Psychosocial characteristics and predictors of health-care use in families of young children with cystic fibrosis in Western Australia.

OBJECTIVE: Early childhood psychosocial experiences determine future health and health-care use. Identifying psychosocial predictors in cystic fibrosis may inform intervention strategies that can reduce health-care utilization. DESIGN: The study was designed as a prospective cohort study. SETTING: The study was set in the only cystic fibrosis clinic in Western Australia. PATIENTS: The patients were children up to 6 years diagnosed with cystic fibrosis in Western Australia between 2005 and 2011. MAIN OUTCOME MEASURES: Psychosocial data collected for each year of life were compared with Australian population data and analysed as predictors of annual hospital, emergency and outpatient visits. RESULTS: Compared with the Australian population, cystic fibrosis families demonstrated lower socio-economic status and labour supply (P < 0.001), increased residential mobility (P < 0.001) and trends towards increased rates of parental separation (P = 0.066). Marital discord and maternal and child psychological stress significantly predicted increased hospital admissions, emergency and outpatient visits. CONCLUSIONS: Social gradients may exist for families of young children with cystic fibrosis in Western Australia with potential implications for child health. Family psychological and relationship stress predicted increased child cystic fibrosis-related health-care use.

Impact of lung disease on respiratory impedance in young children with cystic fibrosis.

This study aimed to evaluate the ability of the forced oscillation technique (FOT) to detect underlying lung disease in preschool children with cystic fibrosis (CF) diagnosed following newborn screening.184 children (aged 3-6 years) with CF underwent lung function testing on 422 occasions using the FOT to assess respiratory resistance and reactance at the time of their annual bronchoalveolar lavage collection and chest computed tomography scan. We examined associations between FOT outcomes and the presence and progression of respiratory inflammation, infection and structural lung disease.Children with CF who had pronounced respiratory disease, including free neutrophil elastase activity, infection with pro-inflammatory pathogens and structural lung abnormalities had similar FOT outcomes to those children without detectable lung disease. In addition, the progression of lung disease over 1 year was not associated with worsening FOT outcomes.We conclude that the forced oscillation technique is relatively insensitive to detect underlying lung disease in preschool children with CF. However, FOT may still be of value in improving our understanding of the physiological changes associated with early CF lung disease.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection.

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF.Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life.Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150-0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484-1.612; p<0.001).Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF.

Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis.

RATIONALE: Pulmonary inflammation, infection, and structural lung disease occur early in life in children with cystic fibrosis. OBJECTIVES: We hypothesized that the presence of these markers of cystic fibrosis lung disease in the first 2 years of life would be associated with reduced lung function in childhood. METHODS: Lung function (forced expiratory volume in the first three-quarters of a second [FEV0.75], FVC) was assessed in individuals with cystic fibrosis diagnosed after newborn screening and healthy subjects during infancy (0-2 yr) and again at early school age (4-8 yr). Individuals with cystic fibrosis underwent annual bronchoalveolar lavage fluid examination, and chest computed tomography. We examined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalizations, antibiotic prophylaxis) measured in the first 2 years of life were associated with reduced lung function in infants and young children with cystic fibrosis, using a mixed effects model. MEASUREMENTS AND MAIN RESULTS: Children with cystic fibrosis (n = 56) had 8.3% (95% confidence interval [CI], -15.9 to -6.6; P = 0.04) lower FEV0.75 compared with healthy subjects (n = 18). Detection of proinflammatory bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Aspergillus species, Streptococcus pneumoniae) in bronchoalveolar lavage fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3 and 15.6%). CONCLUSIONS: The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection, is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood, emphasizing the need for targeted therapeutic interventions in infancy to maximize functional outcomes later in life.

Distribution of early structural lung changes due to cystic fibrosis detected with chest computed tomography.

OBJECTIVE: To examine the distribution of early structural lung changes in clinically stable infants and young children with cystic fibrosis using chest computed tomography (CT). STUDY DESIGN: This cross-sectional study included 62 children aged 1-6 years with volume-controlled volumetric chest CT scans performed under general anesthesia as part of an early surveillance program. Each lobe was scored for presence and extent of bronchiectasis, mucus plugging, and air trapping using a semiquantitative score. The topographic distribution of structural abnormalities was evaluated by comparing the presence and extent of abnormalities in different lung regions and examining relationships between components. RESULTS: Although bronchiectasis was most common in the right upper lobe, overall changes in lung structure were not more common or more extensive in the upper lobes. Rather, bronchiectasis was more common in the right lung (right lung 0.95, left lung 0.68, P = .003), and mucus plugging (upper 0.41, middle 0.41, lower 0.72, P = .028) and air trapping (upper 0.79, middle 0.48, lower 0.96, P < .001) were more common in the lower lobes. The extents of bronchiectasis (P < .001) and air trapping (P = .011) were greater in the right lung. Scans with bronchiectasis were also more likely to have coexisting mucus plugging (P = .008) and air trapping (P < .001). CONCLUSION: Early structural lung disease is heterogeneously distributed in the lung. Quantitative scoring tools for studies using chest CT as an end point, and mechanistic studies that seek to better understand the pathogenesis of early cystic fibrosis lung disease, should take account of this differential topographic expression of disease early in life.

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.

Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis.

BACKGROUND: We hypothesized that the inflammatory response in the lungs of children with cystic fibrosis (CF) would vary with the type of infecting organism, being greatest with Pseudomonas aeruginosa and Staphylococcus aureus. METHODS: A microbiological surveillance program based on annual bronchoalveolar lavage (BAL) collected fluid for culture and assessment of inflammation was conducted. Primary analyses compared inflammation in samples that grew a single organism with uninfected samples in cross-sectional and longitudinal analyses. RESULTS: Results were available for 653 samples from 215 children with CF aged 24 days to 7 years. A single agent was associated with pulmonary infection (≥10(5) cfu/mL) in 67 BAL samples, with P. aeruginosa (n = 25), S. aureus (n = 17), and Aspergillus species (n = 19) being the most common. These microorganisms were associated with increased levels of inflammation, with P. aeruginosa being the most proinflammatory. Mixed oral flora (MOF) alone was isolated from 165 BAL samples from 112 patients, with 97 of these samples having a bacterial density ≥10(5) cfu/mL, and was associated with increased pulmonary inflammation (P < .001). For patients with current, but not past, infections there was an association with a greater inflammatory response, compared with those who were never infected (P < .05). However, previous infection with S. aureus was associated with a greater inflammatory response in subsequent BAL. CONCLUSIONS: Pulmonary infection with P. aeruginosa, S. aureus, or Aspergillus species and growth of MOF was associated with significant inflammatory responses in young children with CF. Our data support the use of specific surveillance and eradication programs for these organisms. The inflammatory response to MOF requires additional investigation.

Determinants of corneal biomechanical properties in an adult Chinese population.

PURPOSE: To investigate variations in corneal hysteresis (CH) and corneal resistance factor (CRF) and their ocular and systemic associations in Chinese adults. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: We included 1136 subjects of Chinese origin from an ongoing population-based study. METHODS: All subjects in this population-based study underwent a standardized ocular examination including keratometry (corneal radius of curvature), intraocular pressure (IOP) measurement with Goldmann applanation tonometry, central corneal thickness (CCT), and axial length (AL) assessments. The CH and CRF were measured with the Ocular Response Analyzer. Participants underwent a detailed interview and laboratory investigations that included estimation of nonfasting serum glucose, glycosylated hemoglobin, and lipid profile. MAIN OUTCOME MEASURES: We assessed CH, CRF, and their associations with demographic, ocular, and systemic factors. RESULTS: The mean age of study subjects was 55.3±8.4 years and 51.2% were females. The mean CH and CRF were 10.6±1.5 and 10.1±1.6 mmHg, respectively. Women had higher mean CH (10.8 vs 10.4 mmHg; P<0.001) and CRF (10.4 vs. 9.8 mmHg; P<0.001) than men. After adjusting for age, gender, IOP, CCT, keratometry, AL, and diabetes, CH was negatively associated with age (ß = -0.034; P<0.001), IOP (ß = -0.037; P = 0.01), corneal radius of curvature (ß = -0.963; P<0.001), and AL (ß = -0.106; P = 0.001); and positively associated with female gender (ß = 0.308; P<0.001) and CCT (ß = 0.020; P<0.001). The CRF showed a negative association with age (ß = -0.023; P<0.001) and corneal radius of curvature (ß = -0.771; P<0.001), and was positively associated with female gender (ß = 0.368; P<0.001), IOP (ß = 0.134; P<0.001) and CCT (ß = 0.024; P<0.001). Subjects with diabetes had a higher CH (ß = 0.324; P<0.001) and CRF (ß = 0.396; P = 0.002) compared with those without diabetes. CONCLUSIONS: With advancing age, the CH and CRF in adult Chinese decreased. Women and subjects with diabetes had greater CH and CRF. Corneal biomechanical properties of hysteresis and resistance factor are significantly influenced by IOP, CCT, corneal radius of curvature, and AL.

Qualitative evaluation of the iris and ciliary body by ultrasound biomicroscopy in subjects with angle closure.

PURPOSE: To qualitatively analyze anterior chamber structures imaged by ultrasound biomicroscopy (UBM) in primary angle-closure patients. METHODS: Subjects diagnosed as primary angle-closure suspect (PACS), primary angle-closure glaucoma (PACG), and previous acute primary angle closure (APAC) were recruited prospectively along with a group of normal controls. UBM was performed under standardized dark room conditions and qualitative assessment was carried out using a set of reference photographs of standard UBM images to categorize the various anatomic features related to angle configuration. These included overall and basal iris thicknesses, iris convexity, iris angulation, ciliary body size, and ciliary sulcus. RESULTS: A total of 60 PACS, 114 PACG, 41 APAC, and 33 normal controls were included. Patients were predominantly older Chinese females. After controlling the confounding effect of age and sex, eyes with overall thicker irides [medium odds ratio (OR) 3.58, thick OR 2.84] when compared with thin irides have a significantly higher likelihood of having PACS/PACG/APAC versus controls. Thicker basal iris component (medium OR 4.13, thick OR 3.39) also have higher likelihood of having angle closure when compared with thin basal iris thickness. Subjects with basal iris insertion, mild iris angulation, and large ciliary body have a higher OR of having angle closure. In contrast, the presence/absence of a ciliary sulcus did not influence the likelihood of angle closure. CONCLUSIONS: Eyes with thicker overall and basal iris thicknesses are more likely to have angle closure than controls. Other features that increase the likelihood of angle closure include basal iris insertion, mild iris angulation, and large ciliary body.

Assessment of early bronchiectasis in young children with cystic fibrosis is dependent on lung volume.

OBJECTIVE: The aim of this study was to determine whether assessment of early CT scan-detected bronchiectasis in young children with cystic fibrosis (CF) depends on lung volume. METHODS: This study, approved by the hospital ethics committee, included 40 young children with CF from a newborn screened population contributing paired volume-controlled inspiratory and expiratory volumetric chest CT scans acquired under general anesthesia while clinically stable. Bronchiectasis was assessed with a semiquantitative CT scan score in inspiration and expiration, and the sensitivity of the expiratory CT scan to detect bronchiectasis was compared with the inspiratory CT scan by sensitivity and intraclass correlation coefficient analysis and Bland-Altman plots. Matched inspiratory and expiratory airway-vessel measurements were obtained in a subset of 10 children, and the relationship between lung volume and airway:vessel ratio after adjusting for age and vessel size was examined with the use of a linear regression model with generalized estimating equations. The number of visible airways in inspiration and expiration was compared in all 40 children by Wilcoxon signed rank test. RESULTS: Expiratory scans had poor sensitivity (0.46) to detect bronchiectasis, underestimating disease extent (P < .001). Airway:vessel ratios were consistently higher in inspiration, independent of age and vessel size (P < .001), with significantly more airways visible in inspiration than in expiration, independent of age (median, 71 vs 28, respectively; P < .001). CONCLUSIONS: In young children with CF, radiologic assessment of early bronchiectasis with chest CT scan depends on lung volume; thus, expiratory scans may not be appropriate for evaluating bronchiectasis in this population. Lung volume during CT image acquisition should be standardized to evaluate airway dimensions in young children.

Respiratory impedance and bronchodilator responsiveness in healthy children aged 2-13 years.

BACKGROUND: The forced oscillation technique (FOT) can be used in children as young as 2 years of age and in those unable to perform routine spirometry. There is limited information on changes in FOT outcomes in healthy children beyond the preschool years and the level of bronchodilator responsiveness (BDR) in healthy children. We aimed to create reference ranges for respiratory impedance outcomes collated from multiple centers. Outcomes included respiratory system resistance (R(rs)) and reactance (X(rs)), resonant frequency (Fres), frequency dependence of R(rs) (Fdep), and the area under the reactance curve (AX). We also aimed to define the physiological effects of bronchodilators in a large population of healthy children using the FOT. METHODS: Respiratory impedance was measured in 760 healthy children, aged 2-13 years, from Australia and Italy. Stepwise linear regression identified anthropometric predictors of transformed R(rs) and X(rs) at 6, 8, and 10 Hz, Fres, Fdep, and AX. Bronchodilator response (BDR) was assessed in 508 children after 200 µg of inhaled salbutamol. RESULTS: Regression analysis showed that R(rs), X(rs), and AX outcomes were dependent on height and sex. The BDR cut-offs by absolute change in R(rs8), X(rs8), and AX were -2.74 hPa s L(-1), 1.93 hPa s L(-1), and -33 hPa s L(-1), respectively. These corresponded to relative and Z-score changes of -32%; -1.85 for R(rs8), 65%; 1.95 for X(rs8), and -82%; -2.04 for AX. CONCLUSIONS: We have established generalizable reference ranges for respiratory impedance and defined cut-offs for a positive bronchodilator response using the FOT in healthy children.

Angle assessment by EyeCam, goniophotography, and gonioscopy.

PURPOSE: To compare EyeCam (Clarity Medical Systems, Pleasanton, CA) and goniophotography in detecting angle closure, using gonioscopy as the reference standard. METHODS: In this hospital-based, prospective, cross-sectional study, participants underwent gonioscopy by a single observer, and EyeCam imaging and goniophotography by different operators. The anterior chamber angle in a quadrant was classified as closed if the posterior trabecular meshwork could not be seen. A masked observer categorized the eyes as per the number of closed quadrants, and an eye was classified as having angle closure if there were 2 or more quadrants of closure. Agreement between the methods was analyzed by κ statistic and comparison of area under receiver operating characteristic curves (AUC). RESULTS: Eighty-five participants (85 eyes) were included, the majority of whom were Chinese. Angle closure was detected in 38 eyes (45%) with gonioscopy, 40 eyes (47%) using EyeCam, and 40 eyes (47%) with goniophotography (P=0.69 in both comparisons, McNemar test). The agreement for angle closure diagnosis (by eye) between gonioscopy and the 2 imaging modalities was high (κ=0.86; 95% Confidence Interval (CI), 0.75-0.97), whereas the agreement between EyeCam and goniophotography was not as good (κ=0.72; 95% CI, 0.57-0.87); largely due to lack of agreement in the nasal and temporal quadrants (κ=0.55 to 0.67). The AUC for detecting eyes with gonioscopic angle closure was similar for goniophotography and EyeCam (AUC 0.93, sensitivity=94.7%, specificity=91.5%; P>0.95). CONCLUSIONS: EyeCam and goniophotography have similarly high sensitivity and specificity for the detection of gonioscopic angle closure.

Corneal arcus is a sign of cardiovascular disease, even in low-risk persons.

PURPOSE: To examine the association of corneal arcus to cardiovascular disease (CVD) in an adult, ethnic Indian population. DESIGN: Population-based cross-sectional study. METHODS: Population-based study of ethnic South Asian Indians 40 to 80 years of age in Singapore from June 2007 through March 2009. We obtained a 75.5% response rate (3397/4497). All participants underwent standardized interview and systemic and ocular examinations, followed by nonfasting blood sampling. Corneal arcus was detected using a standardized slit-lamp examination. The main outcome measure was CVD, defined from a self-reported history of previous myocardial infarction, angina, or stroke. RESULTS: Corneal arcus, found in 1701 (50.1%) of 3397 participants, was associated with older age (odds ratio [OR], 3.07; 95% CI, 2.78 to 3.40; P < .001), male gender (OR, 2.17; 95% CI, 1.81 to 2.62; P < .001), higher levels of total cholesterol (OR, 1.14; 95% CI, 1.05 to 1.24; P = .002), hypertension (OR, 1.14; 95% CI, 1.05 to 1.24; P = .013), and cigarette smoking (OR, 1.59; 95% CI, 1.25 to 2.03; P < .001). Corneal arcus was associated with CVD (OR, 1.31; 95% CI, 1.02 to 1.7; P = .0038) independent of the above-named cardiovascular risk factors. Participants with low-risk Framingham scores were more likely to be associated with CVD if they had corneal arcus (men: OR, 2.02; 95% CI, 1.20 to 3.40; P = .008; women: OR, 2.78; 95% CI, 1.36 to 3.01; P < .001). Corneal arcus was associated with CVD independent of the Framingham score (men: Akaike information criterion, 1524.39 for Framingham Score and corneal arcus vs 1527.38 for Framingham Score alone; women: 1000.14 vs 1003.54, respectively). CONCLUSIONS: Corneal arcus is associated with CVD, independent of risk factors in ethnic Indian adults, even in those at low risk for vascular disease.