Structural lung disease in preschool children with cystic fibrosis: An 18 month natural history study.

BACKGROUND: This study was performed to describe the natural history of CF lung disease in young children over an 18 month period to assess the use of CT scanning as an outcome measure for intervention trials. METHODS: Chest CT scans were obtained at baseline and after 18 months in 42 two- to six-year-old children with CF. CT scans were scored by 2 experienced radiologists for the presence and severity of bronchiectasis, mucous plugging, and air trapping. RESULTS: Mean age at baseline 3.5 (1.3) (mean, sd) years. One or more findings of CF lung disease was seen on the first CT in 27 (64%) and at 18 months in 30 (75%). From baseline to 18 months bronchiectasis, mucous plugging, and air trapping increased from 50% to 53%, 14% to 28%, and 48% to 58% respectively. There was marked variability in the rate of progression, with subjects commonly showing improvement in lung disease. Bronchiectasis worsened in 14 (33%) and improved in 13 (31%). Single subjects with F508del/class III and F508del/class V demonstrated greater worsening and improvement respectively than F508del homozygous and class I genotypes. CONCLUSIONS: The natural history of CF lung disease over 18 months varies widely between subjects. Factors including genotype may affect natural history as well as the effectiveness of mediators and could be an important confounder if not recognized. These findings suggest that the use of CT scanning as an outcome surrogate for CF lung disease in young children may be more challenging than has been previously recognized.

Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease.

OBJECTIVE: To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements. METHODS: Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1 second (ppFEV1 ) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years. RESULTS: No significant changes were noted at 3-month for any variable except for decreased ppFEV1 . Mucus plugging score (MPS) and QATA1andA2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1 , were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS. CONCLUSIONS: MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis.

Changes in Pulmonary Function and Controlled Ventilation-High Resolution CT of Chest After Antibiotic Therapy in Infants and Young Children with Cystic Fibrosis.

BACKGROUND: Infants with cystic fibrosis (CF) develop early progressive lung disease which may be asymptomatic. Infant pulmonary function tests (IPFT) and controlled ventilation-high resolution computed tomography (CV-HRCT) of chest can detect early asymptomatic lung disease. It is not well established that these objective measures can detect changes in lung disease after clinical interventions. OBJECTIVE: The purpose of this study was to evaluate usefulness of IPFT and CV-HRCT to detect changes in lung disease after intravenous (IV) antibiotic therapy in infants with early CF-related lung disease. STUDY DESIGN: IPFTs and CV-HRCT done before and after 2 weeks of IV antibiotics in infants at our institution over the last 12 years were compared. CV-HRCTs were compared using the modified Brody scoring system. RESULTS: The sample included 21 infants, mean age 85.2 ± 47.6 weeks. Mean change in weight was 0.4 ± 0.38 kg (p = 0.001). Significant changes in IPFT included mean % predicted FEV(0.5) (+13.5 %, p = 0.043), mean %FEF(25-75) (+30.2 %, p = 0.008), mean %RV/TLC (-11.2 %, p = 0.008), and mean %FRC/TLC (-4.5 %, p = 0.001). Total Brody scores improved from a median of 10 to 5 (p < 0.001) as did mean scores for airway wall thickening (p = 0.050), air trapping (p < 0.001), and parenchymal opacities (p = 0.003). CONCLUSION: IPFT and CV-HRCT can be used as objective measures of improvement in lung disease for infants with CF treated with antibiotics.

Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation.

BACKGROUND: Ivacaftor corrects the cystic fibrosis transmembrane conductance regulator (CFTR) gating defect associated with G551D mutation and is quickly becoming an important treatment in patients with cystic fibrosis (CF) due to this genetic mutation. METHODS: A single-center study was performed in CF patients receiving ivacaftor to evaluate the usefulness of high resolution computed tomography (HRCT) of the chest as a way to gauge response to ivacaftor therapy. RESULTS: Ten patients with CF were enrolled for at least one year before and after starting ivacaftor. At time of enrollment, mean age was 20.9 ± 10.8 (range 10-44) years. There were significant improvements from baseline to 6 months in mean %FVC (93 ± 16 to 99 ± 16) and %FEV1 (79 ± 26 to 87 ± 28) but reverted to baseline at one year. Mean sweat chloride levels decreased significantly from baseline to one year. Mean weight and BMI improved at 6 months. Weight continued to improve with stabilization of BMI at one year. Chest HRCT showed significant improvement at one year in mean modified Brody scores for bronchiectasis, mucous plugging, airway wall thickness, and total Brody scores. Elevated bronchiectasis and airway wall thickness scores correlated significantly with lower %FEV1, while higher airway wall thickness and mucus plugging scores correlated with more pulmonary exacerbations requiring IV and oral antibiotics respectively. CONCLUSIONS: Based on our findings, HRCT imaging is a useful tool in monitoring response to ivacaftor therapy that corrects the gating defect associated with the G551D-CFTR mutation.

Image analysis for cystic fibrosis: computer-assisted airway wall and vessel measurements from low-dose, limited scan lung CT images.

Cystic fibrosis (CF) is a life-limiting genetic disease that affects approximately 30,000 Americans. When compared to those of normal children, airways of infants and young children with CF have thicker walls and are more dilated in high-resolution computed tomographic (CT) imaging. In this study, we develop computer-assisted methods for assessment of airway and vessel dimensions from axial, limited scan CT lung images acquired at low pediatric radiation doses. Two methods (threshold- and model-based) were developed to automatically measure airway and vessel sizes for pairs identified by a user. These methods were evaluated on chest CT images from 16 pediatric patients (eight infants and eight children) with different stages of mild CF related lung disease. Results of threshold-based, corrected with regression analysis, and model-based approaches correlated well with both electronic caliper measurements made by experienced observers and spirometric measurements of lung function. While the model-based approach results correlated slightly better with the human measurements than those of the threshold method, a hybrid method, combining these two methods, resulted in the best results.

Volume-monitored chest CT: a simplified method for obtaining motion-free images near full inspiratory and end expiratory lung volumes.

BACKGROUND: Lung inflation and respiratory motion during chest CT affect diagnostic accuracy and reproducibility. OBJECTIVE: To describe a simple volume-monitored (VM) method for performing reproducible, motion-free full inspiratory and end expiratory chest CT examinations in children. MATERIALS AND METHODS: Fifty-two children with cystic fibrosis (mean age 8.8 ± 2.2 years) underwent pulmonary function tests and inspiratory and expiratory VM-CT scans (1.25-mm slices, 80-120 kVp, 16-40 mAs) according to an IRB-approved protocol. The VM-CT technique utilizes instruction from a respiratory therapist, a portable spirometer and real-time documentation of lung volume on a computer. CT image quality was evaluated for achievement of targeted lung-volume levels and for respiratory motion. RESULTS: Children achieved 95% of vital capacity during full inspiratory imaging. For end expiratory scans, 92% were at or below the child's end expiratory level. Two expiratory exams were judged to be at suboptimal volumes. Two inspiratory (4%) and three expiratory (6%) exams showed respiratory motion. Overall, 94% of scans were performed at optimal volumes without respiratory motion. CONCLUSION: The VM-CT technique is a simple, feasible method in children as young as 4 years to achieve reproducible high-quality full inspiratory and end expiratory lung CT images.

An airway phantom to standardize CT acquisition in multicenter clinical trials.

RATIONALE AND OBJECTIVES: The purpose of this study was to demonstrate the use of a phantom to standardize low-dose chest computed tomographic (CT) protocols in children with cystic fibrosis. MATERIALS AND METHODS: Spiral chest CT scans of a Plexiglas phantom simulating airway sizes (internal diameter, 1.1-16.4 mm; wall thickness, 0.4-4.6 mm) in children with cystic fibrosis were obtained using two multidetector CT (MDCT) scanners (GE VCT and Siemens Sensation 64). Quantitative airway measurements from both scanners were compared with micro-CT airway measurements over a range of doses (0.2-1.8 mSv) to evaluate bias and variance of measurements. The effective doses for CT protocols were estimated using the ImPACT CT Patient Dosimetry Calculator. RESULTS: Both MDCT scanners were able to accurately measure airway sizes down to 3 mm internal diameter and 1.3 mm airway wall thickness, with errors of <3.5%. ImPACT estimates of effective dose were different for the MDCT scanners for a given peak tube voltage and product of tube current and exposure time. Accuracy and precision were not found to be associated with dose parameters for either machine. Bias in all measurements was strongly associated with airway diameter (P values < .00001), but the magnitude of bias was small (mean, 0.07 mm; maximum, 0.21 mm). Differences between machines in error components were on the order of a few micrometers. CONCLUSIONS: The use of a standard airway phantom confirms that different MDCT scanners have similar results within dose ranges planned for potential future clinical trials. Standardized protocols can be developed that adjust for differences in radiation exposure for different MDCT scanners.

Usefulness of multidetector CT imaging to assess vascular stents in children with congenital heart disease: an in vivo and in vitro study.

OBJECTIVE: To evaluate varying CT settings to visualize pediatric vascular stents in comparison to digital angiography (DA). BACKGROUND: There is a great clinical interest in substituting noninvasive methods to follow up children with congenital heart disease after interventional treatment. MATERIALS AND METHODS: CT studies in small children with transcatheter placed stents were reviewed, retrospectively. Furthermore, eight stents were implanted in tubes and partially obstructed. CT exams were performed on varying scanners (4 up to 64 slices) with corresponding tube settings. The effects of dose on image quality were evaluated regarding stent size, strut thickness, and in-stent stenoses in comparison to DA. RESULTS: Fourteen children with 28 implanted stents were identified. Significant differences between higher and lower radiation settings were not found, corresponding with the phantom, where moderate tube setting showed the best results. In vitro, there was an improvement with increasing number of detector rows, which resulted in a decrease of stent strut overestimation (295% down to 201%; P < 0.0001) and a better agreement with DA measurements for mild (78% up to 91%; P = 0.003) and moderate in-stent stenoses (80% up to 99%; P = 0.0001). CONCLUSION: Higher radiation exposure settings did not improve image quality, suggesting that the exams could be performed at a lower radiation dose.

CT of pediatric vascular stents used to treat congenital heart disease.

OBJECTIVE: The purpose of our study was to assess the visibility of lumen narrowing of pediatric vascular stents using various CT dose parameters in an in vitro model. MATERIALS AND METHODS: Ten steel stents of varying designs and sizes commonly used in the treatment of congenital heart disease were implanted in polyvinyl chloride (PVC) tubes and three of the 10 stents were partially obstructed with wax by filling 25% (mild) to 60% (moderate) of the lumen with contrast material. On a 64-MDCT scanner, the stents were scanned at tube voltages (kVp) of 80, 100, and 120 and at tube currents (mA) of 40, 80, 120, and 160. CT measurements of inner-stent diameter, strut thickness, and percent lumen (in-stent) stenoses were compared with biplane fluoroscopy of digital angiography. RESULTS: The stent diameter and percent stenosis on all CT images were consistently smaller than measured on digital angiography but were highly correlated (r = 0.97; p < 0.0001) with improvement as stent diameter increased (93% agreement with digital angiography for 4-mm stent, up to 99% for 25-mm stent; p = 0.001). Moderate stenosis could be assessed better than mild stenosis (99% vs 91% agreement with digital angiography; p = 0.003). Increasing exposure settings improved CT correlation of all measurements for mA up to 120 and kVp up to 100 (98.1% agreement). Higher settings did not improve accuracy (93.9% for 160 mA at 120 kVp; p = 0.03). CONCLUSION: CT is feasible to assess lumen narrowing of pediatric vascular stents at a wide range of tube settings. The study suggests that it is possible to lower the radiation exposure settings without loss in image quality or accuracy in detecting in-stent stenoses.

High-resolution computed tomography of the lung in children with cystic fibrosis: technical factors.

A standard technique that controls for respiratory motion and lung volumes during imaging is necessary if high-resolution computed tomography is to be used as an outcome measure in children with cystic fibrosis. End-inspiratory and expiratory imaging allows for the detection and differentiation of early lung disease. In children ages 0-5 years, a noninvasive controlled ventilation technique is ideal, and can be used in combination with raised-volume infant pulmonary function tests. In older children, a spirometric-assisted or spirometric-triggered technique should be used. With optimal technique, radiation dose settings (kVp and mA) can be lowered to achieve a diagnostic screening high-resolution computed tomography of the lungs at a dose equivalent to that of the chest radiograph.

Computed tomography dose and variability of airway dimension measurements: how low can we go?

BACKGROUND: Quantitative CT shows promise as an outcome measure for cystic fibrosis (CF) lung disease in infancy, but must be accomplished at a dose as low as reasonably achievable. OBJECTIVE: To determine the feasibility of ultra-low-dose CT for quantitative measurements of airway dimensions. MATERIALS AND METHODS: Two juvenile pigs were anesthetized and their lungs scanned at 25 cm H(2)O face-mask pressure in apnoea using beam currents of 5, 10, 20, 40 and 100 mAs. The lumen diameters and wall thicknesses of matched airways (n=22) at each dose were measured by two observers using validated software. Measurement variability at each dose was compared to that at 100 mAs (reference dose) for large and small airways (lumen diameter <2.5 mm). RESULTS: Lowering CT dose (mAs) affected measurement variability for lumen diameter of small and large airways (P<0.001) and for wall thickness of small (P<0.001), but not large (P=0.63), airways. To obtain the same measurement variability at 5 mAs as at 100 mAs, four to six small airways or one to three large airways have to be measured and averaged. CONCLUSION: Quantitative airway measurements are feasible on images obtained at as low as 5 mAs, but more airways need to be measured to compensate for greater measurement variability.

Assessment of in-stent stenosis in small children with congenital heart disease using multi-detector computed tomography: a validation study.

OBJECTIVES: Our purpose was to investigate the diagnostic reliability of multi-detector computed tomography (MDCT) in assessing in-stent stenosis compared to digital angiography (DA) in small children. BACKGROUND: Little is known about the feasibility of using MDCT to assess stents placed to treat children with congenital heart disease (CHD). METHODS: Twenty-two children (median age [range], 2(3/4) [(1/2) to 12] years) with 42 transcatheter placed stents (median diameter: 7.2 [3.4-16.3] mm) in the pulmonary arteries (n = 36), aorta (2), PDA (1), and SVC (3) underwent both MDCT and DA due to suspected hemodynamic problems. RESULTS: Independent "blinded" observers were able to measure stent and minimal luminal diameters in 115 out of 124 (93%) stent segments on MDCT and DA. The interobserver variability was low (mean difference: 0.5, SD 0.8 mm) with high correlation (r = 0.97; P < .0001). The percent stenosis by MDCT correlated well with DA (r = 0.89, P < .0001; mean error 2.7, SD 10.4%). For all grades of stenosis, the sensitivity and specificity for MDCT were 58% and 97%, respectively. At a threshold of approximately > or =20% stenosis sensitivity became >98%. All stent associated complications [fracture (4), vascular narrowings (11)] were diagnosed by MDCT. As the stent diameter increased, there was significantly reduced variability between MDCT and DA for in-stent stenosis (P < .0001). CONCLUSION: In small children, MDCT is a feasible and promising method for assessing stent associated complications in the treatment of CHD. Cardiac surgeons and interventional cardiologists might rely on this imaging modality to plan specific interventions more precisely and to assess the results upon follow up.

Multislice computed tomography as an adjunct to the management of an in-stent stenosis in an infant with congenital heart disease: imaging for the future.

The case report demonstrates the value of multslice computed tomography for stent imaging and detection of an in-stent stenosis in an infant with pulmonary atresia and ventricular septal defect after stent placement in the right pulmonary artery after biventricular repair.

Computed tomography in the evaluation of cystic fibrosis lung disease.

The first report of computed tomography (CT) scanning to monitor cystic fibrosis (CF)-related lung disease was published in 1986. Further publications followed, but in general there was little interest in this technique until recently. Two factors in particular have led to this increased interest. First is an increasing realization that pulmonary function tests, long the mainstay of CF evaluation, often underestimate the presence and severity of mild and moderate lung disease. Second is the need for more sensitive outcome measures to assess new therapies. This had led to new interest and a series of important publications. The goal of this article is to present the current status of CT scanning in CF.

Comparison of quiet breathing and controlled ventilation in the high-resolution CT assessment of airway disease in infants with cystic fibrosis.

BACKGROUND: Respiratory motion and low lung volumes limit the quality of HRCT examinations in infants and young children. OBJECTIVE: To assess the effects of respiratory motion and lung inflation on the ability to diagnose airway abnormalities and air trapping (AT) using HRCT in infants with cystic fibrosis (CF). MATERIALS AND METHODS: HRCT images of the lungs were obtained at four anatomical levels in 16 sedated children (age 2.4+/-1.1 years, mean+/-SD) with CF using controlled ventilation at full lung inflation (CVCT-I), at resting end exhalation (CVCT-E), and during quiet breathing (CT-B). Two blinded reviewers independently and then by consensus scored all images for the presence or absence of bronchiectasis (BE), bronchial wall thickening (BWT), and AT. RESULTS: Of the 64 images evaluated, BE was identified in 19 (30%) of the CVCT-I images compared to 6 (9%) of the CVCT-E images (P=0.006) and 4 (6%) of the CT-B images (P=0.044). AT was seen in 29 (45%) of the CVCT-E images compared to 14 (22%) of the CVCT-I images (P=0.012) and 12 (19%) of the CT-B images (P=0.012). There were no significant differences in the detection of BWT among the three methods. SUMMARY: In infants with CF, fully inflating the lung improved the ability to diagnose early BE, and obtaining motion-free images at end exhalation enhanced the detection of AT.

Inspiratory and expiratory CT lung density in infants and young children.

BACKGROUND: There is a lack of information on normal inspiratory and expiratory CT lung density in infants. OBJECTIVE: To describe normal regional CT lung density at end inspiratory and end expiratory lung volumes in children ages 0--5 years. MATERIALS AND METHODS: Motionless HRCT images were obtained at 25 cm (inspiratory) and 0 cm (expiratory) water pressure at apical (top of arch) and basal (2 cm above diaphragm) levels in 16 sedated children (mean age 1.5 years) who underwent CT for reasons other than respiratory disease. Density was measured at anterior-posterior and medial-lateral locations at each level in each lung. The influence of level, location, and age was quantified using analysis of variance methods. RESULTS: Lung density declined linearly in the first few years of life and thereafter approximated adult values. Beginning with the anterior-basal location, density at end inspiration (HU)=-835-(16 x age in years)+16 (if apical)+33 (if posterior)+23 (if medial)+14 (if lateral); standard error=38. At resting end exhalation =-616-(41 x age)+50 (if apical)+155 (if posterior)+74 (if medial)+46 (if lateral); standard error=68. CONCLUSION: We provide an initial basis for employing lung densitometry in infants and young children at end inspiration and resting end exhalation lung volumes.

Changes in airway dimensions on computed tomography scans of children with cystic fibrosis.

RATIONALE: In cystic fibrosis (CF), chronic bacterial infection and inflammation lead to progressive airway wall thickening and lumen dilatation. OBJECTIVES: To quantify airway wall thickening and lumen dilatation in children with CF over a 2-year interval. METHODS: Children with CF (n = 23) who had two computed tomography (CT) scans (CT(cf1) and CT(cf2)) combined with pulmonary function tests (PFTs), with a 2-year interval between measurements, were compared with control subjects (n = 21) who had one CT (CT(controls)). On cross-sectional cut airway-artery pairs, airway wall area (WA), airway lumen area (LA) and perimeter, and arterial area (AA) were quantified. LA/AA (= marker of bronchiectasis), airway wall thickness (AWT), and WA/AA (= markers of wall thickness) were calculated. CT scans were scored using four different scoring systems. PFTs were expressed as percent predicted. RESULTS: Airway WA-to-AA ratio was 1.45 (p < 0.001) and airway LA-to-AA ratio was 1.92 times higher (p < 0.001) in children with CF compared with age-matched control subjects. LA/AA and WA/AA remained unchanged from CT(cf1) to CT(cf2) and did not increase with age. AWT as a function of airway size increased from CT(cf1) to CT(cf2) by 2% (0.03 mm; p = 0.02). The change in AWT was inversely related to the change in forced expiratory flow between 25 and 75% of expiratory VC (p = 0.002). CONCLUSIONS: In CF, quantitative measurements of airways on CT scans show an increased ratio between airway LA and AA and progressive airway wall thickening. Scoring systems show progression of bronchiectasis but unchanged AWT. PFTs remained stable.