Quantitation of emphysema by computed tomography using a "density mask" program and correlation with pulmonary function tests

We used a CT program "density mask" outlining areas with attenuation values less than -910 HU, to indicate areas of emphysema on a chest CT and to provide an overall percentage of lung involvement by emphysema. The "density mask" quantitation of emphysema was previously shown to correlate well with the pathologic assessment of emphysema in patients undergoing lung resection. We compared the CT quantitation of emphysema with mean lung density, overall lung volume on CT and pulmonary function tests in 85 patients. There was a significant correlation between the extent of emphysema on CT and FEV/FVC percent of predicted, functional residual capacity percent predicted and Dsb percent predicted. Determination of the percentage of lung with areas of low attenuation by CT provides a useful method for quantitating emphysema in life and correlates significantly with pulmonary function tests.     

Physiological associations of computerized tomography lung density: a factor analysis

Background

Objective quantification of emphysema using computerized tomography (CT) density measurements is rapidly gaining wide acceptance as an in vivo measurement tool. However, some studies have suggested that abnormal lung function in the absence of emphysema can affect lung density, and the role of such measurements in identifying and monitoring the progression of emphysema is not clear.

Objective

To clarify the relationship between lung density measurements and pulmonary function.

Methods

CT measurements of the proportion of lung occupied by low density tissue (as percentage of lung area below predetermined Hounsfield unit [HU] thresholds) were obtained in a large random population (n = 739) and the association with detailed pulmonary function tests studied using factor analysis.

Results

Density measurements showed a greater association with measures of hyperinflation and airflow obstruction than measures of gas transfer (correlation coefficient, high resolution scan, − 950 HU threshold vs FEV₁/FVC, RV, and DLCO/VA of − 0.39, 0.22, and − 0.15 respectively). The strongest lung density factor coefficients of 0.51 (standard resolution scan, − 950 HU threshold) and 0.46 (high resolution scan, − 910 HU threshold) were seen with factors predominantly consisting of measures of airflow obstruction and hyperinflation. Most variation in lung density was not accounted for by lung function measurements (communality 0.21–0.34).

Conclusion

Lung density measurements associate most strongly with measures of airway disease that are not specific to emphysema.     

The effects of radiation dose and CT manufacturer on measurements of lung densitometry

BACKGROUND: To evaluate the effect of radiation dose and scanner manufacturer on quantitative CT scan measurements of lung morphology in smokers. METHODS: Low-dose and high-dose, inspiratory, multislice CT scans were obtained in 50 subjects at intervals of approximately 6 months (mean [+/- SD] interval, 0.5 +/- 0.2 years). In another 30 subjects, multislice CT scans were acquired first using a GE LightSpeed Ultra (General Electric Healthcare; Milwaukee, WI), followed a mean time of 1.2 +/- 0.4 years later by using a Siemens Sensation 16 scanner (Siemens Medical Solutions; Erlangen, Germany). Custom software was used to measure lung volume, mass, mean density, and the extent of emphysema using threshold cutoffs of -950, -910, and -856 Hounsfield units (HU) and the lowest 15th and 5th percentile points. RESULTS: The change in radiograph dose significantly affected measurements of emphysema assessed using mean lung density, threshold, or percentile methods. There were also interactions between dose and total lung volume for all of the measurements except the -950-HU threshold and the lowest fifth percentile point. These two emphysema measurements suggest that there was more emphysema found in the CT scans obtained using a lower radiograph dose. Only the mean lung density and -856-HU threshold showed significant effects between CT scanner manufacturers and interactions between total lung volume and scanner. All other measures of lung structure were not different between the two CT scanners. CONCLUSION: CT scan measurements of very low density lung structures are significantly affected by radiation dose but are less sensitive to the lung volume. Image acquisition parameters including radiation dose, scanner type, and the subject's breath size should be standardized to estimate emphysema severity in longitudinal studies.     

Hyperinflation in asthma and emphysema. Assessment by pulmonary function testing and computed tomography

To assess the role of emphysema on the hyperinflation in chronic asthma, we studied 20 subjects with irreversible airflow limitation. Ten of the subjects had asthma and had never smoked; the other ten were cigarette smokers. Pulmonary function testing and chest computed tomography (CT) scans were performed on all subjects. Emphysema was graded using a score based on the percentage of lung involved on CT scan. There was good inter- and intra-observer agreement for the emphysema scores. The median emphysema score was 0 percent in the nonsmoking group and 10 percent in the smoking group. All smokers with a total lung capacity (TLC) of greater than 120 percent predicted had evidence of emphysema on the CT scan. None of the asthmatic subjects with a TLC greater than 120 percent predicted had emphysema identifiable on CT scan. We conclude that chronic asthma with severe hyperinflation does not result in emphysema.     

Lung volume reduction surgery as a bridge to lung transplantation

Lung volume reduction surgery (LVRS) improves lung function, exercise capacity, and quality of life in patients with advanced emphysema. In some patients with emphysema who are candidates for lung transplantation, LVRS is an alternative treatment option to lung transplantation, or may be used as a bridge to lung transplantation. Generally accepted criteria for LVRS include severe non-reversible airflow obstruction due to emphysema associated with significant evidence of lung hyperinflation and air trapping. Both high resolution computed tomography (CT) scan of the chest and quantitative ventilation/perfusion scan are used to identify lung regions with severe emphysema which would be used as targets for lung resection. Bilateral LVRS is the preferred surgical approach compared with the unilateral procedure because of better functional outcome. Lung transplantation is the preferred surgical treatment in patients with emphysema with alpha1 antitrypsin deficiency and in patients with very severe disease who have homogeneous emphysema pattern on CT scan of the chest or very low diffusion capacity.     

The diagnosis of mild emphysema. Correlation of computed tomography and pathology scores

Early and accurate diagnosis of emphysema is said to be invaluable for identification of clinically silent and mild emphysema. Recently, computed tomography (CT) has been much advocated for its efficacy in detailed diagnosis of emphysema, and the results have been compared with the pathology grade of emphysema in resected lung specimens. To assess the ability of high resolution CT scan in detecting and grading mild emphysema, we correlated the high resolution CT scan with the pathology grade of emphysema and the destructive index (DI) of lung specimens from 42 patients undergoing thoracotomy for a solitary pulmonary nodule. The high resolution CT scan and the cut surface of the lung, corresponding exactly to the same plane of the CT scan image, were assessed using the picture-grading system of Thurlbeck and coworkers on a scale of zero to 100. The CT scores for all patients ranged from 12 to 57, with a mean +/- SD of 22.1 +/- 9.6 using 1-mm collimation (n = 35), and from 7 to 46 with a mean +/- SD of 16.5 +/- 8.3 using 5-mm collimation (n = 33). The pathology scores ranged from 10 to 57, with a mean +/- SD of 23.2 +/- 9.8 (n = 42). The DI ranged from 15.4 to 67.1, with a mean +/- SD of 31.4 +/- 10.8 (n = 42). The CT scores using 1-mm and 5-mm collimation correlated significantly with the pathology scores (r = 0.68 and 0.76, respectively, p less than 0.001), and with the DI (r = 0.62 and 0.74, respectively, p less than 0.001). The pathology scores correlated significantly with the DI (r = 0.72, p less than 0.001). We therefore concluded that high resolution CT can help to identify the presence and grading of mild emphysema.     

Correlation of CT and pathologic findings of pulmonary lymphangioleiomyomatosis

The X-ray CT findings of two cases of pulmonary lymphangioleiomyomatosis were reported. The correlation between high-resolution CT findings and inflated biopsy specimens was studied. The X-ray CT findings are 1) multiple low attenuation areas, 2) diffuse areas of slightly increased density and 3) irregular enlargement of pulmonary vascular images. Each low attenuation are turned out to correspond to emphysematous lesions. Slightly increased densities on CT images seemed to be caused by a summation of many small nodules of a proliferation of smooth muscle cells located in the wall of respiratory bronchioles and alveolar ducts, with or without intraalveolar hemosiderosis. Some nodular lesions in bronchiolar walls were so close to neighboring vessels that they could not be separated from vascular images on CT, so peripheral vascular images were irregularly thickened. X-ray CT reflected more actual pathological findings than routine chest radiographs. As low attenuation areas on CT images have been reported to be representative of pulmonary emphysema, it is thought that the above CT findings must be differentiated from those of pulmonary emphysema. While pulmonary vascular images were thin and stretched on the CT in patients with emphysema, they were irregularly thickened on the CT of patients with LAM. Furthermore, while CT of emphysema often revealed overinflation or decreased density, diffuse areas of slightly increased density were never found in emphysema.     

Expiratory computed tomography for assessment of suspected pulmonary emphysema

Results of computed tomography of the lung performed at two levels in upper lung zones at full inspiration and full expiration were compared with results of tests of ventilatory function, lung mechanics, and single breath carbon monoxide diffusing capacity in 64 subjects, many of whom had some form of airflow obstruction. From the CT scans, the mean percentage of pixels in the range -900 to -1,024 Hounsfield units, or pixel index, was determined for each subject. The highest correlations of pixel index with physiologic variables consistent with a diagnosis of emphysema were observed for CT taken at full expiration. In some subjects, the inspiratory CT would give a "false positive" for emphysema when the hyperaeration observed at inspiration was not observed at expiration. We believe that the CT scan taken at full expiration can effectively reveal the abnormal permanent enlargement of airspaces which defines emphysema and provides a noninvasive method of assessing lung morphology in the living human subject.     

CT measurements of lung density in life can quantitate distal airspace enlargement--an essential defining feature of human emphysema

We used a computerized microscopic image analysis system to directly measure the surface area of distal air spaces in methacrylate-embedded blocks randomly selected from inflation-fixed lobes that were resected from 45 patients as treatment of their peripheral lung tumors. In 28 of these patients, a preoperative computer tomography (CT) scan, at 6 and 10 cm below the sternal notch, was used to generate frequency histograms of CT numbers (measured as EMI units), a measure of lung density, in pixels from the lung or lobe that was subsequently resected. A similar CT number histogram was also derived from the lateral two fifths of the area of lobe/lung that was to be resected. The EMI unit that defined the lowest fifth percentile of this latter histogram correlated (n = 28, r = -0.77, p less than 0.001) with the mean value of the surface area of the walls of distal airspaces per unit lung volume (AWUV) in the five 1 mm x 1 mm microscopic fields with the lowest AWUV values, out of the 20 to 35 such fields examined in each patient. In the 34 of the 45 patients in whom we also measured volume-corrected diffusing capacity (DLCO/VA), this also correlated (n = 34, r = 0.84, p less than 0.001) with this value of AWUV, which measures the surface area of airspaces distal to the terminal bronchioles--reflecting an increase in airspace size, a defining characteristic of emphysema. However, a low DLCO/VA is nonspecific, whereas an abnormally low regional lung density is more likely to be specific for emphysema. In addition, highlighting those pixels of the CT display with low CT numbers (i.e., EMI units -500 [air] to -450, where zero = water) can locate areas of macroscopic emphysema, as shown by subsequent pathologic examination. Thus the quantitative CT scan can diagnose, quantitate, and locate mild to moderate emphysema, in humans, in life, noninvasively.     

Evaluation of pulmonary emphysema with high resolution computed tomography and the effect of smoking

Cigarette smoking is thought to play an important part in the development of pulmonary emphysema. The authors previously reported on the correlation of high resolution computed tomography (CT) with the pathology grade of emphysema and the destructive index of lung specimens from 42 patients undergoing thoracotomy for a solitary pulmonary nodule. High resolution CT was effective to identify the presence and grade of mild emphysema. The mean per cent predicted FEV1 was 97 per cent. There were 28 smokers and 14 nonsmokers. In this report, the correlation of smoking history with pathology score and high resolution CT was analyzed. There was significant correlation among these indices. These results further support the relationship between smoking and pulmonary emphysema. High resolution CT scan may help in the understanding of the role of cigarette smoking in the development of early pulmonary emphysema.     

A comparative study of computed tomographic techniques for the detection of emphysema in middle-aged and older patient populations]

Helical-scan computed tomography (CT) is now widely utilized as a mass screening procedure for lung cancer. By adding 3 slices of high-resolution CT (HRCT) to the standard screening procedure, we were able to compare the efficacy of helical-scan CT and HRCT in detecting pulmonary emphysema. Additionally, the prevalence of emphysema detected by HRCT was examined as a function of patient age and smoking history. The subjects (106 men and 28 women) were all community-based middle-aged and older volunteers who participated in a mass lung cancer screening program. Based on visual assessments of the CT films, emphysema was detected in 29 subjects (22%) by HRCT, but in only 4 (3%) by helical-scan CT. Although the prevalence of emphysema was higher among subjects with a higher smoking index, no correlations with age were observed. We concluded that the efficacy of helical scan CT in detecting pulmonary emphysema can be significantly improved with the inclusion of 3 slices of HRCT, and confirmed that cigarette smoking is linked to the development of pulmonary emphysema.     

"Density mask". An objective method to quantitate emphysema using computed tomography

We used a computed tomography (CT) scanner program ("density mask") that highlights voxels within a given density range to quantitate emphysema by defining areas of abnormally low attenuation. We compared different density masks, mean lung attenuation, visual assessment of emphysema and the pathologic grade of emphysema in 28 patients undergoing lung resection for tumor. In each patient, a single representative CT image was compared with corresponding pathologic specimens of tissue. There was good correlation between the extent of emphysema as assessed by the density mask and the pathologic grade of emphysema. The optimal attenuation level to define areas of emphysema may vary in different scanners, but, once determined for a particular scanner, the density mask accurately assesses the extent of emphysema and eliminates interobserver and intraobserver variability. It has the added advantage of determining the exact percentage of lung parenchyma showing changes consistent with emphysema.     

Computed tomographic-based quantification of emphysema and correlation to pulmonary function and mechanics

Computed tomographic based indices of emphysematous lung destruction may highlight differences in disease pathogenesis and further enable the classification of subjects with Chronic Obstructive Pulmonary Disease. While there are multiple techniques that can be utilized for such radiographic analysis, there is very little published information comparing the performance of these methods in a clinical case series. Our objective was to examine several quantitative and semi-quantitative methods for the assessment of the burden of emphysema apparent on computed tomographic scans and compare their ability to predict lung mechanics and function. Automated densitometric analysis was performed on 1094 computed tomographic scans collected upon enrollment into the National Emphysema Treatment Trial. Trained radiologists performed an additional visual grading of emphysema on high resolution CT scans. Full pulmonary function test results were available for correlation, with a subset of subjects having additional measurements of lung static recoil. There was a wide range of emphysematous lung destruction apparent on the CT scans and univariate correlations to measures of lung function were of modest strength. No single method of CT scan analysis clearly outperformed the rest of the group. Quantification of the burden of emphysematous lung destruction apparent on CT scan is a weak predictor of lung function and mechanics in severe COPD with no uniformly superior method found to perform this analysis. The CT based quantification of emphysema may augment pulmonary function testing in the characterization of COPD by providing complementary phenotypic information.     

Pulmonary Emphysema Subtypes on Computed Tomography: The MESA COPD Study

Background

Pulmonary emphysema is divided into 3 major subtypes at autopsy: centrilobular, paraseptal, and panlobular emphysema. These subtypes can be defined by visual assessment on computed tomography (CT); however, clinical characteristics of emphysema subtypes on CT are not well defined. We developed a reliable approach to visual assessment of emphysema subtypes on CT and examined if emphysema subtypes have distinct characteristics.

Methods

The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with chronic obstructive pulmonary disease (COPD) and controls ages 50-79 years with ≥10 pack-years. Participants underwent CT following a standardized protocol. Definitions of centrilobular, paraseptal, and panlobular emphysema were obtained by literature review. Six-minute walk distance and pulmonary function were performed following guidelines.

Results

Twenty-seven percent of 318 smokers had emphysema on CT. Interrater reliability of emphysema subtype was substantial (K: 0.70). Compared with participants without emphysema, individuals with centrilobular or panlobular emphysema had greater dyspnea, reduced walk distance, greater hyperinflation, and lower diffusing capacity. In contrast, individuals with paraseptal emphysema were similar to controls, except for male predominance. Centrilobular, but not panlobular or paraseptal, emphysema was associated with greater smoking history (+21 pack-years P <.001). Panlobular, but not other types of emphysema, was associated with reduced body mass index (−5 kg/m²; P = .01). Other than for dyspnea, these findings were independent of the forced expiratory volume in 1 second. Seventeen percent of smokers without COPD on spirometry had emphysema, which was independently associated with reduced walk distance.

Conclusions

Emphysema subtypes on CT are common in smokers with and without COPD. Centrilobular and panlobular emphysema, but not paraseptal emphysema, have considerable symptomatic and physiological consequences.     

Lung density and lung mass in emphysema.

Mean lung density (dm) and radiologic (VLx) lung volume can be calculated using CT scan data. As many emphysematous patients are overdistended, the analysis of dm alone could be meaningless. However, lung mass (m) can be calculated as the product of dm and VLx. Twenty-four patients suspected of mild or severe emphysema as judged by roentgenographic and physiologic examinations as well as 16 healthy subjects were included in the protocol. They all underwent both a CT scan of the whole lung and functional tests from which the following were derived: airway resistance, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC), CO transfer capacity, quasi-static compliance at functional residual capacity (FRC), and blood gases. All CT scans were performed at the FRC of each patient. The dm was lower in emphysema patients than in healthy subjects, as m was greater in patients than in healthy subjects; 1,303 +/- 398 g and 997 +/- 133 g, respectively. Although dm values were significantly correlated to FEV1, FEV1/FVC, and TLC, m values were not correlated to any of these functional indices. Unexpectedly, these results show that most patients (22/24) with emphysema have a normal or increased lung mass. Normal or above normal m values might be due to oversecretion in some patients. Nevertheless, the synthesis of new tissue due to chronic inflammation is the most likely explanation that could account for this finding.     

Progression parameters for emphysema: a clinical investigation

In patients with airflow limitation caused by cigarette smoking, lung density measured by computed tomography is strongly correlated with quantitative pathology scores of emphysema, but the ability of lung densitometry to detect progression of emphysema is disputed. We assessed the sensitivity of lung densitometry as a parameter of disease progression of emphysema in comparison to FEV(1) and gas transfer. At study baseline and after 30 months we measured computed tomography (CT)-derived lung density, spirometry and carbon monoxide diffusion coefficient in 144 patients with chronic obstructive pulmonary disease (COPD) in five different centers. Annual change in lung density was 1.31 g/L/year (CI 95%: -2.12 to -0.50 HU, p=0.0015, 39.5 mL/year (CI 95%: -100.0-21.0 mL, p=0.2) for FEV(1) (-39.5 mL) and 24.3 micromol/min/kPa/L/year for gas transfer (CI 95%: -61.0-12.5 micromol/min/kPa/L/year, p=0.2). Signal-to-noise ratio (mean change divided by standard error of the change) for the detection of annual change was 3.2 for lung densitometry, but 1.3 for both FEV(1) and gas diffusion. We conclude that detection of progression of emphysema was found to be 2.5-fold more sensitive using lung densitometry than by using currently recommended lung function parameters. Our results support CT scan as an efficacious test for novel drugs for emphysema.     

Utility of lung density measurements in the diagnosis of emphysema

BACKGROUND: The role of computerised tomography (CT) lung density measurements in objective quantification of emphysema is uncertain. The aim of this study was to determine normal reference values for CT lung density measurements and investigate their utility in identifying subjects with clinical emphysema. METHODS: Normal subjects (non-smokers, no respiratory disease, n=185) and subjects with clinical emphysema (post-bronchodilator FEV(1)/FVC <70%, > or =10 pack years tobacco smoking, no childhood asthma and, either D(LCO)/VA <80% predicted and/or macroscopic emphysema on CT, n=22) were identified from a random population survey. Subjects underwent CT scanning, with measurement of areas of low attenuation as a percentage of total area (RA%) for three standardised slices and two reconstruction algorithms with a density threshold of -950 HU. Reference values in normal subjects, and ability of the measurements to discriminate between the two groups were determined. RESULTS: Reference values for individual subjects showed wide confidence intervals (standard resolution scans, RA% females 0.2-3.9%, males 0.4-8.7%.) Subjects with emphysema had greater RA% values compared with normal subjects, the difference being most marked in apical slices (standard resolution algorithm, apical slice, median RA% 2.9% (95% CI 0.4-11.1%) vs. 0.1% (95% CI 0.0-0.5%), emphysema vs. normal subjects, respectively). Logistic regression analysis showed poor discriminant ability to distinguish between the groups, the most favourable cut-off yielding a sensitivity and specificity of 83.3% and 62.8%, respectively. CONCLUSIONS: CT lung density measurements cannot reliably detect the presence of emphysema in an individual. We recommend further investigation into lung density measurements before their widespread use in clinical practice.     

What to Do When a Smoker's CT Scan Is “Normal”?: Implications for Lung Cancer Screening

Lung cancer is the leading cause of cancer-related mortality in the United States and around the world. There are > 90 million current and ex-smokers in the United States who are at increased risk of lung cancer. The published data from the National Lung Screening Trial (NLST) suggest that yearly screening with low-dose thoracic CT scan in heavy smokers can reduce lung cancer mortality by 20% and all-cause mortality by 7%. However, to implement this program nationwide using the NLST inclusion and exclusion criteria would be extremely expensive, with CT scan costs alone > $2 billion per annum. In this article, we offer a possible low-cost strategy to risk-stratify smokers on the basis of spirometry measurements and emphysema scoring by radiologists on CT scans.     

Asthma COPD Overlap Syndrome on CT Densitometry: A Distinct Phenotype from COPD

Patients with asthma COPD overlap syndrome (ACOS) are an important but poorly characterized group. This study sought to explore the distinct characteristics of ACOS on CT densitometry. The study population was randomly selected from communities via questionnaires. All participants underwent low-dose volumetric chest CT both before and after bronchodilator administration. Each CT scan was performed at full-inspiration and full-expiration for CT densitometry. Emphysema index (EI), air trapping (AT), mean lung density (MLD) and total lung volume (TLV) were measured and compared between the ACOS and COPD groups. The distributions of both EI and AT were compared between patients with ACOS and COPD. The variations between the pre- and post-BD measurements observed in patients with ACOS were compared with those in patients with COPD. A total of 71 patients completed the study, including 32 patients with COPD and 39 patients with ACOS. The patients with ACOS exhibited lower EI and more upper-zone-predominant EI distributions, compared with the patients with COPD. No significant differences were exhibited in AT and its distribution. Following bronchodilator administration, the variations in AT and expiratory MLD were greater in patients with ACOS than in patients with COPD. No differences were observed in the variations of EI and inspiratory MLD. Our results indicate that patients with ACOS have lower extent of emphysema and different emphysema distribution, as well as greater post-BD variations in air trapping, compared with patients with COPD. These findings suggest that CT densitometry characterizes ACOS as a distinct phenotype from COPD.