been achieved.

Infection, Inflammation, and Lung Function Decline in Infants with Cystic Fibrosis

RATIONALE Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies. OBJECTIVES To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation. METHODS Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV(0.5)), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing. MEASUREMENTS AND MAIN RESULTS Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were -0.8 (1.0), -0.9 (1.1), and -1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV(0.5) were -1.4 (1.2), -2.4 (1.1), and -4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P=0.003), and FEV(0.5) z-scores 0.96 lower (P=0.001), respectively. Significantly greater decline in FEV(0.5) z-scores occurred in those infected with Staphylococcus aureus (P=0.018) or Pseudomonas aeruginosa (P=0.021). CONCLUSIONS In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children.

Background: Exhaled nitric oxide (FENO) is raised in asthmatic children, but there are inconsistencies in the relationship between FENO and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FENO and asthma, atopy, and increased AR in children. Methods: One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FENO measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire. Results: In multiple linear regression analyses FENO was associated with atopy (p<0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FENO and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms. Conclusion: Raised FENO seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.

Progression of early structural lung disease in young children with cystic fibrosis assessed using CT

Background Cross-sectional studies implicate neutrophilic inflammation and pulmonary infection as risk factors for early structural lung disease in infants and young children with cystic fibrosis (CF). However, the longitudinal progression in a newborn screened population has not been investigated. Aim To determine whether early CF structural lung disease persists and progresses over 1 year and to identify factors associated with radiological persistence and progression. Methods 143 children aged 0.2–6.5 years with CF from a newborn screened population contributed 444 limited slice annual chest CT scans for analysis that were scored for bronchiectasis and air trapping and analysed as paired scans 1 year apart. Logistic and linear regression models, using generalised estimating equations to account for multiple measures, determined associations between persistence and progression over 1 year and age, sex, severe cystic fibrosis transmembrane regulator (CFTR) genotype, pancreatic sufficiency, current respiratory symptoms, and neutrophilic inflammation and infection measured by bronchoalveolar lavage. Results Once detected, bronchiectasis persisted in 98/133 paired scans (74%) and air trapping in 178/220 (81%). The extent of bronchiectasis increased in 139/227 (63%) of paired scans and air trapping in 121/264 (47%). Radiological progression of bronchiectasis and air trapping was associated with severe CFTR genotype, worsening neutrophilic inflammation and pulmonary infection. Discussion CT-detected structural lung disease identified in infants and young children with CF persists and progresses over 1 year in most cases, with deteriorating structural lung disease associated with worsening inflammation and pulmonary infection. Early intervention is required to prevent or arrest the progression of structural lung disease in young children with CF.

Lung Function in Infants with Cystic Fibrosis Diagnosed by Newborn Screening

RATIONALE Progressive lung damage in cystic fibrosis (CF) starts in infancy, and early detection may aid preventative strategies. OBJECTIVES To measure lung function in infants with CF diagnosed by newborn screening and describe its association with pulmonary infection and inflammation. METHODS Infants with CF (n = 68, 6 weeks to 30 months of age) and healthy infants without CF (n = 49) were studied. Forced vital capacity, FEV(0.5), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume rapid thoracoabdominal compression technique. Forty-eight hours later, infants with CF had bronchoalveolar lavage (BAL) for assessment of pulmonary infection and inflammation. MEASUREMENTS AND MAIN RESULTS In the CF group, the deficit in FEV(0.5) z score increased by -0.77 (95% confidence interval, -1.14 to -0.41; P < 0.001) with each year of age. The mean FEV(0.5) z score did not differ between infants with CF and healthy control subjects less than 6 months of age (-0.06 and 0.02, respectively; P = 0.87). However, the mean FEV(0.5) z score was lower by 1.15 in infants with CF who were older than 6 months of age compared with healthy infants (P < 0.001). FVC and FEF(75) followed a similar pattern. Pulmonary infection and inflammation in BAL samples did not explain the lung function results. CONCLUSIONS Lung function, measured by forced expiration, is normal in infants with CF at the time of diagnosis by newborn screening but is diminished in older infants. These findings suggest that in CF the optimal timing of therapeutic interventions aimed at preserving lung function may be within the first 6 months of life.