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(Chest. 2005;128:2471-2477.)
© 2005 American College of Chest Physicians

Use of CT Morphometry To Detect Changes in Lung Weight and Gas Volume*

Andrew Perez, IV, MD; Harvey O. Coxson, PhD; James C. Hogg, MD, PhD; Kevin Gibson, MD; Paul F. Thompson, BS and Robert M. Rogers, MD

* From the Division of Pulmonary, Allergy and Critical Care Medicine (Dr. Perez and Mr. Thompson) and Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases (Drs. Gibson and Rogers), University of Pittsburgh, Pittsburgh, PA; Department of Radiology (Dr. Coxson), Vancouver General Hospital, Vancouver, BC; and James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research (Dr. Hogg), St. Paul’s Hospital, Vancouver, BC.

Correspondence to: Robert M. Rogers, MD, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, NW 628 MUH, 3459 Fifth Ave, Pittsburgh, PA 15213; e-mail: rogersrm{at}upmc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: CT estimates of lung density have been used to estimate the extent and severity of emphysema. The present study was designed to test the hypothesis that quantitative CT can track the changes that occur in diffuse lung disease.

Design: The study was based on five patients with pulmonary alveolar proteinosis (PAP) who underwent lung lavage. Pulmonary function was measured before and after each individual lung lavage, and the CT scans before and after lavage were used to compare total lung volume, airspace volume, lung weight, and regional lung inflation. The dry weight of proteinaceous material lavaged from the lung was measured and compared to the change in CT lung weight.

Results: All the patients showed improvements in dyspnea, percentage of predicted diffusion capacity of the lung for carbon monoxide, and FVC. There was no change in CT-measured total lung volume or airspace volume, but there was a reduction in lung weight following lavage (p = 0.001), which correlated with the dry weight of the lavage effluent (R2 = 0.73). Therefore, there was a shift in the regional lung inflation toward a more inflated lung with a corresponding increase in the mean lung inflation (p = 0.001).

Conclusion: These data show that quantitative CT can objectively track the changes in lung weight and airspace inflation produced by a standard intervention in PAP, and we postulate that it can provide similar information about the progression of other diffuse lung diseases.

Key Words: CT • diffuse lung disease • lavage • pulmonary alveolar proteinosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
During the last decade, investigators have begun to quantify the amount of disease in patients with chronic lung diseases, including emphysema and interstitial lung disease.123456789101112 This quantification is based on the fact that the changes in lung structure caused by progression of the disease produce changes in lung density, which is linearly related to the attenuation of x-rays.13 This has been best shown for emphysematous destruction of the lung,2414151617 where the decrease in tissue and increase in gas volume lowers lung density, but it also occurs in end-stage interstitial lung disease, where the decrease in the volume of gas in the tissue raises lung density.561819 Because of the spatial information contained with the CT image, CT scans can be used to measure the total volume of the lung. The combination of lung volume and density makes it possible to estimate other volumetric parameters such as lung weight and gas volume. We refer to the collection of techniques used to quantify lung structure using CT as CT morphometry (CTM).

The present study was designed to test the hypothesis that CTM can be used to track the changes in lung density in diffuse lung disease. Pulmonary alveolar proteinosis (PAP) was used as a model of diffuse lung disease because there is significant improvement, and in some instances almost complete resolution, of the infiltrate following an intervention,20 with the unique opportunity that the dry weight of the material removed from the lung can be measured and compared to the change in CT measured lung weight from before to after lavage.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection
Five patients with a diagnosis of PAP were studied before and after lung lavage as an intervention for their disease. The decision to perform lavage was based on clinical, physiologic, and radiographic parameters.21 All patients gave their informed consent to participate in the study, and the protocol was approved by the University of Pittsburgh Institutional Review Board.

Pulmonary Function
Pulmonary function tests (PFTs) were used to measure FVC, FEV1, total lung capacity, and diffusing capacity of the lung for carbon monoxide (DLCO). The PFT data used were obtained within 7 days of the CT scans. When patients underwent lavage, PFTs were performed before and after the lavage procedure. The tests were performed using American Thoracic Society standards. Results are expressed as percentage of predicted using accepted standard formulas.222324

Quantitative Lung Lavage
Five patients underwent sequential single-lung lavage for a total of 14 lavages. The time interval between lavages was usually 1 week. Lung lavage was performed by intubating the patient with a double-lumen endotracheal tube and isolating each lung. The targeted lung was then lavaged with normal saline solution and warmed to body temperature (37°), using aliquots ranging from 500 to 1,500 mL as previously described.25 The effluent from the lavage was collected in 1.5-L bottles labeled sequentially for analysis. Lavage volumes ranged from 45 to 75 L.

The weight of the material removed by lavage was measured by centrifuging a 250-mL aliquot of the effluent and weighing the "pellet." The pellet is composed primarily of surfactant and the phospholipids unique to PAP. This quantitative lung lavage method has been previously described and is based on methods developed in surfactant research.252627

CTM Analysis
All patients undergoing lavage underwent a multislice, helical CT scan (without the use of contrast media) before and after each lavage procedure in the supine position (GE Lightspeed or Lightspeed Plus CT; GE Medical Systems; Milwaukee WI). CT scans were performed using standard clinical settings at our institution (5-mm slice thickness, 155 mA, 140 kilovolt peak) and reconstructed using a low-spatial-frequency reconstruction algorithm. The scanners were calibrated daily using standard water and air phantoms. All postlavage CTs were performed within 1 week of lavage. Of the 14 single lung lavages performed, only 10 had CT scans before and after lavage available for analysis, for the following reasons: patient 1 only underwent a CT scan following lavage of both lungs; a prelavage CT scan for right lung lavage was performed at another institution in patient 2, and data were not available for analysis; following the first lavage of the left lung, pneumonia developed in patient 4, and as a result the follow-up CT for this lung was not used; and patient 5 failed to attend the follow-up for the CT scan within a week after his second lavage of the right lung

The CT scan analysis was performed using custom software (Emphylx; Department of Radiology/iCAPTURE Laboratory, University of British Columbia; Vancouver, BC, Canada) and a modification of a technique previous described.123 Briefly, the lung parenchyma was segmented from the chest and the large central blood vessels using CT values of – 1,000 to – 500 Hounsfield units. The total lung volume of the whole lung (tissue and airspace) was calculated by summing the voxel dimensions in each slice. The density of the lung (grams per milliliter) was estimated by adding 1,000 to the Hounsfield unit of each voxel, and dividing by 1,000.113 Lung weight was calculated by multiplying the lung density of each voxel by the volume of the voxel. The total airspace volume was calculated by subtracting the tissue volume from the total lung volume. The lung inflation (volume of gas per gram of tissue) for each voxel was calculated according to the following equation:

where specific volume is the inverse of density, the density of the lung (tissue and gas) is the measured value from the CT, and the density of tissue is assumed to be 1.065 g/mL.28 The frequency distribution of lung inflation was broken into discrete bins using inflation cutoffs: 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 10.2, and > 10.2 mL/g. These values were obtained for the total lung (both sides) as well as left and right individually.

Data Analysis
Descriptive statistics (mean, SD, and range) were determined for lung volume, weight, and the lung inflation categories (milliliters per gram), as well as the mean of the CTM measured frequency distribution of lung inflation. Comparison of the CTM measurements for lung weight to those measured using quantitative lung lavage and the CTM measurement of airspace volume to plethysmography were performed using a clustered analysis (STATA 7.0; StataCorp; College Station, TX). Using this technique, observations between clusters (individual patients) are assumed to be independent, but the observations within a cluster are not assumed to be independent, thus are given less weight in the regression. PFTs and CTM were compared only if performed within 1 week of each other and without an interceding lung lavage. Paired Student t test was performed on the CTM and PFT data before and after lung lavage; p < 0.05 was considered significant. These statistical analyses were performed using statistical software (release 13.31; Minitab; State College, PA).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Pulmonary Function
All patients had improvement in PFT results after lung lavage. Following lavage, the mean FVC percentage of predicted improved from 64.0 ± 13.0% to 73.6 ± 9.9% (p = 0.003), and the mean percentage of predicted DLCO improved from 39.6 ± 10.1% to 58.7 ± 12.6% (p < 0.001). Patients also reported an improvement in dyspnea.

CTM Measurements
The results of the CTM analysis of the 10 CT scans performed before and after each lung lavage are summarized in Table 1 . There was a significant reduction in the total lung weight (p = 0.001) following the procedure without a significant change in the total lung volume (p = 0.75). While there was an increase in the mean lung inflation (p = 0.001), the increase in airspace volume did not reach significance (p = 0.12), presumably due to a small sample size. The CTM airspace volume was correlated with the total lung capacity measured before and after each lavage procedure (R2 = 0.61, p = 0.001).


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  		Table 1. Before and After Lavage Data as Measured by CTM

 
Figure 1 shows the changes in lung weight and total lung volume as measured by CTM for an individual patient (patient 4) undergoing four separate single-lung lavages over a 7-month period and 7 months follow-up after the fourth lavage, at which time the patient had complete resolution of disease. The patient has remained asymptomatic since that time.



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  		Figure 1. A summary of changes in lung weight and lung volume for patient 4 as measured by CTM over time. The solid line shows the change in lung weight over the course of investigation. The dotted line shows the change in the airspace volume over this same time frame. The points of each individual lung lavage are referenced by the vertical lines labeled with the date of the procedure. Note the decrease in lung weight and the improvement in lung volume over the follow-up time (> 1 year).

 
Figure 2 shows the frequency distribution of lung inflation binned into 2 mL/g categories for all the patients. The percentage of the total lung with the lowest inflation (0 to 2 mL/g) shows the greatest change, decreasing from 67.7 ± 13.9% to 45.7 ± 15.2% (p = 0.02). There was also a significant increase in the proportion of the lung in the 2 to 4 mL/g range (p = 0.03).



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  		Figure 2. Histogram plot of CTM measurements for all patients before (black bars) and after (white bars) lung lavage. It shows the changes in percentage of lung in each inflation range category: 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 10.2, and >10.2 mL/g). Error bars signify SD. The significant changes were noted in the 0 to 2 ml/g and 2 to 4 mL/g ranges (p = 0.02 and p = 0.03, respectively).

 
Figure 3 shows the changes in lung volume for each specific milliliter per gram range as measured by CTM for patient 4. The volumes are illustrated on a slice-by-slice basis for each CT scan. Accompanying each histogram is a representative CT image, shown at the same level, for each CT scan. The histograms illustrate a decrease in the volume of the least well-inflated (most dense) lung (0 to 2 mL/g) and an improvement in the more inflated (less dense) lung (4 to 6 mL/g and 6 to 8 mL/g) into a more normal distribution of lung inflation.



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  		Figure 3. Histograms of lung volumes shown slice by slice for five serial CT scans of patient 4 undergoing two sets of lung lavages and followed up for 13 months. A corresponding CT image accompanies each histogram. Panels A and B correspond to the prelavage condition (October 15, 2001); panels C and D are findings following the first procedure (May 9, 2002); panels E and F are findings following the second lavage (June 20, 2002); panels G and H are findings 3 months after the second lavage (August 22, 2002); and panels I and J are findings 13 months following the first lavage (December 19, 2002). Each bar in the histogram represents the volume of the CT image. The dark blue color represents the volume of the slice occupied by lung inflated from 0 to 2 mL gas/gram tissue; the red color is the volume inflated from 2 to 4 mL/g; the teal color is the volume inflated from 4 to 6 mL/g; the tan color is the volume inflated from 6 to 8 mL/g; and the white color is the lung inflated > 8 mL/g.

 
Lung Weight
Table 2 shows the measured change on CTM in lung weight and the dry weight of the effluent from the lung lavage. Using a clustered analysis, there was a significant relationship correlation between dry weight of material and the changes in CTM measure lung weight with an R2 value of 0.73 (Fig 4 ). This analysis shows that individual data points from the same patient are equally likely to fall above or below the regression line, indicating that the observed high correlation is not due to multiple observations from the same patient. We excluded the quantitative lung lavage from patient 1 because the specimen was not processed properly and the first left-sided lavage from patient 4 because the follow-up CT was not done until 4 weeks after the lavage. We also excluded the data from the second lavage on the right side of patient 5 because the patient did not follow-up within 1 week. Therefore a total of nine effluents were available for our analysis.


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  		Table 2. Weight Changes Measured by Quantitative Lung Lavage and CTM Following Lung Lavage*

 


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  		Figure 4. Clustered analysis between the weight of the lavaged material to the change in the lung weight measured using CTM. This analysis shows a strong correlation between the two measurements and individual data points from the same patient (patient 2 = {blacksquare}, patient 3 = {blacktriangleup}, patient 4 = •, patient 5 = *) are equally likely to fall above or below the regression line, indicating that the observed high correlation is not due to multiple observations from the same patient.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study was based on the hypothesis that a quantitative analysis of CT scans provides information on the changes in lung volume, density, and inflation as a result diffuse lung disease. To address this question, we tracked changes in lung inflation and weight following lung lavage in patients with PAP. PAP was used as a model of diffuse lung disease because it is well established that all patients have some immediate clinical improvement following lung lavage and all of our patients showed improvements in dyspnea, percentage of predicted FVC, and DLCO.

Quantitative CT analysis (CTM) showed that there was a significant decrease in the total lung weight and a trend for an increase in the airspace volume without a significant change in the total lung volume following the lavage procedure (Table 1, Fig 1). Furthermore, when we examined the frequency distribution of the lung inflation (Fig 2, 3), we found that there was a significant decrease in the proportion of lung in the 0- to 2-mL gas per gram of tissue and an increase in the 2 to 4 mL of gas per gram of tissue range, indicating that as the proteinaceous material is removed, the lung becomes inflated toward normal levels.2 There was also a good agreement between the weight of material removed by lavage and the change in lung weight measured by CTM (R2 = 0.73). While there was good agreement between these two measurements, there was a range in differences between the two techniques. We hypothesize that this may be due to the time interval between the collection of the effluent at the time of lavage and the CT scan that was performed 1 week after lavage. During this time interval, there could be further clearing or reaccumulation of the material in the alveolus. We doubt that any saline solution remains in the lung since there is good data to show that it clears rapidly.29

PAP is unique in that there is no other lung disease that shows such dramatic changes in radiographic and clinical parameters following a simple procedure.29 Therefore, it was the ideal disease to test our hypothesis that CTM can be used to measure the changes in lung density and calculate changes in the weight and re-expansion of the lung as the disease improved following the intervention (ie, lung lavage). The results show that changes in lung volume and weight that occur following lung lavage can be monitored using CTM and that the extent and severity of the disease can be mapped. We postulate that these measurements could prove to be a valuable approach to the longitudinal assessment of the lungs from patients with other types of progressive diffuse lung diseases, including diffuse alveolar damage (ARDS), nonspecific interstitial lung disease, hypersensitivity pneumonitis, drug-related lung disease, collagen vascular disease, and the early stages of usual interstitial pneumonia. Combining the CTM data with biopsy, quantitative histology, immunohistochemistry, and molecular techniques could provide new insight into these diseases. Therefore, we recommend that CTM be considered in studies designed to gain insight into the natural history of diffuse lung diseases and the evaluation of their response to therapeutic intervention.

In summary, patients undergoing treatment for PAP show an increase in inflation and a decrease in total lung weight as measured by CTM and quantitative lung lavage. We propose that the application of this technique will improve our ability to follow the progress of other diffuse lung diseases and assess the effects of therapeutic interventions.


   Footnotes
 
Abbreviations: CTM = CT morphometry; DLCO = diffusion capacity of the lung for carbon monoxide; PAP = pulmonary alveolar proteinosis; PFT = pulmonary function test

Funding was provided by the George Love Fund and the Meeker Research Fund.

Dr. Coxson is a Parker B. Francis Fellow in Pulmonary Research.

Received for publication December 16, 2004. Accepted for publication April 19, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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