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Quantitative Analysis of Longitudinal Response to Aerosolized Granulocyte-Macrophage Colony-Stimulating Factor in Two Adolescents With Autoimmune Pulmonary Alveolar Proteinosis FREE TO VIEW

Terry E. Robinson, MD; Bruce C. Trapnell, MD; Michael L. Goris, MD, PhD; Lynne M. Quittell, MD; David N. Cornfield, MD
Author and Funding Information

*From the Center of Excellence in Pulmonary Biology (Drs. Robinson and Cornfield) and Department of Radiology (Dr. Goris), Stanford University Medical Center, Stanford, CA; Division of Pulmonary Biology (Dr. Trapnell), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Pulmonary Medicine (Dr. Quittell), New York-Presbyterian Hospital/ Columbia University Medical Center, New York, NY.

Correspondence to: Terry E. Robinson, MD, Center of Excellence in Pulmonary Biology, Division of Pediatric Pulmonary, Stanford University Medical Center, 770 Welch Rd, Suite 350, Stanford, CA 94305-5715; e-mail: ter@stanford.edu


The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(3):842-848. doi:10.1378/chest.08-1317
Text Size: A A A
Published online

Background:  Autoimmune pulmonary alveolar proteinosis (APAP) is characterized by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood and tissues, resulting in alveolar surfactant protein accumulation. Patients with APAP present with ground-glass opacities (GGOs) and interlobular septal thickening on thin-slice chest CT scans. Aerosolized GM-CSF therapy (aeroGM-SCF) has qualitatively improved the clinical condition of patients with APAP. This report details quantitative chest CT responses to aeroGM-CSF.

Methods:  Two adolescent patients (aged 16 and 19 years) with APAP were treated with aeroGM-CSF. Clinical parameters, including pulmonary function tests and chest CT scans, were obtained before and after aeroGM-CSF therapy. To evaluate the effect of the therapy, serial chest CT scans were analyzed using a novel approach permitting quantitative assessment of improvement in GGOs, lung weight, and gas volume.

Results:  In association with GM-CSF treatment, nutritional status and pulmonary function improved. Quantitative analysis of the CT scans demonstrated reduction in GGOs and lung weight, concomitant with an increase in airspace volume and lung inflation. The findings were consistent with a qualitative reduction in GGOs on chest CT imaging.

Conclusions:  Quantitative analysis of CT holds promise as a sensitive diagnostic tool permitting longitudinal and objective analysis of the therapeutic response to aeroGM-CSF in patients with APAP.

Figures in this Article

Autoimmune pulmonary alveolar proteinosis (APAP) is a rare lung disease characterized by autoantibodies directed at granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood and tissue. The downstream effects of these neutralizing auto-antibodies include impaired alveolar macrophage catabolism of surfactant lipids and proteins, accumulation of lipoproteinaceous material within the alveoli, and impaired antimicrobial function of neutrophils.1 Excessive alveolar surfactant lipids and proteins impair gas exchange, decrease alveolar lung volume, and increase intrapulmonary shunting.1,2 Radiographic findings characteristic of disrupted surfactant homeostasis in APAP include patchy, ground-glass opacities (GGOs) with interlobular and intralobular septal thickening on chest CT, aptly described as a “crazy paving” interstitial lung pattern.3 Until recently the standard therapy for APAP has been removal of accumulated alveolar surfactant material via whole lung lavage.1,2 New insights into the pathophysiology of APAP prompted treatment with aerosolized GM-CSF (aeroGM-CSF). There have been several reports of therapeutic benefits in patients with APAP treated with aeroGM-CSF, as manifested by clinical improvement in symptoms and disease markers,4,5 pulmonary function measurements,6,7 and radiographic imaging (chest CT scans or chest radiographs).6,7 To date, a quantitative approach to the analysis of GGO on CT evaluations, the outcome measure most frequently applied to APAP, has not been used to evaluate the response to aeroGM-CSF in patients with APAP. The present report demonstrates the utility of quantitative chest CT analysis to monitor the response to aeroGM-CSF therapy in two adolescent patients with APAP.

Case 1

In August 2004, a 16-year-old girl presented with a 10-week history of mild shortness of breath. Fifteen weeks prior to presentation, the patient underwent appendectomy. The hospital course was complicated by a pelvic abscess, bilateral pneumonia, and hypoxemia. She was treated with IV antibacterial therapy and discharged home. She had persistent symptoms at home and bilateral lung infiltrates on a chest radiograph. Her oxygen saturation was 97% at rest by pulse oximetry measurements. Her chest examination revealed mildly decreased breath sounds bilaterally. She had a normal peripheral WBC count. Her chest radiograph showed a diffuse bilateral mixed interstitial alveolar pattern consistent with interstitial lung disease. Spirometry demonstrated decreased FVC, FEV1, forced expiratory flow, mid-expiratory phase (FEF25–75%) [66%, 66%, and 68% of predicted values], and a FEV1/FVC of 88%. Her total lung capacity (TLC) by body plethysmography was 68% of the predicted value, and her uncorrected diffusing capacity of the lung for carbon monoxide (Dlco) was 44% of predicted (9.17 mL/min/mm Hg). A spiral chest CT scan revealed patchy areas of GGOs with intralobular and interlobular septal thickening with a crazy paving pattern.

Bronchoscopy with BAL of the bilateral lower lobes revealed white, milky BAL fluid without microorganisms. BAL and serum GM-CSF autoantibody levels were elevated (BAL: 0.56 μg/mL [normal < 0.1 μg/mL] and serum: 33.7 μg/mL [normal < 3 μg/mL]). These findings were consistent with APAP. Despite supportive measures and bronchodilator treatment, shortness of breath and desaturation with exercise persisted. She underwent bilateral sequential whole lung lavage in December 2004 at another institution.

Over the subsequent 2 months, exercise intolerance and shortness of breath persisted. Spiral chest CT scan (test 1, [T1]) performed in February 2005 revealed GGOs, intralobular and interlobular septal thickening in all lung segments with slight progression of GGOs in the lung apices, right middle lobe, and lower lobes. A pulmonary function test (PFT) in March 2005 demonstrated worsened obstructive disease (FVC: 71%; FEV1: 63%; FEF25–75%: 49% of predicted values) but a normal total lung capacity (TLC of 100%) and improved diffusion capacity (uncorrected Dlco, 15.46 mL/min/mm Hg: 74% of her predicted value). Persistent symptoms prompted the initiation of aeroGM-CSF (250 μg bid for 2 weeks on followed by 2 weeks off each month) in May 2005. She was treated from May 2005 through February 2006. Significant symptomatic improvement was noted within 10 days of initiation of her therapy, with sustained and progressive improvement over the subsequent 8 months. After > 8 months of treatment (as of January 2006), percent predicted FEV1 increased by 78% and chest CT imaging (Test 2 [T2]) revealed a 92% reduction in percent of lung demonstrating decrease in GGOs (Fig 1, top, A) with improvement in intralobular and interlobular septal thickening consistent with her clinical improvement.

Figure Jump LinkFigure 1 Comparison of two female adolescents with APAP (top, A: patient 1; bottom, B: patient 2) before (T1) and after (T2) treatment with aeroGM-CSF therapy. Note significant changes in GGOs after ≥ 8 months of treatment. Also note persistent interlobular and intralobular thickening in patient 2, who had long-standing disease and probable fibrotic changes.Grahic Jump Location
Case 2

In December 2006, a nearly 19-year-old woman was referred to our center for initial evaluation and initiation of aeroGM-CSF therapy for APAP. The patient initially presented in 1999 with persistent shortness of breath and interstitial lung disease identified on chest CT imaging. An open-lung biopsy procured in October 1999 was diagnostic for APAP. Over the next 6.5 years she had shortness of breath at rest, did not tolerate exercise, and required supplemental oxygen with viral infections. To address these symptoms, she had undergone 17 procedures wherein whole lung lavage was performed prior to our assessment.

Her oxygen saturation was 92% at rest by pulse oximetry measurements. Her chest examination revealed coarse breath sounds predominantly on the left side. Peripheral WBC and platelet counts were normal, but hemoglobin and hematocrit were decreased (11.2 g/dL and 39%, respectively). Spirometry demonstrated a decrease in FVC, FEV1, and FEF25–75%, (51%, 52%, and 53% of predicted values), and FEV1/FVC of 78%. Her TLC by body plethysmography was 54% of predicted, and uncorrected Dlco was 32% of predicted. Her arterial blood gas showed a Pao2 of 52 mm Hg, with a large alveolar-arterial gradient > 58 mm Hg. A 6-min walk test revealed oxygen desaturation to 77% on room air with recovery of oxygen saturation to 92% 2 min after exercise.

A spiral chest CT scan in December 2005, prior to the initiation of aeroGM-CSF (test 1 [T1]), revealed diffuse GGOs with overlying intralobular septal thickening distributed throughout bilateral lung fields, predominantly at the apices, but also extending throughout the mid lung zones and bases, with a classic crazy paving pattern. Compared to a chest CT scan obtained 5 months earlier, the GGOs were appearing more dense, with further extension in the right upper lobe, superior segment of the right lower lobe, and throughout the right lung base. Some improvement was noted in the apical posterior segment of the left upper lobe.

Due to progressive disease, aeroGM-CSF (250 μg bid for 2 weeks on followed by 2 weeks off each month) was initiated in January 2006. Treatment was continued for 9 months (January 2006 to September 2006). As symptoms continued despite 2 months of aeroGM-CSF therapy, the patient underwent bilateral sequential whole lung lavage at another institution in March 2006. Following lavage, aeroGM-CSF therapy was continued. The patient improved progressively with better exercise tolerance, including participation on a softball team. Her oxygen saturations remained > 96% during exercise, and she had significant weight gain (5.5 kg). Follow-up testing (T2) in September 2006 revealed a 29% increase in percent predicted FEV1 and a 68% reduction in percentage of lung demonstrating decrease in GGOs on chest CT imaging with persistent intralobular and interlobular septal thickening (Fig 1, bottom, B).

Inspiratory thin-slice spiral chest CT scans (Sensation 64 Scanner; Siemens; Erlangen, Germany) were performed on the two female adolescents, in the supine position, before and after long-term aeroGM-CSF therapy. The CT scans were performed using the standard clinical settings of 120 kVp, 200 to 310 mA for patient 1 and 200 mA for patient 2, rotation time 0.5 s, and lung (B60F) reconstruction kernel. Levels of serum lactate dehydrogenase, GM-CSF autoantibody, and surfactant protein D (SP-D) were measured 3.5 months before and > 8 months after aeroGM-CSF in patient 1 and 1 week before and 9 months after aeroGM-CSF in patient 2. For patient 1, PFTs were obtained within 3 weeks of the T1 CT scan and within 1 week of the T2 CT scan. For patient 2, PFTs were obtained on the same day as the T1 CT scan and within 1 day of the T2 CT scan. The highest recorded values of the pre- or post-bronchodilator PFTs were used for each patient (patient 1: post/post for T1/T2; and patient 2: pre/pre for T1/T2). For patient 2, results of a 6-min walk test and arterial blood gas were obtained before and after 9 months of aeroGM-CSF therapy.

The inspiratory CT scans were segmented on the basis of density and topographical location.8,9 A histogram of normalized density (in Hounsfield Units [HU]) was obtained from the segmented lungs obtained before (T1) and after (T2) treatment with aeroGM-CSF therapy. The metric was change in voxel numbers above a limit defined by the crossover of the T1 and T2 histograms (Fig 2). Additional calculations for total lung volume (tissue plus airspace), airspace volume, lung weight, and lung inflation were also obtained for both tests using CT morphometry techniques developed by Perez et al.10

Figure Jump LinkFigure 2 Frequency distribution of lung density (HU) normalized, expressed as volume/1,000 before and after aeroGM-CSF treatment for patient 1 (top, A) and patient 2 (bottom, B). Black lines depict frequency distribution by volume prior to treatment and gray lines after treatment. The cross-over point (black arrow) defines the CT densities in the histograms above which the effect of aeroGM-CSF therapy can be detected. Note the shift of the lung density curve to the left, reflecting an overall decrease in lung density (ie, improvement in GGOs after treatment).Grahic Jump Location

The characteristics of the two female adolescents (ages 16 and 19 years) before and after treatment with aeroGM-CSF are presented in Table 1. AeroGM-CSF was well tolerated by both patients, without untoward sequelae. For both patients, serum GM-CSF autoantibody levels increased after aeroGM-CSF therapy, while serum SP-D decreased in patient 1; T1 and T2 comparisons for SP-D were not available for patient 2. Both patients had a favorable response to therapy with increases in body weight, resting oxygen saturation, and improvements in PFTs (Table 1). On chest auscultation, patient 1 had improved aeration, while patient 2 continued to demonstrate decreased breath sounds and mild coarse rhonchi in the bibasilar regions. The findings on the CT scans in both patients also indicated favorable responses to treatment (Tables 1, 2). The response to therapy was more favorable in patient 1 (greater improvement in lung volumes, flow rates, lung inflation, and GGOs), whose disease was less severe and of shorter duration than that in patient 2. Nonetheless, aeroGM-CSF was associated with substantial clinical improvement in both patients. Despite more advanced and prolonged disease in patient 2, there were still substantial improvements in diffusion capacity, alveolar-arterial oxygen gradient, pulse oximetry measurements during the 6-min walk test, CT-derived lung inflation, and GGOs.

Table Graphic Jump Location
Table 1 Characteristics for Two Patients With APAP Before (T1) and After (T2) Treatment With aeroGM-CSF Therapy

*Postbronchodilator value.

Table Graphic Jump Location
Table 2 Quantitative Chest CT Measurements in Two Adolescent Females Before and After Treatment With aeroGM-CSF Therapy

This report describes two cases of APAP demonstrating the benefits of quantitative CT measurements in ascertaining precise improvements in lung parenchyma as a result of aeroGM-CSF therapy. In both patients significant improvements were noted in all quantitative CT parameters after 8 months of aeroGM-CSF. These changes were consistent with improvements in clinical parameters, PFTs, and pulse oximetry during the 6-min walk test. In our assessment of changes in GGOs, we evaluated histograms in HU from chest CT scans performed before and after treatment. The limit set by the cross-over of the histograms would, like any binary limit, be arbitrary, except that it defines the densities in the histograms above which the effect of therapy (aeroGM-CSF) can be detected. With aeroGM-CSF, both patients showed substantial increases in normal low density (lower HU) voxels and improvement in GGOs, suggesting that aeroGM-CSF therapy is effective in mild to severe APAP. In patient 1, there was nearly complete clearing of previous GGOs and substantial improvement in lung inflation on the follow-up chest CT scan. In patient 2, substantial improvements were demonstrated by quantitative CT parameters, despite the persistence of GGOs and inter-/intra-lobular septal thickening, reflective of the more advanced and chronic disease. Thus, aeroGM-CSF provided a beneficial effect even in the presence of advanced disease, an effect more easily appreciated with the quantitative tools applied in the present study.

To our knowledge, this is the first report on the use of quantitative CT measurements to assess the effect of aeroGM-CSF therapy in patients with APAP. Using this methodology, we were able to demonstrate improvements in regional lung parenchymal GGOs and concomitant increases in airspace volume and lung inflation after aeroGM-CSF therapy. This approach is beneficial because clinical improvements and changes in global pulmonary function measures as a result of therapy can be directly related to changes in quantitative GGO and CT morphometry obtained on chest CT scans during clinical interventions. Such changes may be difficult to appreciate if CT scans are subjected to qualitative analysis alone. While both quantitative CT and spirometry had differing amounts of improvement in the present cases, the two modalities can be considered complementary as quantitative CT provided predominantly morphologic information while spirometry provided functional information. Both modalities were important in the analysis of overall response to aeroGM-CSF therapy.

Several studies have previously demonstrated the beneficial effects of aeroGM-CSF therapy on clinical parameters,4,5 lung function measurements,6,7 and radiographic imaging6,7; however, the direct benefit of aeroGM-CSF therapy on structural changes in APAP has not been previously demonstrated. In contrast to five APAP patients treated with either single or sequential whole lung lavage,10 our two patients treated with aeroGM-CSF experienced greater improvement in CT morphometry. The greater improvements noted in these two patients could be due to the greater effectiveness of aeroGM-CSF therapy, but no definitive conclusions can be drawn given the differences in the patient populations (age, duration of disease) and the limited number of patients in both studies.

The CT measurements noted in this case report are derived from one of several quantitative techniques developed over the last 10 years. These techniques use CT postprocessing algorithms to evaluate pulmonary pathology in asthma, cystic fibrosis, emphysema, and interstitial lung diseases.818 For example, quantitative bronchial airway and air trapping measurements have been used to compare the response in asthma patients to two different formulations of inhaled corticosteroids.8 Quantitative air trapping measurements have also been used to evaluate response to dornase alfa aerosol in children with mild cystic fibrosis lung disease,17 and quantitative measurements of emphysema severity and distribution have been used in the National Emphysema Treatment Trial.18

The major limitation of this case report is that the quantitative CT analysis before and after aeroGM-CSF therapy was performed in only two subjects. Our use of quantitative CT as defined in the present report is also inherently limited by the requirement for serial evaluation. In contrast, quantitative chest CT techniques designed to evaluate disease severity as opposed to response to therapy, may require only a single CT scan. Clearly repeat evaluation increases exposure to radiation, especially if CT scans are obtained with adult CT protocol settings (120 to 140 kVp [radiograph tube voltage] and ≥ 100 mAs [tube current × exposure time]). In our first patient, the initial CT scanner settings were 120 kVp radiograph tube voltage with a higher tube current × exposure time of 155 mAs. Because we were concerned about radiation exposure on follow-up scans, the tube current × exposure time for the second scan was reduced to 100 mAs. In our second patient, who had a baseline CT scan after the first patient's baseline CT scan, we established a lower dose protocol of 120 kVp radiograph tube voltage, and 100 mAs tube current × exposure time. We have recently explored further reduction in radiation dose by using a lower dose chest CT protocol in one of our patients with APAP: 100 kVp radiograph tube voltage and 45 mAs tube current × exposure time.

The present results provide justification for a prospective randomized trial of aerosolized GM-CSF therapy wherein quantitative CT techniques and pulmonary function measurements are applied to patients with APAP. In conclusion, our study demonstrates that quantitative measurements of CT changes may significantly contribute to the longitudinal evaluation of the response to medical interventions such as aeroGM-CSF. The use of quantitative analysis of CT scans may be more broadly applicable to other chronic pediatric pulmonary diseases as well.

aeroGM-CSF

aerosolized granulocyte-macrophage colony-stimulating factor

APAP

autoimmune pulmonary alveolar proteinosis

Dlco

diffusing capacity of the lung for carbon monoxide

FEF25–75%

forced expiratory flow, midexpiratory phase

GGO

ground-glass opacity

GM-CSF

granulocyte-macrophage colony-stimulating factor

HU

Hounsfield Units

PFT

pulmonary function test

SP-D

surfactant protein D

T1

test 1

T2

test 2

TLC

total lung capacity

Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003;349:2527-2539. [PubMed] [CrossRef]
 
Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chron Respir Dis. 2006;3:149-159. [PubMed]
 
Johkoh T, Itoh H, Muller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. 1999;211:155-160. [PubMed]
 
Tazawa R, Hamano E, Arai T, et al. Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2005;171:1142-1149. [PubMed]
 
Tazawa R, Nakata K, Inoue Y, et al. Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long-term treatment with aerosolized granulocyte-macrophage colony-stimulating factor: a case report. Respirology. 2006;11suppl:S61-S64. [PubMed]
 
Price A, Manson D, Cutz E, et al. Pulmonary alveolar proteinosis associated with anti–GM-CSF antibodies in a child: successful treatment with inhaled GM-CSF. Pediatr Pulmonol. 2006;41:367-370. [PubMed]
 
Wylam ME, Ten R, Prakash UB, et al. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006;27:585-593. [PubMed]
 
Goldin JG, Tashkin DP, Kleerup EC, et al. Comparative effects of HFA- and CFC-beclomethasone dipropionate inhalation on small airways: assessment using functional helical thin-section computed tomography. J Allergy Clin Immunol. 1999;104:S258-S267. [PubMed]
 
King GG, Muller NL, Whittal KP, et al. An analysis algorithm for measuring airway lumen and wall areas from high-resolution computed tomography data. Am J Respir Crit Care Med. 2000;161:574-580. [PubMed]
 
Perez A, Coxson HO, Hogg JC, et al. Use of CT morphometry to detect changes in lung weight and gas volume. Chest. 2005;128:2471-2477. [PubMed]
 
Nakano Y, Whittall KP, Kalloger SE, et al. Development and validation of human airway analysis algorithm using multidetector row CT. Proc SPIE. 2002;4683:460-469
 
Goris ML, Zhu HJ, Blankenberg F, et al. An automated approach to quantitative air trapping measurements in mild cystic fibrosis. Chest. 2003;123:1655-1663. [PubMed]
 
Hoffman EA, Reinhardt JM, Sonka M, et al. Characterization of interstitial lung diseases via density-based and texture-based analysis of computed tomography images of lung structure and function. Acad Radiol. 2003;10:1104-1118. [PubMed]
 
Tschirren J, Hoffman EA, McLennan L, et al. Intrathoracic airway tree: segmentation and airway morphology analysis from low dose CT scans. IEEE Trans Med Imaging. 2005;24:1529-1539. [PubMed]
 
Venkatraman R, Raman R, Raman B, et al. Fully automated system for three-dimensional bronchial morphology analysis using volumetric multidetector computed tomography of the chest. J Digit Imaging. 2006;19:132-139. [PubMed]
 
Coxson HO, Quiney B, Sin DD, et al. Airway wall thickness assessed using computed tomography and optical coherence tomography. Am J Respir Crit Care Med. 2008;177:1201-1206. [PubMed]
 
Robinson TE, Goris ML, Zhu HJ, et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest. 2005;128:2327-2335. [PubMed]
 
Martinez FJ, Curtis JL, Sciurba F, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176:243-252. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Comparison of two female adolescents with APAP (top, A: patient 1; bottom, B: patient 2) before (T1) and after (T2) treatment with aeroGM-CSF therapy. Note significant changes in GGOs after ≥ 8 months of treatment. Also note persistent interlobular and intralobular thickening in patient 2, who had long-standing disease and probable fibrotic changes.Grahic Jump Location
Figure Jump LinkFigure 2 Frequency distribution of lung density (HU) normalized, expressed as volume/1,000 before and after aeroGM-CSF treatment for patient 1 (top, A) and patient 2 (bottom, B). Black lines depict frequency distribution by volume prior to treatment and gray lines after treatment. The cross-over point (black arrow) defines the CT densities in the histograms above which the effect of aeroGM-CSF therapy can be detected. Note the shift of the lung density curve to the left, reflecting an overall decrease in lung density (ie, improvement in GGOs after treatment).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Characteristics for Two Patients With APAP Before (T1) and After (T2) Treatment With aeroGM-CSF Therapy

*Postbronchodilator value.

Table Graphic Jump Location
Table 2 Quantitative Chest CT Measurements in Two Adolescent Females Before and After Treatment With aeroGM-CSF Therapy

References

Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003;349:2527-2539. [PubMed] [CrossRef]
 
Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chron Respir Dis. 2006;3:149-159. [PubMed]
 
Johkoh T, Itoh H, Muller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. 1999;211:155-160. [PubMed]
 
Tazawa R, Hamano E, Arai T, et al. Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2005;171:1142-1149. [PubMed]
 
Tazawa R, Nakata K, Inoue Y, et al. Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long-term treatment with aerosolized granulocyte-macrophage colony-stimulating factor: a case report. Respirology. 2006;11suppl:S61-S64. [PubMed]
 
Price A, Manson D, Cutz E, et al. Pulmonary alveolar proteinosis associated with anti–GM-CSF antibodies in a child: successful treatment with inhaled GM-CSF. Pediatr Pulmonol. 2006;41:367-370. [PubMed]
 
Wylam ME, Ten R, Prakash UB, et al. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006;27:585-593. [PubMed]
 
Goldin JG, Tashkin DP, Kleerup EC, et al. Comparative effects of HFA- and CFC-beclomethasone dipropionate inhalation on small airways: assessment using functional helical thin-section computed tomography. J Allergy Clin Immunol. 1999;104:S258-S267. [PubMed]
 
King GG, Muller NL, Whittal KP, et al. An analysis algorithm for measuring airway lumen and wall areas from high-resolution computed tomography data. Am J Respir Crit Care Med. 2000;161:574-580. [PubMed]
 
Perez A, Coxson HO, Hogg JC, et al. Use of CT morphometry to detect changes in lung weight and gas volume. Chest. 2005;128:2471-2477. [PubMed]
 
Nakano Y, Whittall KP, Kalloger SE, et al. Development and validation of human airway analysis algorithm using multidetector row CT. Proc SPIE. 2002;4683:460-469
 
Goris ML, Zhu HJ, Blankenberg F, et al. An automated approach to quantitative air trapping measurements in mild cystic fibrosis. Chest. 2003;123:1655-1663. [PubMed]
 
Hoffman EA, Reinhardt JM, Sonka M, et al. Characterization of interstitial lung diseases via density-based and texture-based analysis of computed tomography images of lung structure and function. Acad Radiol. 2003;10:1104-1118. [PubMed]
 
Tschirren J, Hoffman EA, McLennan L, et al. Intrathoracic airway tree: segmentation and airway morphology analysis from low dose CT scans. IEEE Trans Med Imaging. 2005;24:1529-1539. [PubMed]
 
Venkatraman R, Raman R, Raman B, et al. Fully automated system for three-dimensional bronchial morphology analysis using volumetric multidetector computed tomography of the chest. J Digit Imaging. 2006;19:132-139. [PubMed]
 
Coxson HO, Quiney B, Sin DD, et al. Airway wall thickness assessed using computed tomography and optical coherence tomography. Am J Respir Crit Care Med. 2008;177:1201-1206. [PubMed]
 
Robinson TE, Goris ML, Zhu HJ, et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest. 2005;128:2327-2335. [PubMed]
 
Martinez FJ, Curtis JL, Sciurba F, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176:243-252. [PubMed]
 
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