Warren B. Gefter

Small-Airway Obstruction and Emphysema in Chronic Obstructive Pulmonary Disease

BACKGROUND The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. METHODS We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. RESULTS On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001). CONCLUSIONS These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).

T2* and proton density measurement of normal human lung parenchyma using submillisecond echo time gradient echo magnetic resonance imaging.

OBJECTIVE To obtain T2* and proton density measurements of normal human lung parenchyma in vivo using submillisecond echo time (TE) gradient echo (GRE) magnetic resonance (MR) imaging. MATERIALS AND METHODS Six normal volunteers were scanned using a 1.5-T system equipped with a prototype enhanced gradient (GE Signa, Waukausha, WI). Images were obtained during breath-holding with acquisition times of 7-16 s. Multiple TEs ranging from 0.7 to 2.5 ms were tested. Linear regression was performed on the logarithmic plots of signal intensity versus TE, yielding measurements of T2* and proton density relative to chest wall muscle. Measurements in supine and prone position were compared, and effects of the level of lung inflation on lung signal were also evaluated. RESULTS The signal from the lung parenchyma diminished exponentially with prolongation of TE. The measured T2* in six normal volunteers ranged from 0.89 to 2.18 ms (1.43 +/- 0.41 ms, mean +/- S.D.). The measured relative proton density values ranged between 0.21 and 0.45 (0.29 +/- 0.08, mean +/- S.D.). Calculated T2* values of 1.46 +/- 0.50, 1.01 +/- 0.29 and 1.52 +/- 0.18 ms, and calculated relative proton densities of 0.20 +/- 0.03, 0.32 +/- 0.13 and 0.35 +/- 0.10 were obtained from the anterior, middle and posterior portions of the supine right lung, respectively. The anterior-posterior proton density gradient was reversed in the prone position. There was a pronounced increase in signal from lung parenchyma at maximum expiration compared with maximum inspiration. The ultrashort TE GRE technique yielded images demonstrating signal from lung parenchyma with minimal motion-induced noise. CONCLUSION Quantitative in vivo measurements of lung T2* and relative proton density in conjunction with high-signal parenchymal images can be obtained using a set of very rapid breath-hold images with a recently developed ultrashort TE GRE sequence.

The spectrum of pulmonary aspergillosis

Aspergillus species can produce a wide range of pulmonary disorders. Classically, pulmonary aspergillosis has been categorized into invasive, saprophytic, and allergic forms, all of which differ in their manifestations and therapy. More recently, however, other types of infection by this fungus have been recognized that do not fit into these traditional categories; an example is semi-invasive (chronic necrotizing) aspergillosis. In fact, these forms have features that are intermediate between those of the invasive and saprophytic types. The various types of aspergillosis can be regarded as constituting a continuous spectrum, ranging from invasive disease in the severely immunosuppressed patient to hypersensitivity reactions such as allergic bronchopulmonary aspergillosis (and bronchocentric granulomatosis) in the hyperreactive patient. Between these extremes are chronic necrotizing disease seen in midly immunocompromised hosts, and the noninvasive aspergilloma, which is due to saprophytic growth within a previously diseased area of lung in an otherwise normal host. Other intermediate forms may be encountered, their behavior being determined by the host immune status in combination with the underlying lung morphology. The radiographic and clinical features of these various forms of pulmonary aspergillosis are reviewed, including the more recently reported forms of infection such as Aspergillus tracheobronchitis and aspergillosis associated with acquired immunodeficiency syndrome and cystic fibrosis. The proposed concept of a disease spectrum is emphasized.

A combined pulmonary -radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation

Abstract The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

Fast magnetic resonance imaging of the lung.

The impact of fast MR techniques developed for MR imaging of the lung will soon be recognized as equivalent to the high-resolution technique in chest CT imaging. In this article, the difficulties in MR imaging posed by lung morphology and its physiological motion are briefly introduced. Then, fast MR imaging techniques to overcome the problems of lung imaging and recent applications of the fast MR techniques including pulmonary perfusion and ventilation imaging are discussed. Fast MR imaging opens a new exciting window to multi-functional MR imaging of the lung. We believe that fast MR functional imaging will play an important role in the assessment of pulmonary function and disease process.

Val64Ile Polymorphism in the C-C Chemokine Receptor 2 Is Associated With Reduced Coronary Artery Calcification

Objective—Studies in mice have shown that genetic disruption of monocyte chemotactic protein-1 or its receptor, the C-C chemokine receptor 2 (CCR2), inhibits atherosclerosis, but few data exist in humans to suggest that the monocyte chemotactic protein-1—CCR2 interaction is important in atherogenesis. A common polymorphism in the human CCR2 gene resulting in a substitution of isoleucine for valine (Val64Ile) has been associated with other disease phenotypes in humans. Methods and Results—A cohort of first-degree relatives of persons with premature coronary artery disease was recruited and quantitatively phenotyped for the extent of CAC, a marker of coronary atherosclerosis, by using electron beam CT. The extent of CAC was significantly lower in subjects with the CCR2-Ile64 variant (Val/Ile and Ile/Ile genotypes) than in subjects carrying 2 Val64 alleles, even after adjustment for traditional risk factors. Conclusions—This study provides genetic evidence linking CCR2 with coronary atherosclerosis in humans.

Alignment of CT lung volumes with an optical flow method

RATIONALE AND OBJECTIVES This study was performed to evaluate an optical flow method for registering serial computed tomographic (CT) images of lung volumes to assist physicians in visualizing and assessing changes between CT scans. MATERIALS AND METHODS The optical flow method is a coarse-to-fine model-based motion estimation technique for estimating first a global parametric transformation and then local deformations. Five serial pairs of CT images of lung volumes that were misaligned because of patient positioning, respiration, and/or different fields of view were used to test the method. RESULTS Lung volumes depicted on the serial paired images initially were correlated at only 28%-68% because of misalignment. With use of the optical flow method, the serial images were aligned to at least 95% correlation. CONCLUSION The optical flow method enables a direct comparison of serial CT images of lung volumes for the assessment of nodules or functional changes in the lung.

Association of traditional risk factors with coronary calcification in persons with a family history of premature coronary heart disease: the study of the inherited risk of coronary atherosclerosis.

Background Genetic factors strongly influence the risk of coronary heart disease (CHD), but their contribution to variation in coronary atherosclerosis beyond that measured by traditional CHD risk factors is uncertain. Methods We recruited healthy subjects with family histories of premature CHD. We assessed traditional risk factors and performed electron beam tomography (EBT) to quantitate coronary artery calcification (CAC), a marker of coronary atherosclerosis. Persons with significant risk factors that included diabetes, total cholesterol >300 mg/dL, active cigarette smoking, and poorly controlled hypertension were excluded from the study. In this paper, we report on the relationship between traditional risk factors and CAC in this cohort. Results The incidence of coronary calcification was significantly higher in this cohort than in the population-based Rochester Heart Study. In our cohort, most traditional risk factors were significantly associated with CAC on univariate analysis. On the other hand, in stepwise logistical regression, age and triglycerides were the only predictors of variation in CAC in men and accounted for only 30% of the variation; in women, age, body mass index (BMI), and triglycerides were the only traditional risk factors significantly associated with CAC variation and accounted for 22.2% of CAC variance. Conclusions In a cohort of subjects specifically selected for the characteristic of a family history of premature CHD, traditional risk factors accounted for less than one-third of the variation in CAC, and the most important predictors of CAC after age were plasma triglycerides. This supports the opinion that other inherited risk factors have important effects on the variation in coronary atherosclerosis and that the strategy of using EBT to phenotype clinically asymptomatic subjects with regard to coronary atherosclerosis may be a useful tool for identification of genes that are associated with CHD.

Coronary Artery Calcification at Electron Beam Computed Tomography is Increased in Asymptomatic Type 2 Diabetics Independent of Traditional Risk Factors

Background The risk of cardiovascular disease (CVD) is two- to fourfold greater in type 2 diabetics than in non-diabetics and cannot be accounted for by traditional risk factors alone. Coronary artery calcification (CAC) at electron beam computed tomography (EBCT) is a non-invasive index of coronary atherosclerosis. We hypothesized that the presence and extent of CAC would be greater in asymptomatic type 2 diabetics than in non-diabetics independent of traditional risk factors. Methods We reviewed CAC data of all asymptomatic subjects referred for EBCT between 1996–1999 and compared CAC scores in type 2 diabetics (n = 71) to all non-diabetics (n = 1481) and to a randomly selected group of non-diabetics matched for all traditional CVD risk factors (n = 71). Results CAC scores were greater in type 2 diabetics (272 ± 472, median 41) than in all non-diabetics (104 ± 288, median 4; P < 0.01) and matched non-diabetics (188 ± 354; P < 0.05, median 12; P < 0.05). The odds ratio (OR) for the presence of CAC (scores > 0) in type 2 diabetics was 2.9 [95% confidence intervals (CI) 1.1–7.8] after adjustment for traditional CVD risk factors. Type 2 diabetes was also associated (adjusted OR 2.15, 95%CI 1.3–3.6) with the extent of CAC when categorized as an ordinal outcome (CAC scores 0, 1–79, 80–399 and > 400). In type 2 diabetics, age, sex and body mass index were associated with extent of CAC. Conclusions CAC scores at EBCT are greater in type 2 diabetics than non-diabetic subjects, cannot be accounted for by traditional risk factors alone and may be useful for identifying novel factors for coronary atherosclerosis in type 2 diabetes.

Utility of High Resolution Computed Tomography in Predicting Bronchiolitis Obliterans Syndrome Following Lung Transplantation: Preliminary Findings

This study was undertaken to evaluate the efficacy of high resolution computed tomography (HRCT) in predicting the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. Fifty lung transplant patients who were clinically stable and without evidence of BOS were evaluated for the presence of four HRCT features reported to be associated with bronchiolitis obliterans: mosaic attenuation on inspiratory CT (mosaic perfusion), mosaic attenuation on expiratory CT (air trapping), bronchiectasis, and tree-in-bud opacities. CT exams were part of an annual surveillance process with the hope of predicting subsequent development of BOS. Diagnosis of BOS was made in 9 of 50 patients as indicated by a fall in FEV1 of greater than 20% of a stable baseline. None of the radiographic features associated with clinically established BOS were both sensitive and specific in the prediction of BOS. Air trapping demonstrated moderate sensitivity (56%, 5/9) and moderate specificity (76%, 35/46) for prediction of BOS in the year following the CT exam. Bronchiectasis, the most reliable indicator of the presence of BOS was a poor predictor of subsequent BOS with an 11% (1/9) sensitivity but had high specificity (96%, 44/46). No high resolution CT features accurately predicted the development of BOS.