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1.  The Sensitivity of Lung Disease Surrogates in Detecting Chest CT Abnormalities in Children with Cystic Fibrosis 
Pediatric Pulmonology  2011;47(6):567-573.
Rationale
Chest CT scans detect structural abnormalities in children with cystic fibrosis (CF), even when pulmonary function tests (PFTs) are normal. The use of chest CT is limited in clinical practice, because of concerns over expense, increased resource utilization, and radiation exposure. Quantitative chest radiography scores are useful in detecting mild lung disease, but whether they are sensitive to the presence of CT scan abnormalities has not been evaluated.
Objective
To determine in a cross-sectional study if quantitative chest radiography is a more sensitive marker of chest CT abnormalities than other lung disease surrogates.
Methods
Brody chest CT scores were calculated for 81 children enrolled in the Wisconsin CF Neonatal Screening Project. We determined the sensitivity for Wisconsin (WCXR) and Brasfield (BCXR) chest radiography scores, PFTs, positive cultures for P. aeruginosa (PA), and parental report of symptoms to detect a Brody score worse than the median score for study participants.
Measurements and Main Results
The mean FEV1 for the study population was 91% predicted. Abnormal WCXR and BCXR scores had the highest sensitivity to detect a chest CT score worse than the median; abnormal PFTs, parental report of symptoms, and the presence of PA had much lower sensitivity (p<0.001).
Conclusions
In this cross sectional study, quantitative chest radiography has excellent sensitivity to detect an abnormal chest CT and may have a role in monitoring lung disease progression in children with CF.
doi:10.1002/ppul.21621
PMCID: PMC3309112  PMID: 22170734
Chest x-ray; quantitative radiography; pulmonary function
2.  Regional Differences in the Evolution of Lung Disease in Children with Cystic Fibrosis 
Pediatric Pulmonology  2011;47(7):635-640.
SUMMARY
Progression of lung disease is a major event in children with cystic fibrosis (CF), but regional differences in its evolution are unclear. We hypothesized that regional differences occur beginning in early childhood. We examined this issue by evaluating 132 patients followed in the Wisconsin Neonatal Screening Project between 1985 and 2010. We scored chest x-rays obtained every 1–2 years with the Wisconsin chest x-ray system, in which we divided the lungs into quadrants, and gave special attention to ratings for bronchiectasis (BX) and nodular/branching opacities. We compared the upper and lower quadrant scores, and upper right and left quadrant scores, as patients aged using a multivariable generalized estimation equation (GEE) model. We did a confirmatory analysis for a subset of 81 patients with chest computerized tomography (CT) images obtained in 2000 and scored using the Brody scoring system. The chest x-ray analysis shows that the upper quadrants have higher BX (p<0.001) and nodular/branching opacities (p<0.001) scores than the lower quadrants. CT analysis likewise reveals that the upper quadrants have more BX (p=0.02). Patients positive for mucoid PA showed significantly higher BX scores than patients with nonmucoid PA (p= 0.001). Chest x-ray scoring also revealed that the upper right quadrant has more BX (p< 0.001) than the upper left quadrant, and CT analysis was again confirmatory (p< 0.001). We conclude that pediatric patients with CF develop more severe lung disease in the upper lobes than the lower lobes in association with mucoid PA infections and also have more severe lung disease on the right side than on the left side in the upper quadrants. A variety of potential explanations such as aspiration episodes may be clinically relevant and provide insights regarding therapies.
doi:10.1002/ppul.21604
PMCID: PMC3310260  PMID: 22162514
cystic fibrosis; lung disease; bronchiectasis; upper lobes; mucoid Pseudomonas aeruginosa
3.  Critical evaluation of three chest radiograph scores in cystic fibrosis. 
Thorax  1994;49(9):863-866.
BACKGROUND--A number of chest radiographic scores have been developed to assess the severity of respiratory disease in cystic fibrosis but critical statistical evaluation has been limited. In particular, the chest radiograph component of the National Institutes of Health (NIH) clinical score has not previously been validated. Three different chest radiograph scores have been compared and the association between them and lung function tests investigated. METHODS--The interobserver and intraobserver variation of the Brasfield, NIH chest radiograph, and the Royal Children's Hospital (RCH) chest radiograph score was assessed by three observers--a paediatric radiologist, a junior and a senior respiratory physician--who independently scored, on separate occasions, 62 chest radiographs randomly selected from three age strata of patients ranging from 7 to 18 years. Lung function tests were available for 61 patients obtained within three months of the chest radiograph. Two way analysis of variance was used to estimate components of variation in scores. RESULTS--Results were similar for the Brasfield and NIH scores, both of which demonstrated greater precision than the RCH score, but the estimated repeatability of the Brasfield and NIH scores can be expected to differ by up to 20% of the maximum score. The reliabilities (intraclass correlation) are all reasonably high at 0.74, 0.73, and 0.61 for the Brasfield, NIH, and RCH scores, respectively. The estimated correlation between radiographic scores and lung function tests, adjusted for attenuation caused by measurement error, showed a similar correlation for all three scoring methods ranging from 0.55 to 0.78. Correlations were slightly greater with FEV1% than FVC%. These correlations are substantial but not high, indicating that a large proportion of the variability in radiographic scores cannot be explained by lung function measurements. CONCLUSIONS--The Brasfield and NIH chest radiograph scores have very similar statistical profiles and can be equally recommended if a chest radiograph score is to be used. The RCH radiographic score appears to be less reliable. The limitations of these scores need to be understood.
PMCID: PMC475172  PMID: 7940423
4.  Recovery of birth weight z-score within two years of diagnosis is positively associated with pulmonary status at age six years in children with cystic fibrosis 
Pediatrics  2009;123(2):714-722.
Objective
We recently reported that 60% of newly diagnosed CF children who had pancreatic insufficiency (PI) responded to treatment initiation and achieved catch-up weight gain to a level comparable to their birth weight Z-score within 2 years of diagnosis (“responders”), while the remaining 40% failed to do so (“non-responders”). The present study examined the impact of this early weight recovery on subsequent growth pattern and pulmonary status at age 6 years.
Patients and Methods
Sixty-three children with CF who had PI but no meconium ileus, and were enrolled in the Wisconsin CF Neonatal Screening Project, were studied. “Responders” were defined by a recovery of weight Z-score comparable to that at birth within 2 years of diagnosis. During ages 2–6, growth was evaluated with the combination of height and body mass index. Pulmonary status was evaluated by symptoms, spirometry, quantitative chest radiography and respiratory microbiology.
Results
The majority (71%) of the responders maintained their early weight recovery through age 6 years while only 32% of the non-responders achieved substantial growth improvement during age 2 to 6 years. Proportionately fewer responders reported cough symptoms (10% daytime cough, p =0.02; 22% nighttime cough, p=0.05) compared to non-responders (41% daytime cough, 45% nighttime cough) at age 6. Percent predicted FEV1 (%FEV1) at age 6 was 11% higher in responders (99.5 ± 13.9%) compared to non-responders (88.3 ± 18.5%), p = 0.015. Responders had significantly better Brasfield (20.1 ± 1.4, p = 0.01) and Wisconsin chest radiographic scores (8.3 ± 3.3, p = 0.04) compared to non-responders (Brasfield 18.9 ± 1.8, Wisconsin 12.3 ± 8.3). Respiratory microbiology was not significantly different. Multiple regression analyses indicated that the positive association between responder and %FEV1 at age 6 years remained statistically significant after controlling for infections with Pseudomonas aeruginosa and Staphlococcus aureus and chest radiographic scores. Growth patterns during 2–6 years of age were not associated with pulmonary measures at age 6.
Conclusion
CF patients with PI who achieved early growth recovery within 2 years of diagnosis had fewer cough symptoms, higher lung function and better chest radiography scores at 6 years of age.
doi:10.1542/peds.2007-3089
PMCID: PMC2775492  PMID: 19171643
Cystic Fibrosis; Growth; Malnutrition; Height; Weight; Body mass index; Pulmonary function; Chest radiograph; Newborn screening
5.  Lung diffusing capacity for nitric oxide and carbon monoxide in relation to morphological changes as assessed by computed tomography in patients with cystic fibrosis 
Background
Due to large-scale destruction, changes in membrane diffusion (Dm) may occur in cystic fibrosis (CF), in correspondence to alterations observed by computed tomography (CT). Dm can be easily quantified via the diffusing capacity for nitric oxide (DLNO), as opposed to the conventional diffusing capacity for carbon monoxide (DLCO). We thus studied the relationship between DLNO as well as DLCO and a CF-specific CT score in patients with stable CF.
Methods
Simultaneous single-breath determinations of DLNO and DLCO were performed in 21 CF patients (mean ± SD age 35 ± 9 y, FEV1 66 ± 28%pred). Patients also underwent spirometry and bodyplethysmography. CT scans were evaluated via the Brody score and rank correlations (rS) with z-scores of functional measures were computed.
Results
CT scores correlated best with DLNO (rS = -0.83; p < 0.001). Scores were also related to the volume-specific NO transfer coefficient (KNO; rS = -0.63; p < 0.01) and to DLCO (rS = -0.79; p < 0.001) but not KCO. Z-scores for DLNO were significantly lower than for DLCO (p < 0.001). Correlations with spirometric (e.g., FEV1, IVC) or bodyplethysmographic (e.g., SRaw, RV/TLC) indices were weaker than for DLNO or DLCO but most of them were also significant (p < 0.05 each).
Conclusion
In this cross sectional study in patients with CF, DLNO and DLCO reflected CT-morphological alterations of the lung better than other measures. Thus the combined diffusing capacity for NO and CO may play a future role for the non-invasive, functional assessment of structural alterations of the lung in CF.
doi:10.1186/1471-2466-9-30
PMCID: PMC2708126  PMID: 19531222
6.  Association of Radiographic Emphysema and Airflow Obstruction with Lung Cancer 
Rationale: To study the relationship between emphysema and/or airflow obstruction and lung cancer in a high-risk population.
Objective: We studied lung cancer related to radiographic emphysema and spirometric airflow obstruction in tobacco-exposed persons who were screened for lung cancer using chest computed tomography (CT).
Methods: Subjects completed questionnaires, spirometry, and low-dose helical chest CT. CT scans were scored for emphysema based on National Emphysema Treatment Trial criteria. Multiple logistic regressions estimated the independent associations between various factors, including radiographic emphysema and airflow obstruction, and subsequent lung cancer diagnosis.
Measurements and Main Results: Among 3,638 subjects, 57.5, 18.8, 14.6, and 9.1% had no, trace, mild, and moderate–severe emphysema, and 57.3, 13.6, 22.8, and 6.4% had no, mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD] I), moderate (GOLD II), and severe (GOLD III–IV) airflow obstruction. Of 3,638 subjects, 99 (2.7%) received a lung cancer diagnosis. Adjusting for sex, age, years of cigarette smoking, and number of cigarettes smoked daily, logistic regression showed the expected lung cancer association with the presence of airflow obstruction (GOLD I–IV, odds ratio [OR], 2.09; 95% confidence interval [CI], 1.33–3.27). A second logistic regression showed lung cancer related to emphysema (OR, 3.56; 95% CI, 2.21–5.73). After additional adjustments for GOLD class, emphysema remained a strong and statistically significant factor related to lung cancer (OR, 3.14; 95% CI, 1.91–5.15).
Conclusions: Emphysema on CT scan and airflow obstruction on spirometry are related to lung cancer in a high-risk population. Emphysema is independently related to lung cancer. Both radiographic emphysema and airflow obstruction should be considered when assessing lung cancer risk.
doi:10.1164/rccm.200803-435OC
PMCID: PMC2556456  PMID: 18565949
emphysema; chronic obstructive pulmonary disease; lung cancer
7.  Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age? 
Thorax  2013;69(4):320-327.
Rationale
Sensitive outcome measures applicable in different centres to quantify and track early pulmonary abnormalities in infants with cystic fibrosis (CF) are needed both for clinical care and interventional trials. Chest CT has been advocated as such a measure yet there is no validated scoring system in infants.
Objectives
The objectives of this study were to standardise CT data collection across multiple sites; ascertain the incidence of bronchial dilatation and air trapping in newborn screened (NBS) infants with CF at 1 year; and assess the reproducibility of Brody-II, the most widely used scoring system in children with CF, during infancy.
Methods
A multicentre observational study of early pulmonary lung disease in NBS infants with CF at age 1 year using volume-controlled chest CT performed under general anaesthetic.
Main results
65 infants with NBS-diagnosed CF had chest CT in three centres. Small insignificant variations in lung recruitment manoeuvres but significant centre differences in radiation exposures were found. Despite experienced scorers and prior training, with the exception of air trapping, inter- and intraobserver agreement on Brody-II score was poor to fair (eg, interobserver total score mean (95% CI) κ coefficient: 0.34 (0.20 to 0.49)). Only 7 (11%) infants had a total CT score ≥12 (ie, ≥5% maximum possible) by either scorer.
Conclusions
In NBS infants with CF, CT changes were very mild at 1 year, and assessment of air trapping was the only reproducible outcome. CT is thus of questionable value in infants of this age, unless an improved scoring system for use in mild CF disease can be developed.
doi:10.1136/thoraxjnl-2013-204176
PMCID: PMC3963531  PMID: 24132911
8.  Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age 
Thorax  2013;68(7):643-651.
Background
Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years.
Methods
Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry.
Results
168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient −0.39, 95% CI −0.74 to −0.05).
Conclusions
Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.
doi:10.1136/thoraxjnl-2012-202342
PMCID: PMC3711493  PMID: 23345574
Cystic Fibrosis; Bronchiectasis; Respiratory Infection
9.  The Correlation of Brody High Resolution Computed Tomography Scoring System with Clinical Status and Pulmonary Function Test in Patients with Cystic Fibrosis 
Background: To reduce the mortality and morbidity rates of cystic fibrosis (CF) patients, and to have an effective clinical management, it is important to monitor the progression of the disease. The aim of this study was to evaluate the progression of lung disease in CF patients by means of assessing the correlation of the CT scoring system with clinical status and pulmonary function test at the Pediatric Pulmonary Ward of Masih Daneshvari Hospital in 2008.
Methods: Pulmonary high resolution computed tomography (HRCT) was performed in 23 CF patients using the Brody's scoring system. Morphologic signs as well as the extent and severity of each sign were scored, and the total score was calculated. The correlation of HRCT scores (total score as well as the score for each parameter) with Shwachman Kuczycki scoring system and pulmonary function test were examined.
Results: The study included 9 female and 14 male patients with an age range of 5-23 years (mean: 13.42 years). Bronchiectasis (100%) and peribronchial wall thickening (100%) were the most frequent CT abnormalities. Mucus plugging, air trapping and parenchymal involvements were respectively seen in 95.7%, 91.3% and 47.8% of patients. The overall CT score for all patients was 57.6±24.2 (means±SD). The results of pulmonary function test showed a restrictive pattern; however, in 5.3% of the patients PFT was normal. The overall Shwachman-Kulczycki score was 53.48±13.8. There was a significantly (P=0.015) negative correlation between the total CT score and Shwachman-Kulczycki score; however, there was no significant correlation between total CT score and the results of PFT (P=0.481)
Conclusion: The Brody's scoring system for high resolution computed tomography seems to be a sensitive and efficient method to evaluate the progression of CF, and can be more reliable when we combine the CT scores with clinical parameters.
PMCID: PMC3559112  PMID: 23365473
Clinical status; pulmonary function test; cystic fibrosis
10.  Shwachman-Kulczycki score still useful to monitor cystic fibrosis severity 
Clinics  2011;66(6):979-983.
INTRODUCTION:
The Shwachman-Kulczycki score was the first scoring system used in cystic fibrosis to assess disease severity. Despite its subjectivity, it is still widely used.
OBJECTIVE:
To study correlations among forced expiratory volume in one second (FEV1), chest radiography, chest computed tomography, 6-minute walk test, and Shwachman-Kulczycki score in patients with cystic fibrosis and to test whether the Shwachman-Kulczycki score is still useful in monitoring the severity of the disease.
METHODS:
A cross-sectional prospective study was performed to analyze the correlations (Spearman). Patients with clinically stable cystic fibrosis, aged 3-21 years, were included.
RESULTS:
43 patients, 19F/24M, mean age 10.5 ± 4.7 years, with a median Shwachman-Kulczycki score of 70 were studied. The median Brasfield and Bhalla scores were 17 and 10, respectively. The mean Z score for the 6-minute walk test was −1.1 ± 1.106 and the mean FEV1 was 59 ± 26 (as percentage of predicted values). The following significant correlations versus the Shwachman-Kulczycki score were found: FEV1 (r  =  0.76), 6-minute walk test (r  =  0.71), chest radiography (r  =  0.71) and chest computed tomography (r  =  −0.78). When patients were divided according to FEV1, a statistically significantly correlation with the Shwachman-Kulczycki score was found only in patients with FEV1 <70% (r  =  0.67).
CONCLUSIONS:
The Shwachman-Kulczycki score remains an useful tool for monitoring the severity of cystic fibrosis, adequately reflecting the functional impairment and chest radiography and tomography changes, especially in patients with greater impairment of lung function. When assessing patients with mild lung disease its limitations should be considered and its usefulness in such patients should be evaluated in larger populations.
doi:10.1590/S1807-59322011000600010
PMCID: PMC3129961  PMID: 21808862
Chest radiography; Six minute walk test; Spirometry; Chest tomography; Clinical status
11.  Association of Lung Function, Chest Radiographs and Clinical Features in Infants with Cystic Fibrosis 
The European respiratory journal  2013;42(6):10.1183/09031936.00138412.
Background
The optimal strategy for monitoring cystic fibrosis (CF) lung disease in infancy remains unclear.
Objective
To describe longitudinal associations between infant pulmonary function tests (iPFTs), chest radiograph (CXR) scores and other characteristics.
Methods
CF patients ≤ 24 months old were enrolled in a 10-center study evaluating iPFTs 4 times over a year. CXRs ~1 year apart were scored with the Wisconsin and Brasfield systems. Associations of iPFT parameters with clinical characteristics were evaluated with mixed effects models.
Results
The 100 participants contributed 246 acceptable flow/volume (FEV0.5, FEF75) and 303 acceptable functional residual capacity (FRC) measurements and 171 CXRs. Both Brasfield and Wisconsin CXR scores worsened significantly over the 1 year interval. Worse Wisconsin CXR scores and S. aureus were both associated with hyperinflation (significantly increased FRC) but not with diminished FEV0.5 or FEF75. Parent-reported cough was associated with significantly diminished FEF75 but not with hyperinflation.
Conclusions
In this infant cohort in whom we previously reported worsening in average lung function, CXR scores also worsened over a year. The significant associations detected between both Wisconsin CXR score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of iPFTs and CXRs to detect early CF lung disease.
doi:10.1183/09031936.00138412
PMCID: PMC3795977  PMID: 23722613
cystic fibrosis; imaging; infants; lung function
12.  Risk Factors for the Progression of Cystic Fibrosis Lung Disease throughout Childhood 
Rationale: Previous studies of risk factors for progression of lung disease in cystic fibrosis (CF) have suffered from limitations that preclude a comprehensive understanding of the determinants of CF lung disease throughout childhood. The epidemiologic component of the 27-year Wisconsin Randomized Clinical Trial of CF Neonatal Screening Project (WI RCT) afforded us a unique opportunity to evaluate the significance of potential intrinsic and extrinsic risk factors for lung disease in children with CF.
Objectives: Describe the most important intrinsic and extrinsic risk factors for progression of lung disease in children with CF.
Methods: Variables hypothesized at the onset of the WI RCT study to be determinants of the progression of lung disease and potential risk factors previously identified in the WI RCT study were assessed with multivariable generalized estimating equation models for repeated measures of chest radiograph scores and pulmonary function tests in the WI RCT cohort.
Measurements and Main Results: Combining all patients in the WI RCT, 132 subjects were observed for a mean of 16 years and contributed 1,579 chest radiographs, and 1,792 pulmonary function tests. The significant determinants of lung disease include genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa. The previously described negative effect of female sex was not seen.
Conclusions: Modifiable extrinsic risk factors are the major determinants of progression of lung disease in children with CF. Better interventions to prevent or treat these risk factors may lead to improvements in lung health for children with CF.
doi:10.1513/AnnalsATS.201309-303OC
PMCID: PMC3972988  PMID: 24261460
pulmonary function test; chest X-ray; newborn screening; nutrition; sex
13.  The chest radiograph in cystic fibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores. 
Thorax  1994;49(9):860-862.
BACKGROUND--Scoring systems for the chest radiograph in cystic fibrosis are used to compare patients and different treatment regimens, and to monitor respiratory disease in individual patients. The Northern chest radiograph score was designed to allow one person to assess the radiological features of lung involvement in cystic fibrosis in as simple, rapid and equally reproducible manner as the established Chrispin and Norman, and Brasfield scoring systems. METHODS--Forty five chest radiographs were scored by 10 physicians with a special interest in cystic fibrosis according to the Brasfield and Northern methods, and by five pairs of physicians according to the Chrispin-Norman criteria. Three individuals and two pairs rescored the radiographs after an interval of 3-5 months. The Northern score was performed with and without a lateral view, using the original posteroanterior radiograph. RESULTS--The Northern score showed a better agreement between observers for the ranking of the radiographs. It was equally well related to respiratory function tests, the Shwachman-Kulczycki score of overall clinical status, and in its discrimination between different radiographs as the other two scoring systems. The Northern score performed equally well with or without a lateral film. CONCLUSIONS--The Northern system fulfils the requirements of a chest radiograph score more successfully than the Chrispin-Norman or Brasfield systems, and does not require a lateral film.
PMCID: PMC475170  PMID: 7940422
14.  Clinical and Radiologic Disease in Smokers With Normal Spirometry 
JAMA internal medicine  2015;175(9):1539-1549.
IMPORTANCE
Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free.
OBJECTIVE
To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0.
DESIGN, SETTING, AND PARTICIPANTS
Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 ≥80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011.
MAIN OUTCOMES AND MEASURES
Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life.
RESULTS
One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George’s Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P < .001) and a lower 6-minute walk distance, and 42.3% (127 of 300) of the GOLD 0 group had CT evidence of emphysema or airway thickening. The FEV1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease.
CONCLUSIONS AND RELEVANCE
Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone.
doi:10.1001/jamainternmed.2015.2735
PMCID: PMC4564354  PMID: 26098755
15.  Lung disease assessment in primary ciliary dyskinesia: a comparison between chest high-field magnetic resonance imaging and high-resolution computed tomography findings 
Background
Primary ciliary dyskinesia (PCD) is associated with pulmonary involvement that requires periodical assessment. Chest high-resolution computed tomography (HRCT) has become the method of choice to evaluate chronic lung disease, but entails exposure to ionizing radiation. Magnetic resonance imaging (MRI) has been proposed as a potential radiation-free technique in several chest disorders. Aim of our study is to evaluate whether high-field MRI is as effective as HRCT in identifying PCD pulmonary abnormalities. We also analyzed the relationships between the severity and extension of lung disease, and functional data.
Methods
Thirteen PCD patients (8 children/5 adults; median age, 15.2 yrs) underwent chest HRCT and high-field 3T MRI, spirometry, and deep throat or sputum culture. Images were scored using a modified version of the Helbich system.
Results
HRCT and MRI total scores were 12 (range, 6–20) and 12 (range, 5–17), respectively. Agreement between HRCT and MRI scores was good or excellent (r > 0.8). HRCT and MRI total scores were significantly related to forced vital capacity (r = -0.5, p = 0.05; and r = -0.7, p = 0.009, respectively) and forced expiratory volume at 1 second (r = -0.6, p = 0.03; and r = -0.7, p = 0.009, respectively).
Conclusion
Chest high-field 3T MRI appears to be as effective as HRCT in assessing the extent and severity of lung abnormalities in PCD. MRI scores might be used for longitudinal assessment and be an outcome surrogate in future studies.
doi:10.1186/1824-7288-35-24
PMCID: PMC2737542  PMID: 19660117
16.  A new high resolution computed tomography scoring system for pulmonary fibrosis, pleural disease, and emphysema in patients with asbestos related disease. 
The aim of this study was to describe a scoring system for high resolution computed tomographic (HRCT) scans analogous to the International Labour Office (ILO) scoring system for plain chest radiographs in patients with asbestos related disease. Interstitial fibrosis, pleural disease, and emphysema were scored, the reproducibility and the interobserver agreement using this scoring system were examined, and the extent of the various types of disease was correlated with measurements of lung function. Sixty asbestos workers (five women and 55 men) mean age 59 (range 34-78) were studied. The lungs were divided into upper, middle, and lower thirds. An HRCT score for the extent of pleural disease and pulmonary disease in each third was recorded in a way analogous to the International Labour Office (ILO) method of scoring pleural and parenchymal disease on chest radiographs. A CT score for the extent of emphysema was also recorded. Pleural disease and interstitial fibrosis on the plain chest radiographs were assessed according to the ILO scoring system. A chest radiographic score for emphysema analogous to that used for HRCT was also recorded. Two independent readers assigned HRCT scores that differed by two categories or less in 96%, 92%, and 85% compared with 90%, 78%, and 79% of cases for chest radiographs for fibrosis, emphysema, and pleural disease respectively. There was better intraobserver repeatability for the HRCT scores than for the chest radiograph scores for all disorders. Multiple regression analysis showed that scores for interstitial fibrosis, emphysema, and pleural disease on chest radiographs and HRCT correlated to a similar degree with impairment of lung function.
Images
PMCID: PMC1012071  PMID: 1536823
17.  Computed tomography in the early detection of asbestosis. 
Computed tomography (CT; both conventional (CCT) and high resolution (HRCT)) scans of the thorax were evaluated to detect early asbestosis in 61 subjects exposed to asbestos dust in Québec for an average of 22(3) years and in five controls. The study was limited to consecutive cases with chest radiographs of the International Labour Organisation categories 0 or 1 determined independently. All subjects had a standard high kilovoltage posteroanterior and lateral chest radiograph, a set of 10-15 1 cm collimation CCT scans and a set of three to five 2 mm collimation HRCT scans in the upper, middle, and lower lung fields. Five experienced readers independently read each chest radiograph and sets of CT scans. On the basis of three to five readers agreeing for small opacities of the lung parenchyma, 12/46 (26%) negative chest radiographs were positive on CT scans, but 6/18 (33%) positive chest radiographs were negative on CT scan. On the basis of four to five readers agreeing on a chest radiograph, 36/66 (54%) subjects were normal (group A), 17/66 (26%) were indeterminate (group B), and 13/66 (20%) were abnormal (group C). By the combined readings of CCT and HRCT, 4/31 (13%) asbestos exposed subjects of group A were abnormal (p < 0.001), 6/17 (35%) of group B were abnormal, and in group C, 1/13 (8%) was normal, 2/13 were indeterminate, and 10/13 (77%) were abnormal. Separate readings of CCT and HRCT on distinct films in 14 subjects showed that all cases of asbestosis were abnormal on both CCT and HRCT. Inter-reader analyses by kappa statistics showed significantly better agreement for the readings of CT than the chest radiographs (p < 0.001), and for the reading of CCT than HRCT (p < 0.01). Thus CT scans of the thorax identifies significantly more irregular opacities consistent with the diagnosis of asbestosis than the chest radiograph (20 cases on CT scans v 13 on chest radiographs when four to five readers agreed, 13% of asbestos exposed subjects with normal chest radiographs or 21% of asbestos exposed subjects with normal or near normal chest radiographs. It decreased the number of indeterminate cases significantly from 17 on chest radiographs to 13 on CT scans. All cases of asbestosis detected only on CT scans were similarly seen on CCT and HRCT and did not have significant changes in lung function. The CT scans significantly reduced the inter-reader variability, despite the absence of ILO type reference films for these scans.
Images
PMCID: PMC1012171  PMID: 8398855
18.  Radiography, tomosynthesis, CT and MRI in the evaluation of pulmonary cystic fibrosis: an untangling review of the multitude of scoring systems 
Insights into Imaging  2013;4(6):787-798.
Objective
The first radiographic scoring system for pulmonary cystic fibrosis was presented in 1958. Since then a multitude of scoring systems for radiography and computed tomography (CT) have been presented, recently also for tomosynthesis and magnetic resonance imaging (MRI). The aim of the current review was to analyse and compare the plethora of scoring systems for cystic fibrosis, especially regarding which scoring components are considered most important.
Methods
Four scoring systems for chest radiography, one for tomosynthesis, eight for CT and one for MRI were compared regarding components evaluated and their terminology; the areas scored; scoring levels; the weighting of each component in percentage of the total score; and the calculations for the final score.
Results
In most radiological scoring systems the lungs are evaluated for increased volume, bronchial wall thickening, bronchiectasis, mucus plugging, atelectasis and consolidation. In addition, for instance abscesses, bullae, septal thickening, mosaic perfusion, ground glass opacities and air trapping are evaluated in some CT scoring systems. Pleural affection and perfusion defects are scored on MRI.
Conclusions
Bronchiectasis alone, or in combination with mucus plugging, is given the highest weighting in most scoring systems and is thus commonly considered to be the most significant finding when evaluating cystic fibrosis lung disease.
Teaching points
• Scoring of examinations is used for comparison of outcome in studies.
• Scoring of examinations can also be used for monitoring disease progression.
• Cystic fibrosis can be scored on radiography, tomosynthesis, CT or MRI.
• The typical imaging findings of cystic fibrosis depend on the imaging modality used.
• Bronchiectasis is commonly considered the most significant finding when scoring cystic fibrosis.
doi:10.1007/s13244-013-0288-y
PMCID: PMC3846934  PMID: 24065629
Cystic fibrosis; Magnetic resonance imaging; Radiography; Tomography, X-ray; Tomography, X-ray computed
19.  Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach. 
Journal of Clinical Investigation  1993;91(6):2685-2692.
To assess further the clinical significance of asbestos-induced pleural fibrosis, we used a computer algorithm to reconstruct images three dimensionally from the high-resolution computerized tomography (HRCT) scan of the chest in 60 asbestos-exposed subjects. Pulmonary function tests, chest radiographs, and HRCT scans were performed on all study subjects. The volume of asbestos-induced pleural fibrosis was computed from the three-dimensional reconstruction of the HRCT scan. Among those with pleural fibrosis identified on the HRCT scan (n = 29), the volume of the pleural lesion varied from 0.01% (0.5 ml) and 7.11% (260.4 ml) of the total chest cavity. To investigate the relationship between asbestos-induced pleural fibrosis and restrictive lung function, we compared the computer-derived estimate of pleural fibrosis to the total lung capacity and found that these measures were inversely related (r = -0.40; P = 0.002). After controlling for age, height, pack-years of cigarette smoking, and the presence of interstitial fibrosis on the chest radiograph, the volume of pleural fibrosis identified on the three-dimensional reconstructed image from the HRCT scan was inversely associated with the total lung capacity (P = 0.03) and independently accounted for 9.5% of the variance of this measure of lung volume. These findings further extend the scientific data supporting an independent association between pleural fibrosis and restrictive lung function.
Images
PMCID: PMC443332  PMID: 8514875
20.  Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening 
PLoS ONE  2011;6(8):e23932.
Background
In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution. The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF.
Methods
Data of infants and young children with CF diagnosed following newborn screening consecutively reviewed between August 2005 and December 2009 were analysed. Ventilation distribution (lung clearance index and the first and second moment ratios [LCI, M1/M0 and M2/M0, respectively]), chest CT and airway pathology from bronchoalveolar lavage were determined at diagnosis and then annually. The chest CT scans were evaluated for the presence or absence of bronchiectasis and air trapping.
Results
Matched lung function, chest CT and pathology outcomes were available in 49 infants (31 male) with bronchiectasis and air trapping present in 13 (27%) and 24 (49%) infants, respectively. The presence of bronchiectasis or air trapping was associated with increased M2/M0 but not LCI or M1/M0. There was a weak, but statistically significant association between the extent of air trapping and all ventilation distribution outcomes.
Conclusion
These findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of LCI could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research in which both MBW and chest CT outcomes are obtained is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.
doi:10.1371/journal.pone.0023932
PMCID: PMC3158781  PMID: 21886842
21.  Association between Occupational Exposure and Lung Function, Respiratory Symptoms, and High-Resolution Computed Tomography Imaging in COPDGene 
Rationale: Although occupational exposure to dust and fumes is considered a risk factor for chronic obstructive pulmonary disease, this determination has been limited by reliance on spirometry alone to assess disease severity in predominantly male populations.
Objectives: To determine the effect of occupational exposure on lung function, respiratory symptoms, and findings of emphysema and airway wall thickness measured using quantitative computed tomography in men and women.
Methods: COPDGene is a multicenter study of current and former smokers that underwent standardized volumetric chest computed tomography scans to assess airways, % emphysema, and % gas trapping. Spirometry and a respiratory questionnaire including occupational history were also analyzed in 9,614 subjects (4,496 women). Logistic regression and analysis of covariance was used to assess associations with exposure.
Measurements and Main Results: Occupational exposure to both dust and fumes was reported by 47.9% of men and 20.1% of women. Adjusting for age, race, body mass index, education, and current and lifetime smoking, the odds ratios for persons with dust and fume exposures for chronic cough, chronic phlegm, persistent wheeze, and Global Initiative for Chronic Obstructive Lung Disease stages 2 and higher chronic obstructive pulmonary disease were significantly elevated and similar for men (1.83, 1.84, 2.0, 1.61, respectively) and women (1.65, 1.82, 1.98, 1.90, respectively). The % predicted FEV1 was similarly lower in those with exposure in men (70.7 ± 0.8 vs. 76.0 ± 0.9; P < 0.001) and women (70.5 ± 0.8 vs. 77.2 ± 0.8; P < 0.001). Percent emphysema and gas trapping was greater in those exposed to dust and fumes in men and women. In men, but not in women, persons with exposure had a greater mean square root wall area of 10-mm internal perimeter airways.
Conclusions: Occupational exposure to dust and fumes in men and women is similarly associated with airflow obstruction, respiratory symptoms, more emphysema, and gas trapping in men and women.
doi:10.1164/rccm.201403-0493OC
PMCID: PMC4299608  PMID: 25133327
COPD; occupational exposure; emphysema
22.  Lung Clearance Index and High-Resolution Computed Tomography Scores in Primary Ciliary Dyskinesia 
Rationale: Lung clearance index (LCI) is a more sensitive measure of lung function than spirometry in cystic fibrosis (CF) and correlates well with abnormalities in high-resolution computed tomography (HRCT) scanning. We hypothesized LCI would be equally sensitive to lung disease in primary ciliary dyskinesia (PCD).
Objectives: To test the relationships between LCI, spirometry, and HRCT in PCD and to compare them to the established relationships in CF.
Methods: Cross-sectional study of 127 patients with CF and 33 patients with PCD, all of whom had spirometry and LCI, of which a subset of 21 of each had HRCT performed. HRCT was scored for individual features and these features compared with physiological parameters.
Measurements and Main Results: Unlike in CF, and contrary to our hypothesis, there was no correlation between spirometry and LCI in PCD and no correlation between HRCT features and LCI or spirometry in PCD.
Conclusions: We show for the first time that HRCT, spirometry, and LCI have different relationships in different airway diseases and that LCI does not appear to be a sensitive test of airway disease in advanced PCD. We hypothesize that this results from dissimilarities between the components of large and small airway disease in CF and PCD. These differences may in part lead to the different prognosis in these two neutrophilic airway diseases.
doi:10.1164/rccm.201304-0800OC
PMCID: PMC3827705  PMID: 23815669
spirometry; high-resolution computed tomography; lung clearance index
23.  Neuroimaging for the Evaluation of Chronic Headaches 
Executive Summary
Objective
The objectives of this evidence based review are:
i) To determine the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) scans in the evaluation of persons with a chronic headache and a normal neurological examination.
ii) To determine the comparative effectiveness of CT and MRI scans for detecting significant intracranial abnormalities in persons with chronic headache and a normal neurological exam.
iii) To determine the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Clinical Need: Condition and Target Population
Headaches disorders are generally classified as either primary or secondary with further sub-classifications into specific headache types. Primary headaches are those not caused by a disease or medical condition and include i) tension-type headache, ii) migraine, iii) cluster headache and, iv) other primary headaches, such as hemicrania continua and new daily persistent headache. Secondary headaches include those headaches caused by an underlying medical condition. While primary headaches disorders are far more frequent than secondary headache disorders, there is an urge to carry out neuroimaging studies (CT and/or MRI scans) out of fear of missing uncommon secondary causes and often to relieve patient anxiety.
Tension type headaches are the most common primary headache disorder and migraines are the most common severe primary headache disorder. Cluster headaches are a type of trigeminal autonomic cephalalgia and are less common than migraines and tension type headaches. Chronic headaches are defined as headaches present for at least 3 months and lasting greater than or equal to 15 days per month. The International Classification of Headache Disorders states that for most secondary headaches the characteristics of the headache are poorly described in the literature and for those headache disorders where it is well described there are few diagnostically important features.
The global prevalence of headache in general in the adult population is estimated at 46%, for tension-type headache it is 42% and 11% for migraine headache. The estimated prevalence of cluster headaches is 0.1% or 1 in 1000 persons. The prevalence of chronic daily headache is estimated at 3%.
Neuroimaging
Computed Tomography
Computed tomography (CT) is a medical imaging technique used to aid diagnosis and to guide interventional and therapeutic procedures. It allows rapid acquisition of high-resolution three-dimensional images, providing radiologists and other physicians with cross-sectional views of a person’s anatomy. CT scanning poses risk of radiation exposure. The radiation exposure from a conventional CT scanner may emit effective doses of 2-4mSv for a typical head CT.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used to aid diagnosis but unlike CT it does not use ionizing radiation. Instead, it uses a strong magnetic field to image a person’s anatomy. Compared to CT, MRI can provide increased contrast between the soft tissues of the body. Because of the persistent magnetic field, extra care is required in the magnetic resonance environment to ensure that injury or harm does not come to any personnel while in the environment.
Research Questions
What is the effectiveness of CT and MRI scanning in the evaluation of persons with a chronic headache and a normal neurological examination?
What is the comparative effectiveness of CT and MRI scanning for detecting significant intracranial abnormality in persons with chronic headache and a normal neurological exam?
What is the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Research Methods
Literature Search
Search Strategy
A literature search was performed on February 18, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January, 2005 to February, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Systematic reviews, randomized controlled trials, observational studies
Outpatient adult population with chronic headache and normal neurological exam
Studies reporting likelihood ratio of clinical variables for a significant intracranial abnormality
English language studies
2005-present
Exclusion Criteria
Studies which report outcomes for persons with seizures, focal symptoms, recent/new onset headache, change in presentation, thunderclap headache, and headache due to trauma
Persons with abnormal neurological examination
Case reports
Outcomes of Interest
Primary Outcome
Probability for intracranial abnormality
Secondary Outcome
Patient relief from anxiety
System service use
System costs
Detection rates for significant abnormalities in MRI and CT scans
Summary of Findings
Effectiveness
One systematic review, 1 small RCT, and 1 observational study met the inclusion and exclusion criteria. The systematic review completed by Detsky, et al. reported the likelihood ratios of specific clinical variables to predict significant intracranial abnormalities. The RCT completed by Howard et al., evaluated whether neuroimaging persons with chronic headache increased or reduced patient anxiety. The prospective observational study by Sempere et al., provided evidence for the pre-test probability of intracranial abnormalities in persons with chronic headache as well as minimal data on the comparative effectiveness of CT and MRI to detect intracranial abnormalities.
Outcome 1: Pre-test Probability.
The pre-test probability is usually related to the prevalence of the disease and can be adjusted depending on the characteristics of the population. The study by Sempere et al. determined the pre-test probability (prevalence) of significant intracranial abnormalities in persons with chronic headaches defined as headache experienced for at least a 4 week duration with a normal neurological exam. There is a pre-test probability of 0.9% (95% CI 0.5, 1.4) in persons with chronic headache and normal neurological exam. The highest pre-test probability of 5 found in persons with cluster headaches. The second highest, that of 3.7, was reported in persons with indeterminate type headache. There was a 0.75% rate of incidental findings.
Likelihood ratios for detecting a significant abnormality
Clinical findings from the history and physical may be used as screening test to predict abnormalities on neuroimaging. The extent to which the clinical variable may be a good predictive variable can be captured by reporting its likelihood ratio. The likelihood ratio provides an estimate of how much a test result will change the odds of having a disease or condition. The positive likelihood ratio (LR+) tells you how much the odds of having the disease increases when a test is positive. The negative likelihood ratio (LR-) tells you how much the odds of having the disease decreases when the test is negative.
Detsky et al., determined the likelihood ratio for specific clinical variable from 11 studies. There were 4 clinical variables with both statistically significant positive and negative likelihood ratios. These included: abnormal neurological exam (LR+ 5.3, LR- 0.72), undefined headache (LR+ 3.8, LR- 0.66), headache aggravated by exertion or valsalva (LR+ 2.3, LR- 0.70), and headache with vomiting (LR+ 1.8, and LR- 0.47). There were two clinical variables with a statistically significant positive likelihood ratio and non significant negative likelihood ratio. These included: cluster-type headache (LR+ 11, LR- 0.95), and headache with aura (LR+ 12.9, LR- 0.52). Finally, there were 8 clinical variables with both statistically non significant positive and negative likelihood ratios. These included: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, and migraine type headache.
Outcome 2: Relief from Anxiety
Howard et al. completed an RCT of 150 persons to determine if neuroimaging for headaches was anxiolytic or anxiogenic. Persons were randomized to receiving either an MRI scan or no scan for investigation of their headache. The study population was stratified into those persons with a Hospital Anxiety and Depression scale (HADS) > 11 (the high anxiety and depression group) and those < 11 (the low anxiety and depression) so that there were 4 groups:
Group 1: High anxiety and depression, no scan group
Group 2: High anxiety and depression, scan group
Group 3: Low anxiety and depression, no scan group
Group 4: Low anxiety and depression, scan group
Anxiety
There was no evidence for any overall reduction in anxiety at 1 year as measured by a visual analogue scale of ‘level of worry’ when analysed by whether the person received a scan or not. Similarly, there was no interaction between anxiety and depression status and whether a scan was offered or not on patient anxiety. Anxiety did not decrease at 1 year to any statistically significant degree in the high anxiety and depression group (HADS positive) compared with the low anxiety and depression group (HADS negative).
There are serious methodological limitations in this study design which may have contributed to these negative results. First, when considering the comparison of ‘scan’ vs. ‘no scan’ groups, 12 people (16%) in the ‘no scan group’ actually received a scan within the follow up year. If indeed scanning does reduce anxiety then this contamination of the ‘no scan’ group may have reduced the effect between the groups results resulting in a non significant difference in anxiety scores between the ‘scanned’ and the ‘no scan’ group. Second, there was an inadequate sample size at 1 year follow up in each of the 4 groups which may have contributed to a Type II statistical error (missing a difference when one may exist) when comparing scan vs. no scan by anxiety and depression status. Therefore, based on the results and study limitations it is inconclusive as to whether scanning reduces anxiety.
Outcome 3: System Services
Howard et al., considered services used and system costs a secondary outcome. These were determined by examining primary care case notes at 1 year for consultation rates, symptoms, further investigations, and contact with secondary and tertiary care.
System Services
The authors report that the use of neurologist and psychiatrist services was significantly higher for those persons not offered as scan, regardless of their anxiety and depression status (P<0.001 for neurologist, and P=0.033 for psychiatrist)
Outcome 4: System Costs
System Costs
There was evidence of statistically significantly lower system costs if persons with high levels of anxiety and depression (Hospital Anxiety and Depression Scale score >11) were provided with a scan (P=0.03 including inpatient costs, and 0.047 excluding inpatient costs).
Comparative Effectiveness of CT and MRI Scans
One study reported the detection rate for significant intracranial abnormalities using CT and MRI. In a cohort of 1876 persons with a non acute headache defined as any type of headache that had begun at least 4 weeks before enrolment Sempere et al. reported that the detection rate was 19/1432 (1.3%) using CT and 4/444 (0.9%) using MRI. Of 119 normal CT scans 2 (1.7%) had significant intracranial abnormality on MRI. The 2 cases were a small meningioma, and an acoustic neurinoma.
Summary
The evidence presented can be summarized as follows:
Pre-test Probability
Based on the results by Sempere et al., there is a low pre-test probability for intracranial abnormalities in persons with chronic headaches and a normal neurological exam (defined as headaches experiences for a minimum of 4 weeks). The Grade quality of evidence supporting this outcome is very low.
Likelihood Ratios
Based on the systematic review by Detsky et al., there is a statistically significant positive and negative likelihood ratio for the following clinical variables: abnormal neurological exam, undefined headache, headache aggravated by exertion or valsalva, headache with vomiting. Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al. there is a statistically significant positive likelihood ratio but non statistically significant negative likelihood ratio for the following clinical variables: cluster headache and headache with aura. The Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al., there is a non significant positive and negative likelihood ratio for the following clinical variables: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, migraine type headache. The Grade quality of evidence supporting this outcome is very low.
Relief from Anxiety
Based on the RCT by Howard et al., it is inconclusive whether neuroimaging scans in persons with a chronic headache are anxiolytic. The Grade quality of evidence supporting this outcome is low.
System Services
Based on the RCT by Howard et al. scanning persons with chronic headache regardless of their anxiety and/or depression level reduces service use. The Grade quality of evidence is low.
System Costs
Based on the RCT by Howard et al., scanning persons with a score greater than 11 on the High Anxiety and Depression Scale reduces system costs. The Grade quality of evidence is moderate.
Comparative Effectiveness of CT and MRI Scans
There is sparse evidence to determine the relative effectiveness of CT compared with MRI scanning for the detection of intracranial abnormalities. The Grade quality of evidence supporting this is very low.
Economic Analysis
Ontario Perspective
Volumes for neuroimaging of the head i.e. CT and MRI scans, from the Ontario Health Insurance Plan (OHIP) data set were used to investigate trends in the province for Fiscal Years (FY) 2004-2009.
Assumptions were made in order to investigate neuroimaging of the head for the indication of headache. From the literature, 27% of all CT and 13% of all MRI scans for the head were assumed to include an indication of headache. From that same retrospective chart review and personal communication with the author 16% of CT scans and 4% of MRI scans for the head were for the sole indication of headache. From the Ministry of Health and Long-Term Care (MOHLTC) wait times data, 73% of all CT and 93% of all MRI scans in the province, irrespective of indication were outpatient procedures.
The expenditure for each FY reflects the volume for that year and since volumes have increased in the past 6 FYs, the expenditure has also increased with a pay-out reaching 3.0M and 2.8M for CT and MRI services of the head respectively for the indication of headache and a pay-out reaching 1.8M and 0.9M for CT and MRI services of the head respectively for the indication of headache only in FY 08/09.
Cost per Abnormal Finding
The yield of abnormal finding for a CT and MRI scan of the head for the indication of headache only is 2% and 5% respectively. Based on these yield a high-level estimate of the cost per abnormal finding with neuroimaging of the head for headache only can be calculated for each FY. In FY 08/09 there were 37,434 CT and 16,197 MRI scans of the head for headache only. These volumes would generate a yield of abnormal finding of 749 and 910 with a CT scan and MRI scan respectively. The expenditure for FY 08/09 was 1.8M and 0.9M for CT and MRI services respectively. Therefore the cost per abnormal finding would be $2,409 for CT and $957 for MRI. These cost per abnormal finding estimates were limited because they did not factor in comparators or the consequences associated with an abnormal reading or FNs. The estimates only consider the cost of the neuroimaging procedure and the yield of abnormal finding with the respective procedure.
PMCID: PMC3377587  PMID: 23074404
24.  Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts 
PLoS Medicine  2014;11(12):e1001764.
Martin Tammemägi and colleagues evaluate which risk groups of individuals, including nonsmokers and high-risk individuals from 65 to 80 years of age, should be screened for lung cancer using computed tomography.
Please see later in the article for the Editors' Summary
Background
Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55–64 and ≥65–80 y.
Methods and Findings
Applying the PLCOm2012 model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, n = 53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCOm2012 risk criteria in intervention arm (CXR) smokers (n = 37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCOall2014) evaluated risks in never-smokers. At PLCOm2012 risk ≥0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to −754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCOm2012 risk ≥0.0151 threshold selected 8.8% fewer individuals for screening (p<0.001) but identified 12.4% more lung cancers (sensitivity 80.1% [95% CI 76.8%–83.0%] versus 71.2% [95% CI 67.6%–74.6%], p<0.001), had fewer false-positives (specificity 66.2% [95% CI 65.7%–66.7%] versus 62.7% [95% CI 62.2%–63.1%], p<0.001), and had higher PPV (4.2% [95% CI 3.9%–4.6%] versus 3.4% [95% CI 3.1%–3.7%], p<0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCOm2012 risk ≥0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCOm2012 risk ≥0.0151. None of 65,711 PLCO never-smokers had PLCOm2012 risk ≥0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged ≥65–80 y than in those aged 55–64 y. This study omitted cost-effectiveness analysis.
Conclusions
The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCOm2012 risk ≥0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged ≥65–80 y are a high-risk group who may benefit from screening.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the most commonly occurring cancer in the world and the most common cause of cancer-related deaths. Like all cancers, lung cancer occurs when cells acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The most common trigger for these genetic changes in lung cancer is exposure to cigarette smoke. Symptoms of lung cancer include a persistent cough and breathlessness. If lung cancer is diagnosed when it is confined to the lung (stage I), the tumor can often be removed surgically. Stage II tumors, which have spread into nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced lung cancers that have spread throughout the chest (stage III) or the body (stage IV), surgery is rarely helpful and these tumors are treated with chemotherapy and radiotherapy alone. Overall, because most lung cancers are not detected until they are advanced, less than 17% of people diagnosed with lung cancer survive for five years.
Why Was This Study Done?
Screening for lung cancer—looking for early disease in healthy people—could save lives. In the US National Lung Screening Trial (NLST), annual screening with computed tomography (CT) reduced lung cancer mortality by 20% among smokers at high risk of developing cancer compared with screening with a chest X-ray. But what criteria should be used to decide who is screened for lung cancer? The US Preventive Services Task Force (USPSTF), for example, recommends annual CT screening of people who are 55–80 years old, have smoked 30 or more pack-years (one pack-year is defined as a pack of cigarettes per day for one year), and—if they are former smokers—quit smoking less than 15 years ago. However, some experts think lung cancer risk prediction models—statistical models that estimate risk based on numerous personal characteristics—should be used to select people for screening. Here, the researchers evaluate PLCOm2012, a lung cancer risk prediction model based on the incidence of lung cancer among smokers enrolled in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Specifically, the researchers use NLST and PLCO screening trial data to identify a PLCOm2012 risk threshold for selecting people for screening and to compare the efficiency of the PLCOm2012 model and the USPSTF criteria for identifying “screenees.”
What Did the Researchers Do and Find?
By analyzing NLST data, the researchers calculated that at PLCOm2012 risk ≥0.0151, mortality (death) rates among NLST participants screened with CT were consistently below mortality rates among NLST participants screened with chest X-ray and that 255 people with a PLCOm2012 risk ≥0.0151 would need to be screened to prevent one lung cancer death. Next, they used data collected from smokers in the screened arm of the PLCO trial to compare the efficiency of the PLCOm2012 and USPSTF criteria for identifying screenees. They found that 8.8% fewer people had a PLCOm2012 risk ≥0.0151 than met USPSTF criteria for screening, but 12.4% more lung cancers were identified. Thus, using PLCOm2012 improved the sensitivity and specificity of the selection of individuals for lung cancer screening over using UPSTF criteria. Notably, 8.5% of PLCO former smokers with quit times of more than 15 years had PLCOm2012 risk ≥0.0151, none of the PLCO never-smokers had PLCOm2012 risk ≥0.0151, and the calculated risks and incidence of lung cancer were greater among PLCO smokers aged ≥65–80 years than among those aged 55–64 years.
What Do These Findings Mean?
Despite the absence of a cost-effectiveness analysis in this study, these findings suggest that the use of the PLCOm2012 risk ≥0.0151 threshold rather than USPSTF criteria for selecting individuals for lung cancer screening could improve screening efficiency. The findings have several other important implications. First, these findings suggest that screening may be justified in people who stopped smoking more than 15 years ago; USPSTF currently recommends that screening stop once an individual's quit time exceeds 15 years. Second, these findings do not support lung cancer screening among never-smokers. Finally, these findings suggest that smokers aged ≥65–80 years might benefit from screening, although the presence of additional illnesses and reduced life expectancy need to be considered before recommending the provision of routine lung cancer screening to this section of the population.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001764.
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health-care professionals, including information on lung cancer screening (in English and Spanish)
Cancer Research UK also provides detailed information about lung cancer and about lung cancer screening
The UK National Health Service Choices website has a page on lung cancer that includes personal stories
MedlinePlus provides links to other sources of information about lung cancer (in English and Spanish)
Information about the USPSTF recommendations for lung cancer screening is available
doi:10.1371/journal.pmed.1001764
PMCID: PMC4251899  PMID: 25460915
25.  Rib plating of acute and sub-acute non-union rib fractures in an adult with cystic fibrosis: a case report 
BMC Research Notes  2014;7:681.
Background
Rib fractures associated with osteoporosis have been reported to occur ten times more frequently in adults with cystic fibrosis. Fractures cause chest pain, and interfere with cough and sputum clearance leading to worsened lung function and acute exacerbations which are the two main contributors to early mortality in cystic fibrosis. Usual treatment involves analgesics and time for healing; however considerable pain and disability result due to constant re-injury from chronic repetitive cough. Recently, surgical plating of rib fractures has become commonplace in treating acute, traumatic chest injuries. We describe here successful surgical plating in a White cystic fibrosis patient with multiple, non-traumatic rib fractures.
Case presentation
A-37-year old White male with cystic fibrosis was readmitted to Intermountain Medical Center for a pulmonary exacerbation. He had developed localized rib pain while coughing 2 months earlier, with worsening just prior to hospital admission in conjunction with a “pop” in the same location while bending over. A chest computerized tomography scan at admission demonstrated an acute 5th rib fracture and chronic non-united 6th and 7th right rib fractures. An epidural catheter was placed both for analgesia and to make secretion clearance possible in preparation for the surgery performed 2 days later. Under general anesthesia, he had open reduction and internal fixation of the right 5th, 6th and 7th rib fractures with a Synthes Matrix rib set. After several days of increased oxygen requirements, fever, fluid retention, and borderline vital signs, he stabilized. Numerical pain rating scores from his ribs were lower post-operatively and he was able to tolerate chest physical therapy and vigorous coughing.
Conclusions
In our case report, rib plating with bone grafting improved rib pain and allowed healing of the fractures and recovery, although the immediate post-op period required close attention and care. We believe repair may be of benefit in selected cystic fibrosis patients, such as our patient who had suffered multiple rib fractures that were healing poorly.
doi:10.1186/1756-0500-7-681
PMCID: PMC4197343  PMID: 25270323
Cystic fibrosis; Rib fracture; Rib plating; Bronchiectasis; Pain control

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