Similarity of chest X-ray and thermal imaging of focal pneumonia: a randomised proof of concept study at a large urban teaching hospital.

OBJECTIVE: To assess the diagnostic accuracy of thermal imaging (TI) in the setting of focal consolidative pneumonia with chest X-ray (CXR) as the gold standard. SETTING: A large, 973-bed teaching hospital in Boston, Massachusetts. PARTICIPANTS: 47 patients enrolled, 15 in a training set, 32 in a test set. Age range 10 months to 82 years (median=50 years). MATERIALS AND METHODS: Subjects received CXR with subsequent TI within 4 hours of each other. CXR and TI were assessed in blinded random order. Presence of focal opacity (pneumonia) on CXR, the outcome parameter, was recorded. For TI, presence of area(s) of increased heat (pneumonia) was recorded. Fisher's exact test was used to assess the significance of the correlations of positive findings in the same anatomical region. RESULTS: With TI compared with the CXR (the outcome parameter), sensitivity was 80.0% (95% CIs 29.9% to 98.9%), specificity was 57.7% (95% CI 37.2% to 76.0%). Positive predictive value of TI was 26.7% (95% CI 8.9% to55.2%) and its negative predictive value was 93.8% (95% CI 67.7% to 99.7%). CONCLUSIONS: This feasibility study confirms proof of concept that chest TI is consistent with CXR in suggesting similarly localised focal pneumonia with high sensitivity and negative predictive value. Further investigation of TI as a point-of-care imaging modality is warranted.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Similar performance of Brasfield and Wisconsin scoring systems in young children with cystic fibrosis.

BACKGROUND: To assess the severity of lung disease in cystic fibrosis (CF), scoring systems based on chest radiographs (CXRs), CT and MRI have been used extensively, although primarily in research settings rather than for clinical purposes. It has recently been shown that those based on CXRs (primarily the Brasfield and Wisconsin systems) are as sensitive and valid as those based on CT. The reproducibility and correlation of both systems to pulmonary function tests (PFTs) were recently investigated and were found to be statistically identical. However, the relative performance of these systems has not been specifically assessed in children younger than 5 years old with mild lung disease, a critical age range in which PFTs is rarely performed. OBJECTIVE: To investigate and compare the performance of the Brasfield and Wisconsin systems in children 0-5 years old with predominantly mild lung disease. MATERIALS AND METHODS: Fifty-five patients 0-5 years old with 105 CXRs were included in the study. Given that the goal was to compare system performance in mild disease, only the first two CXRs from each patient were included (all but five patients had two images). When only one image was available in the target age range, it only was included. Agreement between the Brasfield and Wisconsin systems was assessed using a 2X2 contingency table assuming binary classification of CF lung disease using CXR scoring systems (mild vs. non-mild). In the absence of PFTs or another external gold standard for comparison, the Wisconsin system was used as an arbitrary gold standard against which the Brasfield was compared. Correlation between the two systems was assessed via a concordance correlation coefficient (CCC) for repeated measures. RESULTS: Scores were rated as mild or non-mild based on published numerical cutoffs for each system. The systems agreed on 89/105 (85%) and disagreed on 16/105 (15%) of the CXRs. Agreement between the two systems was statistically significant (P < 0.001). Relative sensitivity and specificity of the Brasfield system (which since using the Wisconsin as the gold standard reflects relative agreement rather than absolute performance of the Brasfield) was also fairly high (85% and 84%, respectively). Relatively high correlation between the two systems was also estimated (r = 0.72). CONCLUSION: The current study, powered to find at least a mild correlation between the two systems, confirms the Brasfield and Wisconsin systems are in agreement when assessing CF lung disease even in patients younger than 5 years of age with predominantly mild disease.

Brasfield and Wisconsin scoring systems have equal value as outcome assessment tools of cystic fibrosis lung disease.

BACKGROUND: Several imaging-based scoring systems have been used as outcome measures in assessing the severity of cystic fibrosis (CF) lung disease. It has been shown that chest radiography performs equally to computed tomography (CT). There is the opinion that of the two most commonly used chest radiograph (CXR) systems, the Brasfield system is less sensitive and reliable than the Wisconsin system. OBJECTIVE: This report assesses the reproducibility and reliability of the two systems. MATERIALS AND METHODS: Thirty patients with CXRs during a 5-year period were randomly selected. One hundred eighty-two studies had data for all CXRs and pulmonary function tests (PFTs), Forced Expiratory Volume in One Second (FEV-1) and Forced Vital Capacity (FVC). PFT values closest to the date of each CXR were recorded. Four radiologists scored each image twice by both the Brasfield and Wisconsin systems. Intra- and inter-rater reliability, correlation with PFTs and direct correlation of the two systems were calculated. RESULTS: Intra-rater agreement: r = 0.86-0.99 Brasfield, r = 0.78-0.96 Wisconsin. Inter-rater agreement: 0.76-0.90 Brasfield, r = 0.74-0.97 Wisconsin. Brasfield vs. FEV-1: r = 0.55, vs. FVC r = 0.61. Wisconsin vs. FEV-1: r = 0.57, vs. FVC r = 0.66. Correlation of the two systems: r = 0.86 (all P < 0.001). CONCLUSION: The Brasfield and Wisconsin systems performed very similarly providing equally reproducible, robust and reliable measures.

A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome.

BACKGROUND: Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world's progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with progeria. OBJECTIVE: To define characteristic radiographic features of this syndrome. MATERIALS AND METHODS: Thirty-nine children with classic progeria, ages 2-17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. RESULTS: Sample included 23 girls and 16 boys-the largest number of patients with progeria evaluated prospectively to date. Eight new and two little known progeria-associated radiologic findings were identified (frequencies of 3-36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered and 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P = 0.02-0.0001). CONCLUSION: This study considerably expands the radiographic morphological spectrum of progeria. A better understanding of the radiologic abnormalities associated with progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

Pulmonary MDCT angiography: value of multiplanar reformatted images in detecting pulmonary embolism in children.

OBJECTIVE: The purpose of this study was to determine whether the use of multiplanar reformatted (MPR) MDCT images in the diagnosis of pulmonary embolism (PE) in children by faculty pediatric radiologists and radiology residents affects reader performance parameters and adds diagnostic value compared with the use of axial MDCT images alone. MATERIALS AND METHODS: This retrospective study was conducted with the images of 60 children (28 boys, 32 girls; mean age, 14.7 ± 3.5 years; range, 3.2-18 years) who consecutively underwent pulmonary CT angiography (CTA) for clinically suspected PE. Two faculty pediatric radiologists and two radiology residents independently reviewed images from each study initially using only axial MDCT images and later using MPR MDCT images in any x-, y-, or z-axis. Diagnostic accuracy, confidence level (1-5 ordinal scale), and interpretation time for MPR MDCT images were compared with those for axial MDCT images by use of the McNemar test and paired Student t test. The kappa coefficient was calculated to assess interobserver agreement. Diagnostic accuracy was compared between faculty pediatric radiologists and radiology residents by logistic regression analysis, and confidence level, interpretation time, and added diagnostic value were evaluated by analysis of variance. RESULTS: Nine of 60 pulmonary CTA studies (15%) were found to show PE. Diagnostic accuracy in detection of PE ranged from 91.7% to 100% (mean, 96.7%) with no significant differences between axial and MPR MDCT images (McNemar test for matched binary pairs, p > 0.50 for each reviewer). Logistic regression showed no significant difference between faculty pediatric radiologists and radiology residents in diagnostic accuracy in detection of PE on axial MDCT images (p = 0.48) or MPR MDCT images (p = 0.24). Confidence level and interobserver agreement were significantly higher and average interpretation time was longer in the evaluation of PE with MPR MDCT images than with axial MDCT images for all reviewers (p < 0.001). Compared with faculty pediatric radiologists, radiology residents had significantly greater increases in confidence level, interobserver agreement, interpretation time, and added diagnostic value using MPR MDCT images than they did using axial MDCT images to diagnose PE (p < 0.001). CONCLUSION: Use of MPR MDCT images for pulmonary CTA in the diagnosis of PE in children significantly increases confidence, interobserver agreement, and interpretation time among faculty pediatric radiologists and radiology residents. Because use of MPR MDCT images results in significantly greater improvements in reading parameters for residents than for faculty members, the routine use of this technique by trainees should be encouraged.

Screening of asymptomatic children for tuberculosis is a lateral chest radiograph routinely indicated?

RATIONALE AND OBJECTIVES: The aim of this study was to determine whether a lateral chest radiograph provides additional diagnostic information to a posteroanterior (PA) radiograph in the screening of asymptomatic children with positive purified protein derivative (PPD) skin tests in a nonendemic area. MATERIALS AND METHODS: This was an Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant, retrospective study of 605 consecutive pediatric patients (294 males, 311 females; mean age, 10.8 ± 5.2 years) with positive PPD skin test results, who underwent PA and lateral chest radiographs between July 2003 and May 2009 at a tertiary care pediatric hospital in a nonendemic area for tuberculosis (TB). Two pediatric radiologists independently reviewed each chest radiograph for evidence of abnormalities that may be indicative of acute or chronic TB infection. The reviewers first analyzed the PA radiograph alone and subsequently evaluated the PA and the lateral radiograph together to determine whether any observed abnormality was identified only on the lateral radiograph. When an abnormality was detected on both PA and lateral radiographs, the reviewers determined whether the abnormality on the lateral radiograph changed the reviewer's decision based on the PA radiograph alone. Assessment of nonconcordance between PA and lateral chest radiographs for each reviewer was evaluated by the McNemar test of matched binary pairs. Agreement between reviewers for detecting abnormalities on radiographs was evaluated by using the kappa (κ) statistic. RESULTS: The frequency of an abnormal chest radiograph related to TB was 1.8% (11/605). The PA radiograph showed abnormalities in all 11 (100%) children with radiographic abnormalities. Lateral radiographs showed abnormalities related to TB in 2 (18.2%) of 11 cases found to be abnormal on PA radiographs. Nine (81.8%) of 11 abnormalities on PA radiographs were not detected on the lateral chest radiographs. There was statistical evidence of nonconcordance between PA and lateral chest radiographs in detecting TB-related abnormalities for reviewer 1 (P < .001) and reviewer 2 (P = .004). In cases with abnormalities observed on both PA and lateral radiographs, there were no cases in which information obtained from the lateral chest radiograph resulted in a change in interpretation based on the PA radiograph alone. A high level of agreement was observed between the two independent reviewers in detecting TB-related abnormalities on PA radiographs (κ = 0.84, P < .001). CONCLUSIONS: A PA radiograph alone is sufficient for TB screening of asymptomatic pediatric patients with positive PPD skin test results in an area non-endemic for TB.

Lack of correlation between pulmonary disease and cystic fibrosis transmembrane conductance regulator dysfunction in cystic fibrosis: a case report.

INTRODUCTION: Mutations in both alleles of the cystic fibrosis transmembrane conductance regulator gene result in the disease cystic fibrosis, which usually manifests as chronic sinopulmonary disease, pancreatic insufficiency, elevated sodium chloride loss in sweat, infertility among men due to agenesis of the vas deferens and other symptoms including liver disease. CASE PRESENTATION: We describe a pair of African-American brothers, aged 21 and 27, with cystic fibrosis. They were homozygous for a rare frameshift mutation in the cystic fibrosis transmembrane conductance regulator 3791delC, which would be expected to cause significant morbidity. Although 80% of cystic fibrosis patients are colonized with Pseudomonas aeruginosa by eight years of age, the older brother had no serum opsonic antibody titer to P. aeruginosa by age 13 and therefore would have failed to mount an effective antibody response to the alginate (mucoid polysaccharide) capsule of P. aeruginosa. He was not colonized with P. aeruginosa until 24 years of age. Similarly, the younger brother was not colonized with P. aeruginosa until age 20 and had no significant lung disease. CONCLUSION: Despite a prevailing idea in cystic fibrosis research that the amount of functional cystic fibrosis transmembrane conductance regulator predicts clinical status, our results indicated that respiratory disease severity in cystic fibrosis exhibits phenotypic heterogeneity. If this heterogeneity is, in part, genetic, it is most likely derived from genes outside the cystic fibrosis transmembrane conductance regulator locus.

Cystic fibrosis genotype and assessing rates of decline in pulmonary status.

PURPOSE: To evaluate the hierarchical phenotypic expression of cystic fibrosis transmembrane conductance regulator (CFTR) genotypes in the respiratory system as has been documented in the pancreas. MATERIALS AND METHODS: This study was institutional review board approved; informed consent was not required. HIPAA guidelines were followed. Genotype effects were assessed by using chest radiographic and pulmonary function test (PFT) results in 93 patients. Serial chest radiographic and PFT (percentage of predicted forced expiratory volume in 1 second [FEV(1)], percentage of predicted forced vital capacity [FVC]) results were compared by using analysis of variance with repeated measures. By using CFTR class of mutations, two groups were created: group S (severe disease) and group M (mild disease). Within group S, three subgroups were created: A consisted of patients with two class I alleles; B, class I allele and class II or III allele; C, class II allele and class II or III allele. Group M consisted of patients with at least one allele from class IV-VI. RESULTS: Within group S, subgroup A had a faster deterioration than B or C according to radiographic data (A vs B, P = .014; A vs C, P = .009), with only a borderline difference in FEV(1) for subgroups A versus C (P = .031). Otherwise, PFTs were not sensitive for distinguishing subgroups. Only radiographic results identified that subgroup B had faster progression than C (P = .003); all parameters had trends of decline in the same direction. Group S had a faster decline than group M (radiography, P = .005; FVC, P = .011; FEV(1), P = .529). CONCLUSION: Disease progressed more rapidly with gene class hierarchical correlations seen in pancreatic disease. Radiography was more sensitive for identifying differences.

Clinical predictors of pneumonia among children with wheezing.

OBJECTIVE: The goal was to identify factors associated with radiographically confirmed pneumonia among children with wheezing in the emergency department (ED) setting. METHODS: A prospective cohort study was performed with children or=38 degrees C (positive LR: 2.03 [95% CI: 1.34-3.07]), maximal temperature in the ED of >or=38 degrees C (positive LR: 1.92 [95% CI: 1.48-2.49]), and triage oxygen saturation of <92% (positive LR: 3.06 [95% CI: 1.15-8.16]) were associated with increased risk of pneumonia. Among afebrile children (temperature of <38 degrees C) with wheezing, the rate of pneumonia was very low (2.2% [95% CI: 1.0-4.7]). CONCLUSIONS: Radiographic pneumonia among children with wheezing is uncommon. Historical and clinical factors may be used to determine the need for chest radiography for wheezing children. The routine use of chest radiography for children with wheezing but without fever should be discouraged.

Multidetector CT evaluation of congenital lung anomalies.

Congenital lung anomalies vary widely in their clinical manifestation and imaging appearance. Although radiographs play a role in the incidental detection and initial imaging evaluation in patients with clinical suspicion of congenital lung anomalies, cross-sectional imaging such as computer tomography (CT) is frequently required for confirmation of diagnosis, further characterization, and preoperative evaluation in the case of surgical lesions. Recently, with the development and widespread availability of multidetector CT scanners, CT has assumed a greater role in the noninvasive evaluation of congenital lung anomalies. The combination of fast speed, high spatial resolution, and enhanced quality of multiplanar reformation and three-dimensional reconstructions makes multidetector CT an ideal noninvasive method for evaluating congenital lung anomalies. In this article, the authors review the multidetector CT technique for evaluation of congenital lung anomalies. Important clinical aspects, characteristic imaging features, and key points that allow differentiation among various anomalies are highlighted for a variety of common and uncommon conditions.

Detection of simulated inflicted metaphyseal fractures in a fetal pig model: image optimization and dose reduction with computed radiography.

PURPOSE: To prospectively determine in a fetal pig model whether diagnostic performance comparable to that of high-detail screen-film imaging can be achieved with computed radiography for the detection of simulated classic metaphyseal lesions (CMLs), by using Faxitron digital images as the reference standard, and whether radiation dose reduction is possible. MATERIALS AND METHODS: This study was granted exempt status by the institutional review board and the animal care and use committee. Fractures simulating the CML were produced in distal femurs of 20 deceased fetal pigs. Twenty normal femurs served as control femurs. Femurs were imaged with a standard single-side-read 100-microm pixel sampling imaging plate (IP), a high-resolution dual-side-read 50-microm pixel sampling IP, and a high-detail screen-film imaging system. Eight tube current-time product settings (0.5-10.0 mAs) and two tube voltage selections (56 and 70 kVp) were employed. Two pediatric radiologists evaluated 920 images for fracture by using a five-point Likert scale. Area under the receiver operating characteristic curve (A(z)) values for the imaging systems were compared by using nonparametric chi(2) tests (all P < .05). RESULTS: For pooled rater data, performance of computed radiography was comparable to that of screen-film imaging, and superior performance (P = .04) was achieved with the more experienced rater. The A(z) value tended to increase as the tube current-time product setting was increased. Within each system, there was no significant difference in A(z) values for all images obtained at 56 and 70 kVp (dual-side-read IP, P = .63; single-side-read IP, P = .25; screen-film imaging system, P = .5). At 56 kVp, a dose reduction of up to 69% was achieved, and accuracy of computed radiography was comparable to that of screen-film imaging. CONCLUSION: Findings in this study suggest that computed radiography can replace screen-film imaging in the detection of CMLs and may permit dose reduction.

Chest radiographs for outcome assessment in cystic fibrosis.

We compare a chest radiographic scoring system developed by our group to spirometry in quantifying the longitudinal progression of lung disease among cystic fibrosis (CF) patients, and we evaluate the use of this radiographic scoring system in identifying the treatment effect of an inhaled antibiotic. Results suggest that longitudinally acquired chest radiographs, when scored using our scoring system, are at least as sensitive as lung function in detecting the progression of lung disease in CF patients.

Interpretation of chest radiographs in infants with cough and fever.

An understanding of the appearance of the infant chest radiograph requires an understanding of the anatomy and the physiologic, immunologic, and pathologic processes in the infant's chest. The authors describe the features of the infant chest that most influence the appearance of the chest radiograph in infants with cough and fever. They discuss why confusion sometimes occurs when radiology residents and general radiologists familiar with adult chest radiographs first evaluate the infant chest radiograph. The radiographic appearance of acute inflammation does not look the same in infants as it does in older children and adults. The hallmark of inflammatory lung disease in the infant chest is air trapping on the chest radiograph.

CF: an X-ray database to assess effect of aerosolized tobramycin.

This paper assesses the effectiveness of aerosolized tobramycin (TOBI) on cystic fibrosis (CF) lung disease, using a radiologic tool. The published tool, the age-based severity curve (ABS), is derived from Brasfield scoring of chest X-rays (CXR). This study evaluates both the usefulness of the ABS as an assessment tool and the effectiveness of TOBI. Thirty-eight patients were treated with TOBI. Twenty-four treated with dornase alfa were excluded. Fourteen patients, aged 2 months to 22 years (mean, 17 months of TOBI treatment), comprised the study group. Radiographs were obtained over a mean of 7.8 years (SD = 6.5 years; range, 9 months-18 years). Two hundred and eighty-two CXR of TOBI patients were analyzed following the ABS protocol. Rate of decline in radiologic status of the TOBI group and ABS were compared. Also, TOBI was assessed by comparing rate of decline before and after initiation of treatment. The TOBI group's radiologic assessment was compared to its rate of decline in pulmonary function studies and published population data. Rate of decline in ABS was 0.175 Brasfield points/year vs. 0.150 points/year in the TOBI group (P < 0.001). Before treatment, the TOBI group's rate of decline was 0.169 Brasfield points/year; after treatment, it was 0.150 points/year (P = 0.02). Forced vital capacity revealed a statistically significant slowing in rate of decline on TOBI. Although not statistically significant, rate of decline in forced expiratory volume at 1 sec showed a similar trend. The degree of slowing in decline is similar to that previously reported for pulmonary function studies.