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 (R(2) = 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.

OBJECTIVE. The purpose of this investigation was to determine the effect of lung volume reduction surgery on measured tracheal features.MATERIALS AND METHODS. Twenty-four male and 19 female patients with emphysema underwent lung volume reduction surgery, pulmonary function testing, and repeated CT. The tracheal air column was segmented from axial images. The sagittal and coronal dimensions of the intrathoracic trachea were determined. Tracheal morphology was quantified using the tracheal (coronal and sagittal dimensions) and circularity indexes. The results were compared with pulmonary function test results.RESULTS. Morphologic appearance of the intrathoracic trachea was consistent before and 3 months after surgery. The group means of the tracheal length, mean area, and volume were 78.60 mm (+/- 16.88 mm), 283.84 mm(2) (+/- 61.47 mm(2)), and 22.59 cm(3) (+/- 7.69 cm(3)), respectively, before surgery and 67.53 mm (+/- 15.78 mm), 309.12 mm(2) (+/- 79.83 mm(2)), and 20.99 cm(3) (+/- 7.27 cm(3)), respectively, after surgery (p < 0.05). Mean tracheal indexes were 0.85 (+/- 0.11) before surgery and 0.82 (+/- 0.04) after surgery (p < 0.01). Mean circularity indexes were 0.91 (+/- 0.03) before surgery and 0.90 (+/- 0.04) after surgery (P < 0.05). The size of the trachea was significantly correlated with lung volume before and after surgery (p < 0.05). The changes in tracheal features and changes in pulmonary function were not correlated (p > 0.05), except for tracheal area (p < 0.05).CONCLUSION. Our data suggest that tracheal dimensions reflect the severity of emphysema as reflected by increased lung volumes. Tracheal features were poor predictors of changes in postsurgical pulmonary function parameters evaluated in this preliminary study.

Pulmonary alveolar proteinosis has traditionally been treated with whole-lung lavage (WLL). The literature describes a variety of techniques used in performing the WLL, including mechanical vs manual chest percussion, use of prone positioning, and variances in lavage volume. We have quantified and compared the effective alveolar clearance for each component of the lavage by measuring the dry weight of material in the lavage effluent. We measured this in five patients who underwent six consecutive WLLs at the University of Pittsburgh Medical Center. We performed the lavage in the following three stages: stage I, passive drainage; stage II, assisted clearance; and stage III, positional clearance. Aliquots of lavage effluent were centrifuged to determine the dry weight of material present in sequentially recorded bottles within each stage. At the initiation of each augmentation, there was a statistically significant improvement in the clearance of material (stage II, p = 0.009; stage III, p = 0.012). Furthermore, we show that lipoproteinaceous material is present in the lavage effluent in all stages of latter portions of the lavage. The effective removal of material would be expected to have an impact on the physiologic and clinical response to WLL. This finding emphasizes the importance of performing an adequate and standardized lavage.

We developed and tested an automated scheme to segment lung areas depicted in CT images. The scheme includes a series of six steps. 1) Filtering and removing pixels outside the scanned anatomic structures. 2) Segmenting the potential lung areas using an adaptive threshold based on pixel value distribution in each CT slice. 3) Labeling all selected pixels ingo segmented regions and deleting isolated regions in non-lung area. 4) Labeling and filling interior cavities (e.g., pleural nodules, airway wall, and major blood vessels) inside lung areas. 5) Detecting and deleting the main airways (e.g., trachea and central bronchi) connected to the segmented lung areas. 6) Detecting and separating possible anterior or posterior junctions between the lungs. Five lung CT cases (7-10 mm in slice thickness) with variety of disease patterns were used to train or set up the classification rules in the scheme. Fifty examinations of emphysema patients were then used to test the scheme. The results were compared with the results generated from a semi-automated method with manual interaction by an expert observer. The experimental results showed that the average difference in estimated lung volumes between the automated scheme and manually corrected approach was 2.91%±0.88%. Visual examination of segmentation results indicated that the difference of the two methods was larger in the areas near the apices and the diaphragm. This preliminary study demonstrated that a simple multi-stage scheme had potential of eliminating the need for manual interaction during lunch segmentation. Hence, it can ultimately be integrated into computer schemes for quantitative analysis and diagnosis of lung diseases.

Rationale and Objectives. To develop and evaluate a reliable, fully-automated lung segmentation scheme for application in X-ray computed tomography.Materials and Methods. The automated scheme was heuristically developed using a slice-based, pixel-value threshold and two sets of classification rules. Features used in the rules include size, circularity, and location. The segmentation scheme operates slice-by-slice and performs three key operations: (1) image preprocessing to remove background pixels, (2) computation and application of a pixel-value threshold to identify lung tissue, and (3) refinement of the initial segmented regions to prune incorrectly detected airways and separate fused right and left lungs.Results. The performance of the automated segmentation scheme was evaluated using 101 computed tomography cases (91 thick slice, 10 thin slice scans). The 91 thick cases were pre- and post-surgery from 50 patients and were not independent. The automated scheme successfully segmented 94.0% of the 2,969 thick slice images and 97.6% of the 1,161 thin slice images. The mean difference of the total lung volumes calculated by the automated scheme and functional residual capacity plus 60% inspiratory capacity was -24.7 +/- 508.1 mL. The mean differences of the total lung volumes calculated by the automated scheme and an established, commonly used semi-automated scheme were 95.2 +/- 52.5 mL and -27.7 +/- 66.9 mL for the thick and thin slice cases, respectively.Conclusion. This simple, fully-automated lung segmentation scheme provides an objective tool to facilitate lung segmentation from computed tomography scans.

BACKGROUND:A study was undertaken to test the hypothesis that patients respond better to lung volume reduction surgery (LVRS) if their emphysema is confluent and predominantly located in the upper lobes.METHODS:A density mask analysis was used to identify voxels inflated beyond 10.2 ml gas/g tissue (-910 HU) on preoperative and postoperative CT scans from patients receiving LVRS. These hyperinflated regions were considered to represent emphysematous lesions. A power law analysis was used to determine the relationship between the number (K) and size (A) of the emphysematous lesions in the whole lung and two anatomical regions using the power law equation Y=KA(-D).RESULTS:The analysis showed a positive correlation between the change in the power law exponent (D) and the change in exercise (Watts) after surgery (r=0.47, p=0.03). There was also a negative correlation between the power law exponent D in the upper region of the lung preoperatively and the change in exercise following surgery (r=-0.60, p<0.05).CONCLUSIONS:These results confirm that patients with large upper lobe lesions respond better to LVRS than patients with small uniformly distributed disease. Power law analysis of lung CT scans provides a quantitative method for determining the extent and location of emphysema within the lungs of patients with COPD.

This study examines the hypothesis that the cigarette smoke-induced inflammatory process is amplified in severe emphysema and explores the association of this response with latent adenoviral infection. Lung tissue from patients with similar smoking histories and either no (n = 7), mild (n = 7), or severe emphysema (n = 7) was obtained by lung resection. Numbers of polymorphonuclear cells (PMN), macrophages, B cells, CD4, CD8 lymphocytes, and eosinophils present in tissue and airspaces and of epithelial cells expressing adenoviral E1A protein were determined using quantitative techniques. Severe emphysema was associated with an absolute increase in the total number of inflammatory cells in the lung tissue and airspaces. The computed tomography (CT) determined extent of lung destruction was related to the number of cells/m(2) surface area by R(2) values that ranged from 0.858 (CD8 cells) to 0.483 (B cells) in the tissue and 0.630 (CD4 cells) to 0.198 (B cells) in the airspaces. These changes were associated with a 5- to 40-fold increase in the number of alveolar epithelial cells expressing adenoviral E1A protein in mild and severe disease, respectively. We conclude that cigarette smoke-induced lung inflammation is amplified in severe emphysema and that latent expression of the adenoviral E1A protein expressed by alveolar epithelial cells influenced this amplification process.

Computed tomography (CT) has shown that emphysema is more extensive in the inner (core) region than in the outer (rind) region of the lung. It has been suggested that the concentration of emphysematous lesions in the outer rind leads to a better outcome following lung volume reduction surgery (LVRS) because these regions tend to be more surgically accessible. The present study used a recently described, computer-based CT scan analysis to quantify severe emphysema (lung inflation > 10.2 ml gas/g tissue), mild/moderate emphysema (lung inflation = 10.2 to 6.0 ml gas/g tissue), and normal lung tissue (lung inflation < 6.0 ml gas/g tissue) present in the core and rind of the lung in 21 LVRS patients. The results show that the quantification of severe emphysema independently predicts change in maximal exercise response and FEV(1). We conclude that a greater extent of severe emphysema in the rind of the upper lung predicts greater benefit from LVRS because it identifies the lesions most accessible to removal by LVRS.

It is a privilege to have been asked to summarize my views of the clinical relevance of this conference. It is always a wonderful honor to be asked to participate in the Thomas Petty Aspen Lung Conference, which I attended for the first time in 1968. This is a conference that I've always thoroughly enjoyed. I have invariably gone away from it inspired and motivated to look differently at some aspects of lung research and clinical medicine. It is exciting to see so many basic and clinical investigators gathered to discuss COPD and emphysema, particularly now when for the first time in many years there are new therapeutic modalities on the horizon.

We compared noninvasive positive-pressure ventilation (NPPV), using bilevel positive airway pressure, with usual medical care (UMC) in the therapy of patients with acute respiratory failure (ARF) in a prospective, randomized trial. Patients were subgrouped according to the disease leading to ARF (chronic obstructive pulmonary disease [COPD], a non-COPD-related pulmonary process, neuromuscular disease, and status postextubation), and were then randomized to NPPV or UMC. Thirty-two patients were evaluated in the NPPV group and 29 in the UMC group. The rate of endotracheal intubation (ETI) was significantly lower in the NPPV than in the UMC group (6.38 intubations versus 21.25 intubations per 100 ICU days, p = 0.002). Mortality rates in the intensive care unit (ICU) were similar for the two treatment groups (2.39 deaths versus 4.27 deaths per 100 ICU days, p = 0.21, NPPV versus UMC, respectively). Patients with hypoxemic ARF in the NPPV group had a significantly lower ETI rate than those in the UMC group (7.46 intubations versus 22.64 intubations per 100 ICU days, p = 0.026); a similar trend was noted for patients with hypercapnic ARF (5.41 intubations versus 18.52 intubations per 100 ICU days, p = 0.064, NPPV versus UMC, respectively). Patients with ARF in the non-COPD category had a lower rate of ETI with NPPV than with UMC (8.45 intubations versus 30.30 intubations per 100 ICU days, p = 0.01). Although the rate of ETI was lower among COPD patients receiving NPPV, this trend did not reach statistical significance (5.26 intubations versus 15.63 intubations per 100 ICU days, p = 0.12, NPPV versus UMC, respectively). In conclusion, NPPV with bilevel positive airway pressure reduces the rate of ETI in patients with ARF of various etiologies.

STUDY OBJECTIVE To determine how the volume and severity of emphysema measured by CT morphometry (CTM) before and after lung volume reduction surgery (LVRS) relates to the functional status of patients after LVRS. DESIGN A histologically validated CT algorithm was used to quantify the volume and severity of emphysema in 35 patients before and after LVRS: total lung volume (TLV), normal lung volume (< 6.0 mL gas per gram of tissue), volume of mild/moderate emphysema (ME; 6.0 to 10.2 mL gas per gram of tissue), volume of severe emphysema (> 10.2 mL gas per gram of tissue), surface area/volume (SA/V; meters squared per milliliter), and surface area (SA; meters squared). Outcome parameters included maximal cardiopulmonary exercise (CPX) performance in 21 patients and routine pulmonary function in all patients. We hypothesized that baseline CTM parameters predict response to LVRS and that the change in these parameters may offer insight into mechanisms of improvement. PATIENTS AND INTERVENTION Thirty-five patients with severe emphysema who had successful LVRS. RESULTS The significant decrease in TLV following LVRS was entirely accounted for by a decrease in severe emphysema. The SA/V and the SA both increased significantly following LVRS. The change in maximal CPX in watts following surgery correlated significantly with baseline values of severe emphysema (r = 0.60), which was collinear with TLV, and SA/V. The change in diffusing capacity of the lung for carbon monoxide revealed a significant positive linear relationship with preoperative severe emphysema (r = 0.37) and a negative relationship with ME (r = -0.37). Change in watts revealed a strong relationship with changes in severe emphysema (r = -0.75) and weaker but significant relationships with change in TLV, ME, SA/V, and SA. Other measures of pulmonary function revealed significant albeit less dominant relationships with baseline CTM and change in these indexes. CONCLUSION Using CTM, we have identified a close relationship between baseline severe emphysema, or change in severe emphysema, and the improvement in CPX after LVRS. These observations support a potential role of CTM in future clinical trials for predicting responders to LVRS and identifying mechanisms of improvement.

The effects of growth hormone (GH) on diaphragm muscle myosin heavy chain (MHC) composition and mechanical performance were investigated in Fischer 344 male rats aged to senescence (24.5 mo of age). Chronic undernutrition (UN), refeeding (RF), and RF+GH were compared with ad libitum feeding by using a model of UN that produced a 50% decrease in body weight over a 12-mo period. The effect of aging was assessed by comparing MHC composition of ad libitum-fed rats at 12 and 24.5 mo of age. At senescence, significant decreases in slow type I (-23%) and fast type IIA (-31%) MHC had occurred with aging. Conversely, UN over this aging period increased types I (32-73%) and IIA (22-23%) MHC and decreased fast types IIB (32-54%) and IIX (30-31%) MHC. RF and RF+GH reversed these shifts back toward control values. At senescence, maximal specific force, maximal velocity, and specific power capacity were not different across treatment groups. During repetitive isotonic contraction trials, the diaphragms of UN rats maintained power production over time (54% of initial power at 60 s), whereas the power production of diaphragms of ad libitum-fed rats fell to 0% (P < 0.05). In comparison with UN rats, the diaphragms of RF and RF+GH rats produced 23 (not significant) and 11% (P < 0.05) of initial power, respectively, suggesting that RF+GH treatment restored performance characteristics after UN. We conclude that RF+GH can reverse alterations in MHC composition and mechanical performance produced by chronic UN in the aged rat diaphragm.

Quantitative analysis of computed tomography (CT) has been combined with a stereologically based histologic analysis of lung structure to assess regional lung inflation and the structural features of the lung parenchyma. In this study, CT measurements of lung inflation were compared with histologic estimates of surface area in order to develop prediction equations that allow lung surface to volume ratio and surface area to be predicted from an analysis of the CT scan. The results show that mild emphysema is associated with an increase in lung volume and a reduction in surface to volume ratio, whereas surface area and tissue weight were only decreased in severe disease. The CT predicted surface to volume ratio correlated with histology, and both predicted and measured surface areas correlated with the diffusing capacity. We conclude that this CT analysis can be used to monitor the progression of emphysematous lung destruction in individual patients, and to assess the impact of both surgical and medical treatments for emphysema.

The effects of growth hormone (GH) administration and refeeding after chronic undernutrition (UN) were investigated in Fischer 344 male rats aging into senescence (24.5 mo of age) during UN initiated at 12.5 mo of age that produced muscle atrophy and a 50% decrease in body mass. Muscle mass, protein, myosin heavy-chain (MHC) composition and circulating testosterone levels were measured and compared to controls with free access to food. Within 9 wk, refeeding + GH restored body mass to control levels, whereas it was still decreased with refeeding alone. By 24.5 mo of age, refeeding alone restored body mass, while addition of GH resulted in overshoot. UN uniformly decreased mass of the gastrocnemius, extensor digitorum longus, soleus and diaphragm muscles to 50–60% of controls. Refeeding and refeeding + GH restored these losses with some overshoot of gastrocnemius muscle suggesting hypertrophy. UN more than doubled slow Type I MHC composition and approximately halved fast Type IIB and IIX MHC in the deep gastrocnemius muscle while it increased Type IIA MHC in the diaphragm. Refeeding and refeeding + GH reversed these shifts. MHC shifts in the extensor digitorum longus and soleus muscles were not statistically significant, whereas UN increased fast Type IIA MHC followed by decrease with refeeding + GH. UN decreased testosterone levels to nearly zero followed by restoration with refeeding and refeeding + GH. We conclude that the phenotype of mixed-MHC muscles such as the gastrocnemius and diaphragm are most affected by chronic UN, which is reversible with refeeding and refeeding + GH. These alterations were associated with changes in circulating testosterone, which may be a key regulatory element in these processes.

The effects of chronic undernutrition (UN) on respiratory muscle were investigated during UN producing a 50% decrease in body weight over a prolonged period (45 weeks) in Fischer 344 male rats. This model focused on progressive, aging-related changes in myosin heavy chain (MHC) profile over time, in which the confounding effects of early development and late senescence were avoided. With aging toward late adulthood (68 weeks), MHC composition of control diaphragms was shifted, with decreased type I (slow) and IIA MHC, and increased type IIB and IIX (fast) MHC. UN produced a divergence of this profile, with an increase in type I and IIA MHC, and decreased type IIX MHC. UN diaphragms in vitro were more resistant to loss of active force with fatigue, during repetitive contractions. However, passive tension rose disproportionately during fatigue, suggesting increased fatigability. We conclude that the observed changes in diaphragm mechanical function are consistent with the UN-induced shifts in MHC composition; however, the elevated passive tension with fatigue suggests additional UN-induced changes in mechanical properties that are possibly detrimental to respiratory muscle function. The UN-dependent divergence in phenotype and mechanical properties may be amplified by aging-related shifts in muscle MHC composition over time, in the control group.