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DOI: 10.1148/radiol.2271011063
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(Radiology 2003;227:222-231.)
© RSNA, 2003

Thoracic Imaging

Thin-Section CT Findings in Flock Worker’s Lung, a Work-related Interstitial Lung Disease1

David A. Weiland, MD, David A. Lynch, MB, Steven P. Jensen, MD, John D. Newell, MD, David E. Miller, PhD, Robert S. Crausman, MD, Charles Kuhn, III, MD and David G. Kern, MD

1 From the Departments of Radiology of University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262 (D.A.W., D.A.L., S.P.J., J.D.N., D.E.M.); Brown University School of Medicine and Memorial Hospital of Rhode Island, Pawtucket (R.S.C., C.K.); and Penobscot Bay Medical Center, Rockport, Me (D.G.K.). From the 2000 RSNA scientific assembly. Received June 18, 2001; revision requested August 10; final revision received August 7, 2002; accepted August 22. Address correspondence to D.A.L. (e-mail: david.lynch@uchsc.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To characterize the thin-section computed tomographic (CT) features of flock worker’s lung (FWL) and to determine whether these features may be used to distinguish workers with FWL from flock workers who do not fulfill diagnostic criteria for FWL.

MATERIALS AND METHODS: Thin-section CT images obtained in 43 flock workers (including 11 with FWL) were reviewed independently by radiologists blinded to occupational and clinical details. CT features recorded included ground-glass opacities, consolidation, micronodules, reticular abnormality, and septal thickening. Thirty-five of the CT scans (including nine obtained in patients with FWL) were also studied by using quantitative image analysis. The Student t test was used to compare mean lung attenuation between the workers with FWL and those without it.

RESULTS: Every patient with FWL and 19 (59%) of the 32 exposed flock workers who did not meet criteria for the disease had an abnormal thin-section CT scan. The most common findings in FWL were ground-glass opacities and micronodules. Quantitative analysis showed a mean lung attenuation of -736.4 HU in patients with FWL, compared with -775.0 HU in workers without the disease (P < .05).

CONCLUSION: While ground-glass opacities, micronodules, or both were found in all cases of FWL, these abnormalities were also present in a substantial proportion of symptomatic flock workers who did not satisfy current criteria for FWL. Although nonspecific, these findings should suggest the diagnosis of FWL in exposed individuals.

© RSNA, 2003

Index terms: Images, analysis • Lung, CT, 60.12118 • Lung, function • Lung, ground-glass opacification • Lung, interstitial disease, 60.917 • Pneumoconiosis, 60.779


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A work-related interstitial lung disease has been described in the flocking industry (1–4). Flock is made by cutting cords or bundles of thin continuous nylon filaments into small fragments. The resulting small nylon filaments have multiple uses. One of the more common uses is to apply the flock to an adhesive-backed fabric to produce a velvety material that can be used in upholstery and luxury products. Twenty-four cases of interstitial lung disease have been identified to date at four separate flocking facilities in two different countries (4). These cases represent an occurrence rate of interstitial lung disease that is 50–250 times that expected (2,3). Presenting symptoms include persistent dry cough and dyspnea. All those affected have improved after they were removed from their work-related exposure; however, none has returned to his or her baseline level of health.

At biopsy, most patients have had a characteristic histologic pattern of lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia (5). The term flock worker’s lung (FWL) has been coined to describe the interstitial lung disease that develops in these workers (2). Proposed diagnostic criteria for FWL require (a) previous employment in the flocking industry, (b) persistent respiratory symptoms, and (c) histologic evidence of interstitial lung disease without better explanation. In the absence of biopsy findings, the histologic criterion may be replaced by the presence of all of the following: grossly abnormal cell count at bronchoalveolar lavage; restrictive lung function at pulmonaryfunction testing; and diffuse ground-glass opacity, micronodularity, or interstitial fibrosis at thin-section computed tomography (CT) (3,4).

While some chest radiographs obtained in patients with FWL show diffuse areas of reticulonodular or patchy infiltrates, others are normal. Thin-section CT, in contrast, has revealed abnormalities in all patients whose CT findings have been described, although at times the abnormalities were so subtle that they were overlooked (3). Patchy areas of ground-glass opacity are the most common finding, although diffuse micronodularity, areas of consolidation, and peripheral honeycombing are also seen (3).

In view of the reliability of thin-section CT, it may play a useful role in the early diagnosis and follow-up of patients with FWL. The goals of this study were to further characterize the thin-section CT features of this disease and to determine whether these features may be used to distinguish patients with FWL from unexposed individuals as well as from exposed flock workers who do not fulfill the diagnostic criteria for the disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Group
Eighty-seven subjects were included in the study. The 87 study subjects included 43 workers from a single flocking plant and 44 non–flock worker control subjects. The flock worker study group initially included all workers evaluated with thin-section CT for FWL. Two workers with silicosis and one with pulmonary histiocytosis X were excluded from the study cohort. The majority of the 43 flock workers were symptomatic: 11 were given a diagnosis of FWL, and the other 32 had been exposed to flock. These 32 exposed workers, who underwent thin-section CT because of pulmonary symptoms, did not meet the diagnostic criteria for the disease (Table 1).


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  		TABLE 1. Demographic Data for 43 Flock Workers

 
Nine of the 11 cases of FWL were diagnosed by means of open or transbronchial biopsy. The two remaining cases were diagnosed by using the triad of abnormal bronchoalveolar lavage findings, restrictive lung function, and thin-section CT findings of ground-glass opacities, micronodules, or interstitial fibrosis. The clinical features of these patients have previously been described (3,4), but neither of the previous articles included a systematic description of the imaging features, which is the focus of this report. The 43 flock workers were members of a group of approximately 200 production and nonproduction flock workers at a single flocking plant.

A group of 44 non–flock-exposed subjects that was composed of all patients who underwent thin-section CT for various other reasons at the same institution during the study period (May 1996 through November 1998) was included to ensure that the reviewers were truly blinded. This group included 11 subjects with a diagnosis of interstitial lung disease (unspecified interstitial lung disease in four subjects; idiopathic pulmonary fibrosis in two; and sarcoidosis, Wegener granulomatosis, lymphoid interstitial pneumonia, chronic eosinophilic pneumonia, and scleroderma in one each), seven with emphysema, and 26 with nonspecific pulmonary symptoms but no prior diagnosis of pulmonary disease.

All of the flock workers in the study underwent a complete physical examination, and all but one underwent pulmonary function testing, including spirometry, plethysmography for assessment of lung volume, and a single-breath test for measurement of diffusing capacity. The reference values used as the predicted normal values for the results of spirometry, lung volume testing, and diffusing capacity testing were those outlined by Crapo and colleagues (6–8). Our institutional review board did not require its approval or patient informed consent for this retrospective study.

Thin-Section CT
All images were obtained with the same HiSpeed Advantage helical scanner (GE Medical Systems, Milwaukee, Wis). One-millimeter-thick transverse images were obtained from the lung apices through the bases in 10-mm increments with subjects in the supine position. Images were reconstructed by using high-spatial-resolution techniques and retargeted to one lung. They were then photographed at a window width of 1,500 HU and a level of -700 HU. Five of the patients with FWL underwent follow-up CT examinations for evaluation of the resolution of the CT abnormalities.

Image Evaluation
The thin-section CT images were randomized and reviewed independently by two of three chest radiologists (D.A.L., J.D.N., S.P.J.). The radiologists were blinded to each patient’s occupational history, clinical history, and diagnosis. The right and left lungs were divided into three zones each, with the upper zone being at and above the aortic arch, the middle zone between the aortic arch and the inferior pulmonary vein, and the lower zone below the inferior pulmonary vein. The imaging features recorded included air trapping, ground-glass opacity, consolidation, large nodules (>=7 mm), micronodules (<7 mm), reticular opacities, honeycombing, and overall extent of disease.

The extent of disease for each of the above features was scored on a scale of 0–4, in which 0, 1, 2, 3, and 4 represented zonal involvement of 0%, 25% or less, 26%–50%, 51%–75%, and more than 75%, respectively. In addition, a score of 0 or 1 was used to identify the absence or presence, respectively, of each of the following features: septal thickening, traction bronchiectasis, other bronchiectasis, pleural effusion, and pleural thickening. An average score for the extent of disease was calculated for each zone by averaging the mean score for the right lung and that for the left lung between the two observers. This was done for each of the diagnostic categories; the results were then used to evaluate for any zonal predominance that may have existed among the cases of FWL.

For each category, a cumulative mean score for both lungs was also obtained and averaged between the two observers. Each reader provided a list of the three most likely differential diagnoses on the basis of the CT pattern. If a CT study was interpreted as yielding entirely normal results by one observer but not by the other, the images were reread by both radiologists simultaneously and a consensus was reached.

Pathologic Evaluation
Nine of the patients with FWL underwent biopsy (three biopsies were transbronchial and six were surgical). All biopsy results were interpreted by the same pathologist (C.K.). Nine histologic features (mural lymphocytes and germinal centers, smoker’s respiratory bronchiolitis, intraacinar lymphoid nodules, lymphocytes within the alveolar wall, fibrosis, alveolar macrophages, giant cells, eosinophils, and fibroblastic foci) were graded by using a four-point ordinal scale (0,1,2,3) to denote normal, mild, moderate, or severe intensity. The pathologic findings were directly compared with the CT findings. Occasionally, a specimen was inadequate for the assessment of a particular criterion.

Quantitative Analysis
For computer analysis, the study group was limited to those subjects for whom scans were available on optical disk. This group, therefore, included nine patients with FWL and 25 exposed flock workers who did not meet diagnostic criteria for the disease. Follow-up thin-section CT scans were available on disk for four of the patients with FWL and provided limited longitudinal data.

The thin-section CT scans were saved on Pioneer DEC-702 optical disks (Pioneer Communications of America, Upper Saddle River, NJ). The CT data were subsequently downloaded to a SUN workstation (SUN Microsystems, San Jose, Calif) and transferred across a local area network to a personal computer (Data Stor P5-166; Data Storage Marketing, Boulder, Colo). Each image was analyzed by using a program written in Interactive Data Language (IDL version 5.2; Research Systems, Boulder, Colo). The lungs were isolated on each CT image by using a semiautomated thresholding technique with upper and lower thresholds of -200 HU and -1,000 HU, respectively. The appearance of air within the trachea, the bronchial tree up to the bronchus intermedius, and the bowel was manually excluded from each image. A frequency histogram of the overall lung attenuation was then calculated for each subject. The mean lung attenuation, skewness, and kurtosis derived for each subject were then averaged among the individual study groups and compared.

Statistical Analysis
A statistical software package (JMP version 3.2.6; SAS Institute, Cary, NC) was used in the analysis of all data. The Student t test was used to compare mean lung density, skewness, and kurtosis among the study groups. {chi}2 tests (with Fisher exact tests when appropriate) were used to compare the prevalence of findings among groups. The Wilcoxon-Kruskal-Wallis test was used to compare the extent of CT abnormalities among groups. To determine interreader reliability for diagnosis of normal versus abnormal lung findings, a {kappa} score was calculated for each combination of readers. Spearman rank correlation coefficients were used to determine correlations between the thin-section CT results and the pathologic findings and pulmonary function data.

We examined five CT variables (ground-glass opacity, centrilobular nodules, consolidation, reticular abnormality, and overall extent of disease) in step-down regression models as independent predictors of worker group (multivariate logistic regression) and FEV1 and DLCO (multivariate linear regression). We used both the observer-scored version of the CT variables and a dichotomized version that assigned each variable a score of 1 if it was present on CT scans or a score of 0 if it was not. We entered all five CT variables into the initial models and then used changes in -2 log likelihood to remove variables from the models until a state was reached in which removal of any of the remaining variables created a significant change in the -2 log likelihood. We tested the final models for first-order interaction among the variables. A P value less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Table 2 summarizes the CT findings among subjects with FWL and among exposed workers without FWL. Every patient with the diagnosis of FWL had abnormal thin-section CT results. The extent of disease was reported as mild to moderate (ie, overall extent of disease was less than 50%) in six (55%) of the 11 cases of FWL and as severe (ie, overall extent of disease was greater than 50%) in five cases (45%). The most common abnormalities found were ground-glass opacity (10 [91%] of 11 cases) and micronodules (nine [82%] of 11 cases). Figures 1 and 2, respectively, show typical examples of ground-glass opacity and micronodules in two separate cases of FWL. Reticular opacities, traction bronchiectasis, septal thickening, and consolidation were also reported, but none was present in more than four of the 11 cases of FWL. Emphysema was found in one patient with FWL. Areas of hypoattenuation compatible with air trapping were seen in two cases, but the extent of this abnormality was slight. Pleural effusion was not seen, but pleural thickening was seen in one case. One patient had mild cylindric bronchiectasis. Large nodules were not seen in any patient. No zonal predominance was observed for any of the findings described.


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  		TABLE 2. Prevalence of Thin-Section CT Findings in 43 Flock Workers

 


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  		Figure 1. Transverse thin-section CT scan through the right lower lung lobe in a supine patient with FWL shows extensive ground-glass opacity (arrows).

 


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  		Figure 2. Transverse thin-section CT scan through the right upper lung lobe in a supine patient with FWL shows profuse micronodules (arrows).

 
Nineteen (59%) of the 32 exposed workers had abnormal thin-section CT results. Ground-glass opacity and micronodules, respectively, were reported in 26 (41%) and 32 (50%) of the 64 readings. Figure 3 shows micronodules that were observed in an exposed worker who did not meet the diagnostic criteria for FWL. Emphysema was found in two of the exposed workers. When we compared the pulmonary function data, we found that the 19 exposed workers without FWL but with abnormal CT results had a significantly lower DLCO than did the 13 with normal CT results (P < .05). However, there was no difference in spirometric results or lung volumes between the two groups.



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  		Figure 3. Transverse thin-section CT scan through the right midlung in a supine exposed worker who did not meet the diagnostic criteria for FWL shows profuse fine micronodules (arrows) with a pattern similar to that of hypersensivity pneumonitis.

 
The prevalence of ground-glass opacities, reticular opacities, and septal thickening was statistically greater among workers with FWL than among exposed workers who did not fulfill the diagnostic criteria for the disease (P < .05). The mean extent-of-disease scores for ground-glass opacities, reticular opacities, and consolidation, as well as the mean overall disease score, were also statistically higher among subjects with FWL (Table 3). There was no significant difference in the prevalence and mean extent-of-disease scores for micronodules between the two groups.


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  		TABLE 3. Group Mean Extent-of-Disease Scores ± SDs in 43 Flock Workers According to Category

 
The readers agreed that CT results were normal or abnormal 82% of the time. The {kappa} scores for the three readers indicated that overall agreement was fair to good ({kappa} = 0.37–0.66). A higher level of observer agreement (87%) occurred between the two more experienced readers. In the patients with FWL, the CT pattern was thought to resemble that of hypersensitivity pneumonitis or respiratory bronchiolitis in 13 (59%) of the 22 readings. Less commonly, the pattern was thought to resemble that of usual interstitial pneumonia (Fig 4), nonspecific interstitial pneumonia (Fig 5), or desquamative interstitial pneumonia. Other differential diagnostic considerations included collagen vascular disease and sarcoidosis. Similarly, in the exposed workers with an abnormal CT scan, the pattern was thought to resemble hypersensitivity pneumonitis or respiratory bronchiolitis in 40 (63%) of the 64 readings.



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  		Figure 4. Transverse thin-section CT scan through the right lower lung lobe in a prone patient with FWL shows subpleural-predominant reticular abnormalities (arrows) associated with honeycombing and traction bronchiectasis; this pattern is similar to that of usual interstitial pneumonia.

 


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  		Figure 5. Transverse thin-section CT scan through the right lower lung lobe in a supine patient with FWL shows extensive basal-predominant ground-glass opacity (arrows) similar to that seen in nonspecific interstitial pneumonia or desquamative interstitial pneumonia.

 
Quantitative analysis revealed that the mean lung density in patients with FWL was -736.4 HU, compared with -775.0 HU in exposed workers without disease (P < .05) (Fig 6a). Skewness was also significantly lower in patients with FWL (P < .05) (Fig 6b). However, there was no difference in kurtosis between the two groups (Fig 4).



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  		Figure 6a. Bar graphs show the results of quantitative analysis. The unshaded bars denote the patients with FWL, while the shaded bars denote the exposed workers. (a) Mean lung attenuation was significantly lower in workers with FWL than in exposed workers (P < .05). (b) Skewness was significantly lower in workers with FWL than in exposed workers (P < .05). (c) Kurtosis did not differ significantly between the two groups.

 


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  		Figure 6b. Bar graphs show the results of quantitative analysis. The unshaded bars denote the patients with FWL, while the shaded bars denote the exposed workers. (a) Mean lung attenuation was significantly lower in workers with FWL than in exposed workers (P < .05). (b) Skewness was significantly lower in workers with FWL than in exposed workers (P < .05). (c) Kurtosis did not differ significantly between the two groups.

 


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  		Figure 6c. Bar graphs show the results of quantitative analysis. The unshaded bars denote the patients with FWL, while the shaded bars denote the exposed workers. (a) Mean lung attenuation was significantly lower in workers with FWL than in exposed workers (P < .05). (b) Skewness was significantly lower in workers with FWL than in exposed workers (P < .05). (c) Kurtosis did not differ significantly between the two groups.

 
Of the five patients with FWL who underwent follow-up thin-section CT (mean follow-up period, 9 months; range, 3–20 months), all but one showed improvement in terms of the overall extent of disease (Fig 7a). The difference in the depicted extent of disease between initial and follow-up CT examinations, however, was not statistically significant. Furthermore, none of the CT scans obtained in these five patients was interpreted as normal at follow-up.



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  		Figure 7a. Graphs show results of analysis of follow-up CT data for five patients with FWL. (a) The overall visual extent of disease decreased in all but one patient (represented by the dotted line). (b) Mean lung attenuation decreased in all four patients for whom digital data were available (P < .05).

 


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  		Figure 7b. Graphs show results of analysis of follow-up CT data for five patients with FWL. (a) The overall visual extent of disease decreased in all but one patient (represented by the dotted line). (b) Mean lung attenuation decreased in all four patients for whom digital data were available (P < .05).

 
Results of computer analysis of data for four of the five patients with FWL who underwent follow-up imaging (mean follow-up period, 7 months; range, 2–20 months) revealed a decrease in mean lung attenuation (Table 4 and Fig 7b) and an increase in skewness and kurtosis in all cases (Table 4). The overall mean lung attenuation for the group decreased from -714.8 HU to -754.9 HU (P < .05). The group mean values for skewness and kurtosis increased from 1.37 to 1.66 and from 1.67 to 2.92, respectively. The changes in skewness and kurtosis were not statistically significant, perhaps because of the small sample size.


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  		TABLE 4. Results of Quantitative Analysis of CT Scans at Initial Presentation and Follow-up in Four Patients with FWL

 
Interestingly, the only patient (subject 8 in Table 4) who did not show improvement at visual scoring of overall extent of disease did show improvement at quantitative analysis of CT features. Figures 8a and 8b show the profound improvement observed at follow-up in one patient with FWL (subject 7 in Table 4) 3 months after the patient had stopped working at the flocking plant.



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  		Figure 8a. Transverse thin-section CT scans through the right midlung in a supine patient with FWL. (a) CT scan obtained before treatment shows patchy, peripheral areas of consolidation (arrows). Biopsy revealed organizing fibrous tissue within alveoli and widespread lymphocytic infiltrates with perivascular nodules. (b) CT scan obtained after the removal of the patient, who did not undergo steroid treatment, from work exposure shows substantial decrease in parenchymal opacity, with residual ground-glass opacity.

 


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  		Figure 8b. Transverse thin-section CT scans through the right midlung in a supine patient with FWL. (a) CT scan obtained before treatment shows patchy, peripheral areas of consolidation (arrows). Biopsy revealed organizing fibrous tissue within alveoli and widespread lymphocytic infiltrates with perivascular nodules. (b) CT scan obtained after the removal of the patient, who did not undergo steroid treatment, from work exposure shows substantial decrease in parenchymal opacity, with residual ground-glass opacity.

 
Table 5 shows the correlations between the pathologic findings and the presence of ground-glass opacities and micronodules and the overall extent of disease. The overall extent of disease at CT correlated with many of the indexes of pathologic abnormality, particularly the extent of fibrosis (Spearman {rho} = 0.74). The extent of ground-glass opacity also correlated with several of the pathologic indexes, particularly fibrosis (Spearman {rho} = 0.56).


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  		TABLE 5. Comparison of Spearman {rho} Correlation Coefficients Describing the Relationships between Pathologic and Thin-Section CT Findings in Patients with FWL Who Underwent Biopsy

 
Table 6 shows the associations between radiographic findings and the pulmonary function data in the exposed flock workers who underwent pulmonary function testing. There were significant correlations between the overall extent of disease and percent predicted FVC, FEV1, and DLCO (Fig 9). Ground-glass opacities showed significant correlation with percent predicted FVC, FEV1, TLC (Fig 10), FRC, RV, and DLCO. There was also a significant correlation between micronodules and both FEV1/FVC and percent predicted RV.


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  		TABLE 6. Spearman {rho} Correlation Coefficients Describing Relationship between Extent of CT Findings and Pulmonary Function Test Results in 42 Flock Workers, Including 11 Workers with Diagnosis of FWL

 


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  		Figure 9. Scatterplot with line of best fit for percent predicted DLCO versus overall extent of disease. There is an inverse correlation between extent of disease and percent predicted DLCO.

 


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  		Figure 10. Scatterplot with line of best fit for percent predicted TLC versus ground-glass opacity score. There is a weak inverse correlation between TLC and ground-glass opacity score.

 
Table 7 shows the parameter estimates, R2 values, and Wald significance test P values for the variables in the final logistic regression model regarding the extent of abnormality as scored at CT. There were no significant interactions among the variables in this or other final models. When the ability of CT features to enable prediction of the worker group (exposed workers versus workers with FWL) was evaluated, the extent of ground-glass opacity was the only feature that predicted the presence of FWL (estimate = 3.34, R2 = 0.49, P = .002). In fact, all subjects who had a ground-glass opacity score above 1.1 had FWL. In a dichotomized model, the presence of ground-glass opacity was the only feature that predicted the presence of FWL (estimate = 1.28, R2 = 0.17, P = .02).


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  		TABLE 7. Parameter Estimates and R2 values for Logistic Regression Model for Predicting FEV1 and DLCO on the Basis of Extent Scores at CT

 
Table 8 summarizes the correlations between the results of quantitative analysis of the CT images and those of pulmonary function tests in the exposed flock workers for whom images were available on disk. Mean lung attenuation showed significant correlation with FEV1/FVC and with percent predicted FVC, TLC (Fig 11), and FRC. All of these indexes except FEV1/FVC varied inversely with mean lung attenuation. The strongest correlations were between mean lung attenuation and both TLC (r = -0.49) and FRC (r = -0.51). Figure 11 shows a scatterplot of mean lung attenuation versus percent predicted TLC. Significant correlations were also found between skewness and kurtosis and FEV1/FVC and between skewness and kurtosis and percent predicted FVC, TLC, FRC, and RV.


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  		TABLE 8. Pearson Correlation Coefficients Describing the Relationship between Quantitative CT Results and Pulmonary Function Test Results in 34 Flock Workers, Including Nine Workers with the Diagnosis of FWL

 


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  		Figure 11. Scatterplot with line of best fit for percent predicted TLC versus mean lung attenuation. There is an inverse correlation between mean lung attenuation and TLC.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Interstitial lung disease in flock workers was reported in 1995 (1). Five workers from a Canadian plant that employed 88 workers developed a lung parenchymal abnormality that at biopsy (n = 3) was initially reported to represent desquamative interstitial pneumonitis and diffuse alveolar damage. At the time of presentation to the hospital, all five workers complained of cough and dyspnea of 5–7 days duration. From 1997–1998, eight more cases were reported from a separate manufacturing facility in the United States (3). Like the first five patients, the latter patients also had symptoms of progressive cough and dyspnea, and all improved after leaving the workplace, although none regained normal lung function. Biopsy (n = 7) revealed peribronchovascular interstitial lymphoid nodules, usually with germinal centers, and most of these patients had lymphocytic bronchiolitis and interstitial fibrosis, but none had granulomas; a reevaluation of the biopsy results for the Canadian cases revealed comparable findings.

In 1999, a clinical pathology workshop was organized to review the pathologic findings in 15 cases of FWL (5). A characteristic lesion common among cases of FWL was described as a lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia represented by lymphoid aggregates. Other features that were variably present included acute alveolar injury and increased macrophages with some areas that could be misinterpreted as desquamative interstitial pneumonitis. Fibrosis was not a predominant finding, and no granulomas were observed. In comparison, the classic histologic pattern of hypersensivity pneumonitis demonstrates lymphocytic interstitial infiltrates associated with noncaseating granulomas and bronchiolitis that can progress to interstitial fibrosis (9,10). The peribronchiolar distribution of the lymphocytic aggregates distinguishes FWL from lymphoid interstitial pneumonia. The pathologic findings in FWL may be similar to those of follicular bronchiolitis, but the peribronchiolar lymphocytic infiltration of FWL commonly extends into the adjacent parenchyma.

Initial assessment for potential environmental exposures in the flocking plants could not identify a known cause of interstitial lung disease. However, a large amount of respirable-sized nylon particles (of 3 µm in diameter or smaller) were collected during air sampling, and a possible etiologic role was suspected for these particles (2,3,11). Further studies have revealed that respirable-sized nylon fragments cause pulmonary toxicity when administered intratracheally to rats (12).

All of the patients with FWL described in the present report had abnormal thin-section CT scans. The most common findings were ground-glass opacities (91%) and micronodules (82%). These findings are consistent with those previously described by Kern et al (3). The changes were diffuse, involving the entire lung, and appeared similar to hypersensitivity pneumonitis or respiratory bronchiolitis at thin-section CT. FWL, hypersensitivity pneumonitis, and respiratory bronchiolitis all have a peribronchiolar pattern histologically; this may account for their similar thin-section CT features (5,9,10,13).

Interestingly, 59% of the exposed workers who did not fulfill diagnostic criteria for FWL had abnormal CT scans. It is unclear why such a large percentage of these individuals had abnormal imaging results. Given that all of these workers were symptomatic, it is possible that they had early or subclinical disease. There were several imaging features that enabled differentiation between the patients with FWL and the other exposed workers. First, the overall extent of disease was clearly less severe in the exposed workers without the diagnosis than in the group with FWL. In addition, ground-glass opacities, reticular opacities, and septal thickening were found in a greater percentage of patients with FWL. Furthermore, overall lung involvement was more extensive in the patients with FWL. However, the prevalence and extent of micronodules were more similar between the two groups. It seems likely that the micronodules seen in the exposed workers represented an early phase of FWL, perhaps a lymphocytic bronchiolitis.

Many of the thin-section CT findings in the cases of FWL were nonspecific. The differential diagnosis for ground-glass opacity, which was the most commonly reported abnormality, is extensive. It includes many of the diagnoses given by the readers in this study, including hypersensitivity pneumonitis, respiratory bronchiolitis, desquamative interstitial pneumonitis, and collagen vascular disease (13–18). The clinical history, the anatomic distribution of the opacities, and any corresponding parenchymal changes can be of some use in narrowing the group of differential diagnoses (15). However, none of the aforementioned factors is pathognomonic.

The finding of ground-glass opacities corresponds histologically to interstitial thickening or partial filling of alveoli with fluid or cellular material. The results of imaging and pathologic correlation in this study suggest that the extent of ground-glass opacity was related to the extent of alveolar macrophages, alveolar lymphocytes, and fibrosis, but the results did not provide a specific histologic explanation for the CT finding of micronodules. However, this may have been due to the small sample size. The only statistically significant CT-pathologic correlations were those between overall extent of disease and both histologic fibrosis and alveolar macrophages. However, there were also relatively strong correlations between the presence of ground-glass opacities and both fibrosis and alveolar macrophages; these correlations might have been statistically significant with a larger sample size.

Follow-up evaluation revealed improvement in all but one of the five patients with FWL in whom follow-up results were available. However, the change in the mean extent of disease for the entire group was not statistically significant. A statistically significant decrease in mean lung attenuation was revealed at follow-up in the four patients with FWL in whom results of quantitative analysis of CT images were available. This group of patients included the one patient in whom the grade of disease did not change at visual scoring. All five of the patients reported symptomatic improvement in their disease status; objective improvement was also observed at pulmonary function testing. However, none of the individuals had normal results at repeat CT scanning, just as none of them had regained normal pulmonary physiology.

The use of computer analysis has been described as a means of assessing interstitial lung disease (19,20). The quantitative results in this study are similar to those of prior studies (19). We found statistically significant correlations between quantitative features (mean attenuation, skewness, and kurtosis) and lung volumes. In addition, quantitative analysis of CT images revealed several differences in measured parameters between the patients with FWL and the exposed workers who did not have the disease. Mean lung attenuation was significantly greater in the patients with FWL. This finding may be related to the increased extent of ground-glass opacity that was reported by the independent readers in these patients. In addition, the skewness of the frequency histogram was statistically lower in the patients with FWL. However, the mean attenuation and skewness for the two groups showed substantial overlap.

Efforts to correlate pulmonary function test results with quantitative radiographic indexes revealed that the strongest correlations were with indicators of restrictive lung function (FVC and TLC). Interestingly, while the quantitative radiographic indexes showed no relation to DLCO, the overall extent of disease and ground-glass opacities as determined by the readers showed a strong inverse relationship. The reason for this is unclear.

In conclusion, the CT features of ground-glass opacities and micronodules, though nonspecific, should suggest the diagnosis of FWL in exposed individuals. In known cases of the disease, CT may be useful in tracking progression of the disease. The limited longitudinal data in this study revealed improvement in the CT findings, which correlated with symptomatic improvement. CT may play a role in screening those employed in the flocking industry and identifying those individuals with early signs of the disease who can most benefit from being removed from environmental exposure.


   ACKNOWLEDGMENTS
 
We thank James Murphy, PhD, of the National Jewish Medical and Research Center, for his valuable help with statistical analysis.


   FOOTNOTES
 
Abbreviations: DLCO = diffusion capacity of carbon monoxide, FEV1 = forced expiratory volume in 1 second, FRC = functional residual capacity, FVC = forced vital capacity, FWL = flock worker’s lung, RV = residual volume, TLC = total lung capacity

Author contributions: Guarantors of integrity of entire study, D.A.W., D.A.L., D.G.K.; study concepts and design, D.A.W., D.A.L.; literature research, D.A.W.; clinical studies, D.G.K., R.S.C.; data acquisition, D.A.L., S.P.J., J.D.N.; data analysis/interpretation, D.A.L., D.A.W., D.E.M.; statistical analysis, D.A.L., D.A.W.; manuscript preparation, D.A.W., D.G.K.; manuscript definition of intellectual content, D.A.W.; manuscript editing, revision/review, and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
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