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Flock Worker's Lung
occupational and environmental lung disease Flock Worker’s Lung* Broadening the Spectrum of Clinicopathology, Narrowing the Spectrum of Suspected Etiologies David G. Kern, MD; Charles Kuhn, III, MD; E. Wesley Ely, MD, FCCP; Glenn S. Pransky, MD; Curtis J. Mello, MD, FCCP; Armando E. Fraire, MD, FCCP; and Joachim Mu¨ller
Study objectives: Workers in the nylon flocking industry recently have been found to be at increased risk of chronic nongranulomatous interstitial lung disease. Although a spectrum of cytologic and histopathologic abnormalities has been observed, nonspecific interstitial pneumonia, lymphoid nodules, and lymphocytic bronchiolitis predominated in the 19 previously reported cases of flock worker’s lung. Here we describe five additional patients who appear to expand the histopathologic spectrum and add to the evidence suggesting a causative role for respirable-sized nylon fragments. Methods: We studied all North American patients (n 5 5) found in 1998 to satisfy our previous case definition of flock worker’s lung. Two pulmonary pathologists independently reviewed each biopsy specimen. Results: All five patients reported cough and dyspnea. Only one patient had crackles on chest auscultation. High-resolution CT scan, interpreted with attention to subtle ground-glass attenuation, remained a highly sensitive diagnostic test. Pulmonary function tests and plain chest radiograph were less sensitive. One patient’s wedge biopsy showed previously described prototypical findings. Two others had transbronchial biopsies showing some of the same features. The fourth patient’s wedge biopsy showed desquamative interstitial pneumonia. The fifth patient had bilateral synchronous adenocarcinoma but with radiographic evidence of diffuse interstitial fibrosis. These 5 patients and the 19 patients studied previously were exposed to nylon flock manufactured by a rarely used cutting technology. Conclusion: Findings in these five patients appear to broaden the spectrum of the clinicopathology of flock worker’s lung and add to the evidence incriminating respirable-sized nylon particulates produced during the manufacture and use of rotary-cut nylon flock. (CHEST 2000; 117:251–259) Key words: interstitial lung disease; nonspecific interstitial pneumonia; nylon; occupational lung disease Abbreviations: ANA 5 antinuclear antibody; DIP 5 desquamative interstitial pneumonia; HP 5 hypersensitivity pneumonitis; HRCT 5 high-resolution CT; NIOSH 5 National Institute for Occupational Safety and Health
*From the Departments of Medicine (Drs. Kern and Mello) and Pathology (Dr. Kuhn), Brown University, Providence, RI; the Department of Medicine (Dr. Ely), Vanderbilt University, Nashville, TN; the Departments of Medicine (Dr. Pransky) and Pathology (Dr. Fraire), University of Massachusetts, Worcester, MA; and EFT Consultants (Mr. Mu¨ller), Budingen, Germany. Supported, in part, by the Leonard J. Feldberg Memorial Fund. Manuscript received April 16, 1999; revision accepted June 24, 1999. Correspondence to: Charles Kuhn, III, MD, Department of Pathology, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860
we reported workers in the nylon flockR ecently, ing industry to be at markedly increased risk of a chronic interstitial lung disease characterized by bronchiolocentric nodular and diffuse lymphocytic For editorial comment see page 10 interstitial infiltrates, a lymphocytic bronchiolitis, and variable interstitial fibrosis.1 After working between 1 and 30 years at a Rhode Island textile CHEST / 117 / 1 / JANUARY, 2000
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plant that employs , 200 people, the 8 individuals so affected experienced the onset of persistent dry cough and dyspnea with or without atypical chest pain. Most had crackles on chest examination. Chest radiographs either were normal or showed diffuse reticulonodular or patchy infiltrates. High-resolution CT (HRCT) scans showed patchy ground-glass opacity, scattered areas of consolidation, diffuse micronodularity, or peripheral honeycombing. Pulmonary function testing generally showed restrictive, although occasionally obstructive or normal, physiology. BAL revealed eosinophilia (. 25%) or lymphocytosis (. 30%), with or without neutrophilia. All those affected had symptomatic, radiographic, and functional improvement within weeks to months of leaving work, but in none was recovery complete. Calculations of standardized incidence ratios revealed rates of interstitial lung disease for flock workers to be 48 to 250 times higher than those for the general population.1 To date, 19 cases of what has been termed flock worker’s lung have been reported among Rhode Island, Massachusetts, and Ontario workers.1,2 Here, we describe five additional, more recently identified cases, including four that arose among workers employed at the two index sites of disease in the United States, and the first case from North Carolina. As with all previously described cases, the five were exposed to nylon flock manufactured by a rarely used cutting technology. Findings in these cases appear to broaden the spectrum of the clinicopathology of flock worker’s lung and add to the evidence incriminating rotary-cut nylon flock.
Background The flocking industry produces fleeced fabric and plush objects for use in the manufacture of upholstery, clothing, carpets, automobiles, and novelty items. Flock manufacturers cut nylon, rayon, polyester, and other natural and synthetic fibers, as well as textile waste, to produce a powder of short fibers (0.2 to 5.0 mm), termed flock. This material subsequently is applied (flocked) to adhesive-coated fabrics and other objects to impart a velvety surface. Some companies only manufacture flock, others solely do flocking, and others do both. At the high-quality end of the industry, flock manufacturers cut flock from long cables (tow) of parallel monofilaments of nylon, rayon, or polyester. With but two known exceptions in the world, manufacturers cut tow with guillotines and in doing so produce fibers of precisely defined length (6 5%), termed precision-cut flock. Guillotine-cut flock may be dyed before it is bath-finished, dried, screened, 252
and bagged. As guillotine blades become dull, a tell-tale tone signals their need to be sharpened. Two large North American flock manufacturers, in contrast, cut nylon tow with rotary cutters, which generate fibers of less-precisely defined length (6 20%), termed random-cut flock. In this process, which is much faster than that using guillotine cutters, tow is dyed, finished, cut, dried, screened, and bagged in one continuous operation. However, as rotary-cutter blades become dull, it is difficult to detect a tone change; increasing friction results in rising blade temperatures, and nylon tow may be cut uncleanly, melted, or both. Nylon flock produced under such conditions is more likely to have tiny protuberances, which during subsequent processing may be released as respirable-sized particles (aerodynamic diameter , 10 mm). Quality-control inspectors have described such protuberances on flock fibers, and investigators from the National Institute for Occupational Safety and Health (NIOSH) have demonstrated their presence both in bulk samples of rotary-cut flock and as respirable-sized particles in work-room air.3 Notably, recent intratracheal instillation studies in rats have suggested that respirablesized nylon particles have substantial pulmonary toxicity.4 All 19 workers reported thus far to have flock worker’s lung1,2 were exposed to rotary-cut flock. Of the 19, 17 were employees of a single company (8 in Rhode Island, 9 in Kingston, Ontario) that manufactures both flock and flocked fabric. The two other affected workers were exposed to flock made by a Massachusetts company, one of the largest flock suppliers in North America; one worker was exposed at the flock manufacturing company itself, and the other worker at the flocking facility of one of its nearby customers. Of the five additional patients to be described in this report, one was employed at the index Massachusetts flock manufacturing facility, three at the index Rhode Island facility, and one at the North Carolina plant of the latter company.
Materials and Methods We included all North American patients (n 5 5) found in 1998 to satisfy our previously articulated case definition of flock worker’s lung: persistent respiratory symptoms, previous work in the flocking industry, and histologic evidence of interstitial lung disease without better explanation.1 Moreover, as before, in the absence of a tissue specimen, the triad of an abnormal distribution of cell types on BAL, restrictive lung function, and HRCT findings of diffuse ground-glass opacity or micronodularity (or obvious fibrosis) was allowed to serve as a surrogate for the histologic criterion.1 We used the pulmonary function reference values of Crapo and colleagues5–7 and the severity scale of the American Medical Association.8 Two pulmonary pathologists (CK Occupational and Environmental Lung Disease
Table 1—Pulmonary Function Test Results at Time of Diagnosis* Case No. Test
1
2
3
4
5
FEV1, L FVC, L TLC, L Dlco, mL/min/mm Hg
3.83 (86) 5.15 (95) 7.10 (103) 30.2 (75)
2.24 (55) 2.73 (55) — —
1.79 (62) 2.36 (62) 4.07 (64) 7.41 (28)
3.60 (78) 4.76 (86) 6.43 (92) 26.2 (63)
2.34 (52) 2.90 (52) 4.72 (64) 9.20 (23)
*Values are presented as absolute (percent of predicted normal values taken from Crapo et al5–7); Dlco 5 diffusing capacity of the lung for carbon monoxide; TLC 5 total lung capacity.
and AEF) independently reviewed the four biopsy specimens. In three, there was complete agreement on the features present; in the fourth, a minor discrepancy was resolved by re-review and discussion.
Case 1 A 30-year-old white male textile worker reported the sudden onset of wheezing and shortness of breath at work in March 1997, 1 year after beginning employment at the index facility in Rhode Island. The following day, spirometry was normal and asthma was diagnosed. Inhaled corticosteroids and b-agonists were initiated without subjective benefit as the patient developed grade II dyspnea, frequent prolonged substernal chest pressure, occasional wheezing, and a minimal nonproductive cough. During the subsequent 8 months, within 2 hours of leaving the plant each day, he would become asymptomatic. During the next 4 months, however, his symptoms became persistent. The patient had never smoked and had no history of atopic illness. A brother was reported to have asthma. At the time of his referral in March 1998, the patient had been working for 2 years in the cutting department, immediately adjacent to the work station of a coworker previously found to have biopsy-confirmed flock worker’s lung. Physical examination revealed no abnormalities. Chest radiographs were normal. Pulmonary function test results (Table 1) were reported to be normal although the diffusing capacity was mildly reduced according to the reference values of Crapo and Morris.7 In any case, the results were identical to those recorded 2 years earlier by NIOSH just 2 weeks after the patient began working at the company. After a 2-week period off all medications, the patient was found to have normal airway responsiveness (ie, dose provoking a 20% decrement in FEV1 was 189 cumulative U of methacholine). An HRCT scan was officially interpreted as normal, but one of the authors and a consulting pulmonologist concluded that there were gravityindependent areas of patchy ground-glass opacity in the lower lung fields bilaterally (Fig 1, top, A).
After a 2-week period out of work, without change in symptoms, the patient proceeded to BAL and transbronchial biopsy. BAL revealed 10% neutrophils and 15% lymphocytes, exceeding the upper limit of the 95% confidence interval for these values in our laboratory.9 Biopsy revealed minimal interstitial lymphocytic infiltrates and a lymphoid nodule in the specimen’s only respiratory bronchiole (Fig 1, bottom, B). Rheumatoid factor was negative, antinuclear antibody (ANA) was positive at a titer of 1:80 in a speckled pattern, and CBC count and differential
Figure 1. Case 1. Top, A: HRCT shows subtle ground-glass opacity. Bottom, B: transbronchial biopsy shows a nodule of lymphocytes in the only respiratory bronchiole present in the biopsy specimen (hematoxylin-eosin, original 3 240). CHEST / 117 / 1 / JANUARY, 2000
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blood count were within the normal range. Within 4 months of leaving work, the patient no longer was having respiratory symptoms, his pulmonary function was unchanged, his ANA was negative, and his previously equivocal HRCT scan findings were less apparent. Case 2 A 38-year-old white male textile worker had right posterior pleuritic chest pain in March 1998 and, a week later, dyspnea on effort. His chest pain disappeared shortly thereafter, but when his dyspnea persisted for 6 weeks, he was referred for pulmonary evaluation to one of the authors. Two decades earlier, the patient had worked at the index facility in Rhode Island for 2 years. Subsequently, he spent 10 years repairing automobiles and 6 years as a shipyard welder building new submarines. He then returned to the flock manufacturing facility and worked for 6 years as a screen printer on the mezzanine above the cutting and flocking departments before developing the symptoms that prompted his evaluation. An active 50-pack-year smoker, the patient denied medical history of note other than for sinus surgery. Physical examination revealed no abnormalities. Chest radiographs revealed subtle haziness and equivocal reticular infiltrates. FEV1 and FVC were 55% of predicted, and FEV1/FVC was 99% of predicted (Table 1). After remaining out of work for 5 weeks, he felt somewhat better, his FEV1 and FVC increased substantially to 84% of predicted, and his airway responsiveness to methacholine challenge was normal. An HRCT scan revealed striking diffuse ground-glass opacity, assuming a macronodular appearance in some areas, and prominent subpleural interlobular septa (Fig 2, top, A). Rheumatoid factor, ANA, and antinuclear cytoplasmic antibody were negative. Erythrocyte sedimentation rate was 15 mm/h. CBC count and leukocyte differential were normal. Four weeks later, an open lung biopsy revealed a monotonous homogeneous pattern of intra-alveolar macrophages, mild interstitial fibrosis, and occasional lymphoid aggregates in the walls of small airways, compatible with desquamative interstitial pneumonia (DIP; Fig 2, bottom, B). Prednisone therapy, 60 mg qd, was initiated. Two months later, the patient was still smoking, taking prednisone, and experiencing mild dyspnea on effort. Full pulmonary function testing revealed the following: a further improvement in FVC; total lung capacity, 90% of predicted; residual volume, 54% of predicted; and single-breath diffusing capacity, 82% of predicted. Although the patient’s FVC and diffusing capacity measurements by then were both nor254
Figure 2. Case 2. Top, A: HRCT shows striking ground-glass opacity, assuming a macronodular appearance in some areas, and prominent subpleural interlobular septa. Bottom, B: open lung biopsy showing typical histopathology of DIP, alveoli packed with macrophages, and slight thickening of alveolar walls with mild inflammation (hematoxylin-eosin, original 3 150).
mal and essentially the same as those recorded by NIOSH personnel 2 years earlier when the patient was asymptomatic, and although his chest radiographs no longer showed diffuse haziness, a repeat HRCT scan showed extensive diffuse ground-glass opacity without improvement. Six months later, the patient reported no change in symptoms, he was still smoking, prednisone was being tapered, an HRCT scan showed no change, and his pulmonary function remained stable other than for a 20% decline in diffusing capacity. Case 3 A 77-year-old retired white male textile worker was admitted to the Memorial Hospital of Rhode Island in January 1996 for presumed pneumonia and parapneumonic effusion. At the time, he reported a Occupational and Environmental Lung Disease
1- to 2-year history of dyspnea on effort and a minimally productive chronic cough. A former 33pack-year smoker, he had discontinued all tobacco use 36 years earlier. Further evaluation revealed ill-defined synchronous bilateral pulmonary adenocarcinomas detected both by BAL and percutaneous needle biopsies. Other than for 4 years of military service, the patient had worked in the textile industry from 1934 to 1983 and had no known occupational or familial exposures to asbestos. After cancer was diagnosed, the patient received carboplatin, paclitaxel, and vinorelbine for 15 months without evidence of disease progression. Radiation was not administered. In April 1997, on reading in the newspapers about an outbreak of interstitial lung disease at the index plant, he asked to be evaluated by one of the authors and queried whether his illness might have been caused by his 20-year tenure at the Rhode Island plant. He reported working in the cutting and finishing departments from 1964 to 1970, and, subsequently, performing machine maintenance throughout the plant from 1970 to 1983. At the time of his referral, physical examination revealed an elderly deaf man in no apparent distress. Chest auscultation revealed inspiratory crackles over the lower lung fields bilaterally. The patient’s pulmonary function test results of the preceding 15 months revealed mild restriction and a severe diffusion impairment. Review of a previous CT scan without high-resolution imaging raised the possibility of diffuse interstitial lung disease. An HRCT was ordered and showed the previously appreciated illdefined basilar tumor masses but also bilateral peripherally distributed reticular infiltrates and prominent subpleural interlobular septa (Fig 3). Fourteen months later, in July 1998, HRCT scan showed no change. Case 4 A 25-year-old Hispanic white male textile worker presented in February 1998 with a 2- to 3-month history of worsening dyspnea on effort, dry cough, and the more recent onset of substernal burning discomfort on deep inspiration. At the time, he had been working for 2.5 years in the cutting department of a large Massachusetts flock manufacturing plant where a coworker previously had been found to have flock worker’s lung. The patient had never smoked, and denied history of atopic illness, previous respiratory disease, and exposure to agents known to cause hypersensitivity pneumonitis (HP). His mother was reported to have asthma. Chest auscultation revealed clear lung fields. The patient coughed throughout spirometry, making it difficult to interpret the results; FEV1 and FVC were both
Figure 3. Case 3. HRCT shows peripherally distributed reticular infiltrates and prominent subpleural interlobular septa.
found to be approximately 1 L lower than his normal baseline values established 17 months earlier. Chest radiographs were formally interpreted as being normal, but the treating physician detected subtle patchy areas of haziness at both the lung bases and the periphery of the right upper and middle lobes. An HRCT scan revealed definite areas of patchy ground-glass opacity. On the recommendation of his physician, the patient left work and began prednisone. When seen a few weeks later at the University of Massachusetts Medical Center, he reported feeling better. Physical examination revealed no abnormalities. Pulmonary function was reported to be normal other than for borderline-low FEV1 and diffusing capacity; the patient’s FEV1 was 500 mL lower than his normal baseline value, and his diffusing capacity was definitely reduced according to the reference values of Crapo and Morris.7 Mild airway hyperresponsiveness to methacholine challenge was demonstrated (dose provoking a 20% decrement in the FEV1 was 6.14 mmols). A follow-up HRCT scan was formally interpreted as normal other than for a small number of peripheral small densities, raising the possibility of minimal bronchiolitis. Prednisone was discontinued, and 3 weeks later, the patient returned to work. A day or two later, his symptoms CHEST / 117 / 1 / JANUARY, 2000
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Figure 4. Case 4. Top, A: HRCT shows patchy ground-glass opacity and focal areas of frank consolidation. Bottom, B: open lung biopsy shows nodules of lymphocytes (top) and widespread thickening and chronic inflammation of alveolar walls. This is the most common histologic pattern we have seen in flock workers (hematoxylin-eosin, original 3 60).
recurred and then gradually worsened over the following month, prompting him to leave work again. An HRCT scan at the time (Fig 4, top, A) revealed bilateral patchy ground-glass opacity and focal areas of frank consolidation. Rheumatoid factor and ANA were negative. Erythrocyte sedimentation rate, WBC count, and leukocyte differential were normal. Two weeks later, thoracoscopic lung biopsy revealed lymphoplasmacytic bronchiolitis, lymphoid hyperplasia, lymphocytic interstitial infiltrates, and fibroblastic foci (Fig 4, bottom, B). Shortly thereafter, prednisone was resumed, quickly tapered, and discontinued after 6 months of treatment. One month before prednisone was discontinued, pulmonary function testing revealed FEV1 and FVC to be 1 L lower than his normal baseline values and his diffusing capacity to be stable. When last seen, 1 year after first presenting, he reported a stable persistent cough and dyspnea on effort. Case 5 A 37-year-old year white male textile worker presented with severe shortness of breath in January 256
1998 to the Baptist Hospital Medical Center in Winston-Salem, NC. Six years earlier, he had begun working at an area plant (owned by the index Rhode Island company) engaged in the manufacture of flock and flocked fabrics. After a 2-year period in the flock room, he had worked continuously for 4 years in the cutting department. Toward the end of his second year in the flock room, he developed a nonproductive cough and mild dyspnea on effort and was given a symptom-based diagnosis of asthma. After moving to the cutting department, he continued to experience dyspnea, which slowly progressed. Bronchodilators and inhaled corticosteroids provided negligible relief. Six weeks before admission, as his dyspnea intensified, he noticed that he was less short of breath each time he stayed out of work for a few days. A trial of clarithromycin brought no relief. At the time of presentation, the patient also reported a mild nonproductive cough, intermittent cyanosis, mild anorexia, and a 20-lb weight loss over the prior month. A former 20-pack-year smoker, the patient had stopped all tobacco use 5 years earlier. He denied history of atopy, previous respiratory illness, and exposure to potential causes of HP other than a pet ferret. Physical examination revealed a well-nourished cyanotic man in obvious respiratory distress who was afebrile with a heart rate of 122 beats/min, respiratory rate 24 breaths/min, and BP of 111/66 mm Hg. His lungs were clear to auscultation, and the remainder of his examination was normal as well. Chest radiographs revealed bilateral reticulonodular infiltrates. An arterial blood gas on room air revealed pH of 7.42, Paco2 of 36 mm Hg, and Pao2 of 47 mm Hg. The patient was hospitalized, and oxygen was administered. An HRCT scan revealed patchy ground-glass opacity assuming a macronodular appearance in some areas (Fig 5, top, A). Pulmonary function testing (Table 1) revealed moderate restriction, a severe impairment of diffusion, and no obstruction. CBC count and leukocyte differential were normal and rheumatoid factor, ANA, and an HP panel of precipitins were negative. On the fourth hospital day, BAL revealed 35% neutrophils and 7% eosinophils. Transbronchial biopsy revealed modest nodular and diffuse mononuclear cell interstitial infiltrates, moderate interstitial fibrosis, and lesser amounts of intraalveolar macrophages and fibroblastic foci, findings consistent with nonspecific interstitial pneumonia (Fig 5, bottom, B). The patient was discharged on prednisone, 60 mm qd, and supplemental oxygen. Six weeks later, he felt much better, he was no longer using supplemental oxygen, and most of his radiographic infiltrates had resolved. Prednisone was tapered and discontinued within 6 months of its being started. Occupational and Environmental Lung Disease
Figure 5. Case 5. Top, A: HRCT shows ground-glass opacity assuming a macronodular appearance in some areas. Bottom, B: transbronchial biopsy shows moderately severe thickening and mononuclear infiltration of airspace walls and focal epithelial hyperplasia consistent with nonspecific interstitial pneumonia (hematoxylin-eosin, original 3 150).
Near the end of the treatment course, with the patient still out of work, his diffusing capacity had improved from 23% of predicted to 46% of predicted. One year after hospital discharge, the patient remained on inhaled corticosteroids and b-agonists, in an effort to control his intermittent dyspnea. By then, his spirometry and lung volumes had become normal, but his diffusing capacity had improved no further. He currently works in the company’s warehouse. Discussion Each of the five patients described here reported chronic dyspnea and dry cough with or without atypical chest pain, just as did the first eight patients defined to have flock worker’s lung.1 Crackles were all but absent in the current series, despite their presence in all but one of our previous patients. Pulmonary function testing generally revealed restriction and impaired diffusion. Consistent with our previous findings, however, one of the five patients was reported to have normal lung function; notably, another recovered his previously established normal
baseline level of lung function despite the fact that his HRCT scan remained grossly abnormal. Chest radiographs were not reliably informative. HRCT scans, however, if interpreted with a liberal diagnostic threshold, were considered abnormal for all five patients just as they had been for the first eight patients we described. Yet, once again, in disagreement with the treating physicians, hospital radiologists occasionally concluded that an HRCT scan was normal when biopsy would later confirm the presence of disease. The two patients who had BAL cell counts showed an excessive proportion of neutrophils; one also showed a slightly increased proportion of lymphocytes, and the other an increased proportion of eosinophils. As with our initial series, BAL findings were nonspecific. In our previous report,1 we concluded that the observed histopathologic findings of flock worker’s lung were most readily encompassed by the term nonspecific interstitial pneumonia as defined by various authors.10 –12 We noted that whereas all of our patients with biopsies had nodular peribronchovascular lymphocytic infiltrates, and that most also had diffuse lymphocytic interstitial infiltrates, germinal centers, and lymphocytic bronchiolitis, there was considerable variation. In fact, one patient had findings of bronchiolitis obliterans organizing pneumonia, and another had findings consistent with usual interstitial pneumonia. Yet, in both cases, there were a striking number of peribronchovascular lymphoid nodules. The report of a recently convened NIOSH workshop on flock worker’s lung emphasizes the central role of a lymphocytic bronchiolitis and peribronchiolitis with associated lymphoid nodules in the histopathologic recognition of this condition.2 Although the emphasis is deserved, we believe the workshop report underemphasizes the accompanying diffuse interstitial inflammation that is responsible presumably for the severely reduced diffusing capacity and interstitial fibrosis observed in a number of our patients. Furthermore, given the relatively small number of cases described to date, the vagaries of lung biopsy, and the potential for varying host responses, we believe it would be premature to conclude that the causative agents responsible for flock worker’s lung cause but a single stereotypic response pattern. Consequently, for the time being, we continue to prefer our previously articulated case definition, namely: persistent respiratory symptoms, previous work in the flocking industry, and histologic evidence of interstitial lung disease without better explanation. Moreover, in the absence of a tissue specimen, we believe that the triad of an abnormal distribution of cell types on BAL, restrictive lung function, and HRCT findings of diffuse ground-glass CHEST / 117 / 1 / JANUARY, 2000
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opacity or micronodularity (or obvious fibrosis) may serve as a surrogate for the histologic criterion. All five of the cases described herein satisfy this case definition. The severity and acuity of illness in the five patients ranged from minor to severe. The marked subtlety of the radiographic and pathologic findings observed in one patient (case 1) raises the possibility that if asymptomatic flock workers were investigated as intensely, similar findings might be detected. Whether individuals having such minimal abnormalities are less likely to develop clinically progressive disease is unknown. Our one patient with DIP (case 2) is distinctive in being the first flock worker to have such pathologic findings. Canadian investigators previously reported a five-case cluster of what was then believed to be DIP and diffuse alveolar damage among employees manufacturing flock and flocked fabric at the Kingston, Ontario plant.13 However, when we reviewed the Canadian tissue specimens,1 we observed bronchiolocentric lymphocytic interstitial infiltrates and lymphoid nodules comparable to those we were seeing in Rhode Island. Although intra-alveolar collections of macrophages were conspicuous, both their heterogeneity and the presence of other histologic findings were incompatible with a diagnosis of DIP.1 A NIOSH-convened panel of pulmonary pathologists subsequently reached the same conclusion.2 What is particularly interesting about our patient with DIP is that his wedge biopsy specimen revealed a profusion of lymphoid nodules no greater than that typically observed in DIP. Given the previously reported strong association between cigarette smoking and DIP, it is conceivable, then, that the patient’s active smoking habit was solely responsible for his interstitial lung disease.14 This appears unlikely, however, in that a few weeks after the patient left work, before he began corticosteroid therapy, and without changing his smoking practices, his symptoms decreased and his spirometric lung function improved dramatically. Our patient with bilateral synchronous pulmonary adenocarcinoma (case 3), was at low risk of developing tobacco-related lung cancer because he had stopped smoking long ago.15 Presumably, this patient developed flock worker’s lung decades earlier and was left at retirement with subclinical pulmonary fibrosis, the documented fate of a previously described patient.1 Although the prevailing belief is that pulmonary fibrosis is an independent risk factor for lung cancer,16 –19 the results of two recent carefully conducted country-wide studies of death certificates, in the United States20 and England,21 challenge this dogma. The designs of the two studies, 258
however, preclude them from confirming that the mortality rate of lung cancer is increased among patients with pulmonary fibrosis. A well-designed cohort study, which will be necessary to answer this question, is being planned (J. Harris, MSc; personal communication; April 14, 1999). However, the occurrence of cancer in case 3 raises the possibility, and nothing more, that there are carcinogenic exposures in the flocking industry. The patient whose lung biopsy showed the prototypical pathologic features of flock worker’s lung (case 4) is instructive for yet another reason. He improved clinicoradiographically on leaving work only to deteriorate again on returning to the same facility. Although such a temporal pattern might appear to support an occupational nexus, such an interpretation is problematic given the patient’s use of systemic corticosteroids during his time out of work. The patient living with a pet ferret (case 5) raises the possibility of HP. Although exposure to ferrets is not known to cause HP, HP remains a possibility because it has been caused by exposure to rats and gerbils.22,23 Although the patient’s clinical course and pathologic findings are consistent with HP, his BAL findings of marked neutrophilia and modest eosinophilia would be distinctly unusual for this condition.24 –29 Furthermore, both the absence of granuloma from all of the 18 pathologic specimens reviewed to date as well as the marked BAL eosinophilia ($ 25%) in three of our previous patients makes it extremely unlikely that flock worker’s lung is a form of HP.24 –32 Each of the now two dozen reported cases of flock worker’s lung arose among workers exposed to rotary-cut flock; moreover, all but three of the affected workers were employed by one particular company. Whether this tight clustering of cases reflects a specific causative role for rotary-cut nylon flock, relatively high concentrations of air contaminants in the plants of this particular company, or both, currently remains unclear. To date, the results of NIOSH laboratory studies appear to incriminate respirable-sized nylon particulate.3,4 However, much further study will be necessary before it can be conclusively determined that long-term exposure to ambient air concentrations of respirable-sized nylon fragments in the flocking industry is the cause of flock worker’s lung. Additional field and laboratory studies will need to focus on the role of dull cutting blades, heat, mechanical shearing, and alternate current vs direct current flocking in the generation of respirable-sized flock fragments; the relative risk of guillotine-cut vs rotary-cut flock; the air concentrations of respirable dust generated when rotary cutters are used to produce ground flock from nylon Occupational and Environmental Lung Disease
textile waste; the relative toxicity of nylon, rayon, and polyester flock fragments; and whether, within this industry, facilities having higher air concentrations of respirable dust are found to have correspondingly higher rates of interstitial lung disease. In considering the diagnosis of flock worker’s lung, the symptom profile is crucial in raising clinical suspicion. Of the noninvasive tests studied to date, only HRCT with close attention to subtle groundglass attenuation holds promise of being adequately sensitive to detect the condition early. It is conceivable that HRCTs could be interpreted more conservatively without sacrificing sensitivity if workers at risk were studied at baseline and again serially should respiratory symptoms develop. A therapeutic role for corticosteroids and other immunosuppressive agents remains to be demonstrated. Terminating exposure is crucial and is the only intervention that has been shown to be efficacious. Since the submission of this manuscript, we have seen a second worker from the Rhode Island plant with a lung carcinoma, this one an epidermoid carcinoma in a current smoker. ACKNOWLEDGMENTS: The authors thank Drs. Inna Ketsler, Richard S. Irwin, and Marilyn E. Miller for referring patients; Dr. Robert Chin for his clinical observations; Dr. Robert S. Crausman for his careful review of both the radiographic studies and the manuscript; and Mary Martino, Sandra Coppolino, and Mary Lee Nunes for their secretarial skills.
References 1 Kern DG, Crausman RS, Durand KTH, et al. Flock worker’s lung. Ann Intern Med 1998; 129:261–272 2 Eschenbacher WL, Kreiss K, Lougheed MD, et al. Clinical pathology workshop summary: nylon flock-associated interstitial lung disease. Am J Respir Crit Care Med 1999; 159:2003– 2008 3 Burkhart J, Piacitelli C, Schwegler-Berry D, et al. Environmental study of nylon flocking process. J Toxicol Environ Health 1999; 57:1–23 4 Porter DW, Castranova V, Robinson VA, et al. Acute inflammatory reaction in rats after intratracheal instillation of material collected from a nylon flocking plant. J. Toxicol Environ Health 1999; 57:25– 45 5 Crapo RO, Morris AH, Gardner PM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123:659 – 664 6 Crapo RO, Morris AH. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir 1982; 18:419 – 425 7 Crapo RO, Morris AH. Standardized single breath normal values for carbon monoxide diffusing capacity. Am Rev Respir Dis 1981; 123:185–189 8 American Medical Association. Guides to the evaluation of permanent impairment. 4th ed. Chicago, IL: American Medical Association, 1993; 162 9 Ettensohn DB, Jankowski MJ, Duncan PG, et al. Bronchoalveolar lavage in the normal volunteer subject: I. Technical aspects and intersubject variability. Chest 1988; 94:275–280 10 Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance. Am J
Surg Pathol 1994; 18:136 –147 11 Griffiths MH, Miller RF, Semple SJ. Interstitial pneumonitis in patients infected with the human immunodeficiency virus. Thorax 1995; 50:1141–1146 12 Travis WD, Fox CH, Devaney KO, et al. Lymphoid pneumonitis in 50 adult patients infected with the human immunodeficiency virus: lymphocytic interstitial pneumonitis versus nonspecific interstitial pneumonitis. Hum Pathol 1992; 23:529 –541 13 Lougheed MD, Roos JO, Waddell WR, et al. Desquamative interstitial pneumonitis and diffuse alveolar damage in textile workers: potential role of mycotoxins. Chest 1995; 108:1196 – 1200 14 Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298:801– 809 15 US Dept of Health and Human Services. Health benefits of smoking cessation: a report of the Surgeon General. Washington, DC: US Dept of Health and Human Services; 1990. CDC publication 90 – 8416 16 Griffin JP. Interstitial pulmonary fibrosis and lung cancer. Chest 1995; 108:1193–1194 17 Mizushima Y, Kobayashi M. Clinical characteristics of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis: a review of Japanese cases. Chest 1995; 108:1272–1277 18 Turner-Warwick M, Lebowitz M, Burrows B, et al. Cryptogenic fibrosing alveolitis and lung cancer. Thorax 1980; 35:496 – 499 19 Fraire AE, Greenberg SD. Carcinoma and diffuse interstitial fibrosis of lung. Cancer 1973; 31:1078 – 86 20 Wells C, Mannino DM. Pulmonary fibrosis and lung cancer in the United States: analysis of the multiple cause of death mortality data, 1979 through 1991. South Med J 1996; 89:505–510 21 Harris JM, Cullinan P, McDonald JC. Does cryptogenic fibrosing alveolitis carry an increased risk of death from lung cancer? J Epidemiol Community Health 1998; 52:602– 603 22 Carrol KB, Pepys J, Longbottom J, et al. Extrinsic allergic alveolitis due to rat serum proteins. Clin Allergy 1975; 5:443– 456 23 Pimental JC. Furrier’s lung. Thorax 1970; 15:387–398 24 Allen JN, Davis WB, Pacht ER. Diagnostic significance of increased bronchoalveolar lavage fluid eosinophils. Am Rev Respir Dis 1990; 142:642– 647 25 Davis WB, Fells GA, Sun XH, et al. Eosinophil-mediated injury to lung parenchymal cells and interstitial matrix. J Clin Invest 1984; 74:269 –278 26 Reynolds HY, Fulmer JD, Kazmierowski JA, et al. Analysis of cellular and protein content of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest 1977; 59:165–175 27 Drent M, van Nierop MAMF, Gerritsen FA, et al. A computer program using BALF-analysis results as a diagnostic tool in interstitial lung diseases. Am J Respir Crit Care Med 1996; 153:736 –741 28 Trentin L, Marcer G, Chilosi M, et al. Longitudinal study of alveolitis in hypersensitivity pneumonitis patients: an immunologic evaluation. J Allergy Clin Immunol 1988; 82:577–585 29 Drent M, van Velzen-Blad H, Diamant M, et al. Bronchoalveolar lavage in extrinsic allergic alveolitis: effect of time elapsed since antigen exposure. Eur Respir J 1993; 6:1276 –1281 30 Kawanami O, Basset F, Barrios R, et al. Hypersensitivity pneumonitis in man. Am J Pathol 1983; 110:275–289 31 Reyes CN, Wenzel FJ, Lawton BR, et al. The pulmonary pathology of farmer’s lung disease. Chest 1982; 81:142–146 32 Sutinen S, Reijula K, Huhti E, et al. Extrinsic allergic bronchioloalveolitis: serology and biopsy findings. Eur J Respir Dis 1983; 64:271–282 CHEST / 117 / 1 / JANUARY, 2000
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Study objectives: Workers in the nylon flocking industry recently have been found to be at increased risk of chronic nongranulomatous interstitial lung disease. Although a spectrum of cytologic and histopathologic abnormalities has been observed, nonspecific interstitial pneumonia, lymphoid nodules, and lymphocytic bronchiolitis predominated in the 19 previously reported cases of flock worker’s lung. Here we describe five additional patients who appear to expand the histopathologic spectrum and add to the evidence suggesting a causative role for respirable-sized nylon fragments. Methods: We studied all North American patients (n 5 5) found in 1998 to satisfy our previous case definition of flock worker’s lung. Two pulmonary pathologists independently reviewed each biopsy specimen. Results: All five patients reported cough and dyspnea. Only one patient had crackles on chest auscultation. High-resolution CT scan, interpreted with attention to subtle ground-glass attenuation, remained a highly sensitive diagnostic test. Pulmonary function tests and plain chest radiograph were less sensitive. One patient’s wedge biopsy showed previously described prototypical findings. Two others had transbronchial biopsies showing some of the same features. The fourth patient’s wedge biopsy showed desquamative interstitial pneumonia. The fifth patient had bilateral synchronous adenocarcinoma but with radiographic evidence of diffuse interstitial fibrosis. These 5 patients and the 19 patients studied previously were exposed to nylon flock manufactured by a rarely used cutting technology. Conclusion: Findings in these five patients appear to broaden the spectrum of the clinicopathology of flock worker’s lung and add to the evidence incriminating respirable-sized nylon particulates produced during the manufacture and use of rotary-cut nylon flock. (CHEST 2000; 117:251–259) Key words: interstitial lung disease; nonspecific interstitial pneumonia; nylon; occupational lung disease Abbreviations: ANA 5 antinuclear antibody; DIP 5 desquamative interstitial pneumonia; HP 5 hypersensitivity pneumonitis; HRCT 5 high-resolution CT; NIOSH 5 National Institute for Occupational Safety and Health
*From the Departments of Medicine (Drs. Kern and Mello) and Pathology (Dr. Kuhn), Brown University, Providence, RI; the Department of Medicine (Dr. Ely), Vanderbilt University, Nashville, TN; the Departments of Medicine (Dr. Pransky) and Pathology (Dr. Fraire), University of Massachusetts, Worcester, MA; and EFT Consultants (Mr. Mu¨ller), Budingen, Germany. Supported, in part, by the Leonard J. Feldberg Memorial Fund. Manuscript received April 16, 1999; revision accepted June 24, 1999. Correspondence to: Charles Kuhn, III, MD, Department of Pathology, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860
we reported workers in the nylon flockR ecently, ing industry to be at markedly increased risk of a chronic interstitial lung disease characterized by bronchiolocentric nodular and diffuse lymphocytic For editorial comment see page 10 interstitial infiltrates, a lymphocytic bronchiolitis, and variable interstitial fibrosis.1 After working between 1 and 30 years at a Rhode Island textile CHEST / 117 / 1 / JANUARY, 2000
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plant that employs , 200 people, the 8 individuals so affected experienced the onset of persistent dry cough and dyspnea with or without atypical chest pain. Most had crackles on chest examination. Chest radiographs either were normal or showed diffuse reticulonodular or patchy infiltrates. High-resolution CT (HRCT) scans showed patchy ground-glass opacity, scattered areas of consolidation, diffuse micronodularity, or peripheral honeycombing. Pulmonary function testing generally showed restrictive, although occasionally obstructive or normal, physiology. BAL revealed eosinophilia (. 25%) or lymphocytosis (. 30%), with or without neutrophilia. All those affected had symptomatic, radiographic, and functional improvement within weeks to months of leaving work, but in none was recovery complete. Calculations of standardized incidence ratios revealed rates of interstitial lung disease for flock workers to be 48 to 250 times higher than those for the general population.1 To date, 19 cases of what has been termed flock worker’s lung have been reported among Rhode Island, Massachusetts, and Ontario workers.1,2 Here, we describe five additional, more recently identified cases, including four that arose among workers employed at the two index sites of disease in the United States, and the first case from North Carolina. As with all previously described cases, the five were exposed to nylon flock manufactured by a rarely used cutting technology. Findings in these cases appear to broaden the spectrum of the clinicopathology of flock worker’s lung and add to the evidence incriminating rotary-cut nylon flock.
Background The flocking industry produces fleeced fabric and plush objects for use in the manufacture of upholstery, clothing, carpets, automobiles, and novelty items. Flock manufacturers cut nylon, rayon, polyester, and other natural and synthetic fibers, as well as textile waste, to produce a powder of short fibers (0.2 to 5.0 mm), termed flock. This material subsequently is applied (flocked) to adhesive-coated fabrics and other objects to impart a velvety surface. Some companies only manufacture flock, others solely do flocking, and others do both. At the high-quality end of the industry, flock manufacturers cut flock from long cables (tow) of parallel monofilaments of nylon, rayon, or polyester. With but two known exceptions in the world, manufacturers cut tow with guillotines and in doing so produce fibers of precisely defined length (6 5%), termed precision-cut flock. Guillotine-cut flock may be dyed before it is bath-finished, dried, screened, 252
and bagged. As guillotine blades become dull, a tell-tale tone signals their need to be sharpened. Two large North American flock manufacturers, in contrast, cut nylon tow with rotary cutters, which generate fibers of less-precisely defined length (6 20%), termed random-cut flock. In this process, which is much faster than that using guillotine cutters, tow is dyed, finished, cut, dried, screened, and bagged in one continuous operation. However, as rotary-cutter blades become dull, it is difficult to detect a tone change; increasing friction results in rising blade temperatures, and nylon tow may be cut uncleanly, melted, or both. Nylon flock produced under such conditions is more likely to have tiny protuberances, which during subsequent processing may be released as respirable-sized particles (aerodynamic diameter , 10 mm). Quality-control inspectors have described such protuberances on flock fibers, and investigators from the National Institute for Occupational Safety and Health (NIOSH) have demonstrated their presence both in bulk samples of rotary-cut flock and as respirable-sized particles in work-room air.3 Notably, recent intratracheal instillation studies in rats have suggested that respirablesized nylon particles have substantial pulmonary toxicity.4 All 19 workers reported thus far to have flock worker’s lung1,2 were exposed to rotary-cut flock. Of the 19, 17 were employees of a single company (8 in Rhode Island, 9 in Kingston, Ontario) that manufactures both flock and flocked fabric. The two other affected workers were exposed to flock made by a Massachusetts company, one of the largest flock suppliers in North America; one worker was exposed at the flock manufacturing company itself, and the other worker at the flocking facility of one of its nearby customers. Of the five additional patients to be described in this report, one was employed at the index Massachusetts flock manufacturing facility, three at the index Rhode Island facility, and one at the North Carolina plant of the latter company.
Materials and Methods We included all North American patients (n 5 5) found in 1998 to satisfy our previously articulated case definition of flock worker’s lung: persistent respiratory symptoms, previous work in the flocking industry, and histologic evidence of interstitial lung disease without better explanation.1 Moreover, as before, in the absence of a tissue specimen, the triad of an abnormal distribution of cell types on BAL, restrictive lung function, and HRCT findings of diffuse ground-glass opacity or micronodularity (or obvious fibrosis) was allowed to serve as a surrogate for the histologic criterion.1 We used the pulmonary function reference values of Crapo and colleagues5–7 and the severity scale of the American Medical Association.8 Two pulmonary pathologists (CK Occupational and Environmental Lung Disease
Table 1—Pulmonary Function Test Results at Time of Diagnosis* Case No. Test
1
2
3
4
5
FEV1, L FVC, L TLC, L Dlco, mL/min/mm Hg
3.83 (86) 5.15 (95) 7.10 (103) 30.2 (75)
2.24 (55) 2.73 (55) — —
1.79 (62) 2.36 (62) 4.07 (64) 7.41 (28)
3.60 (78) 4.76 (86) 6.43 (92) 26.2 (63)
2.34 (52) 2.90 (52) 4.72 (64) 9.20 (23)
*Values are presented as absolute (percent of predicted normal values taken from Crapo et al5–7); Dlco 5 diffusing capacity of the lung for carbon monoxide; TLC 5 total lung capacity.
and AEF) independently reviewed the four biopsy specimens. In three, there was complete agreement on the features present; in the fourth, a minor discrepancy was resolved by re-review and discussion.
Case 1 A 30-year-old white male textile worker reported the sudden onset of wheezing and shortness of breath at work in March 1997, 1 year after beginning employment at the index facility in Rhode Island. The following day, spirometry was normal and asthma was diagnosed. Inhaled corticosteroids and b-agonists were initiated without subjective benefit as the patient developed grade II dyspnea, frequent prolonged substernal chest pressure, occasional wheezing, and a minimal nonproductive cough. During the subsequent 8 months, within 2 hours of leaving the plant each day, he would become asymptomatic. During the next 4 months, however, his symptoms became persistent. The patient had never smoked and had no history of atopic illness. A brother was reported to have asthma. At the time of his referral in March 1998, the patient had been working for 2 years in the cutting department, immediately adjacent to the work station of a coworker previously found to have biopsy-confirmed flock worker’s lung. Physical examination revealed no abnormalities. Chest radiographs were normal. Pulmonary function test results (Table 1) were reported to be normal although the diffusing capacity was mildly reduced according to the reference values of Crapo and Morris.7 In any case, the results were identical to those recorded 2 years earlier by NIOSH just 2 weeks after the patient began working at the company. After a 2-week period off all medications, the patient was found to have normal airway responsiveness (ie, dose provoking a 20% decrement in FEV1 was 189 cumulative U of methacholine). An HRCT scan was officially interpreted as normal, but one of the authors and a consulting pulmonologist concluded that there were gravityindependent areas of patchy ground-glass opacity in the lower lung fields bilaterally (Fig 1, top, A).
After a 2-week period out of work, without change in symptoms, the patient proceeded to BAL and transbronchial biopsy. BAL revealed 10% neutrophils and 15% lymphocytes, exceeding the upper limit of the 95% confidence interval for these values in our laboratory.9 Biopsy revealed minimal interstitial lymphocytic infiltrates and a lymphoid nodule in the specimen’s only respiratory bronchiole (Fig 1, bottom, B). Rheumatoid factor was negative, antinuclear antibody (ANA) was positive at a titer of 1:80 in a speckled pattern, and CBC count and differential
Figure 1. Case 1. Top, A: HRCT shows subtle ground-glass opacity. Bottom, B: transbronchial biopsy shows a nodule of lymphocytes in the only respiratory bronchiole present in the biopsy specimen (hematoxylin-eosin, original 3 240). CHEST / 117 / 1 / JANUARY, 2000
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blood count were within the normal range. Within 4 months of leaving work, the patient no longer was having respiratory symptoms, his pulmonary function was unchanged, his ANA was negative, and his previously equivocal HRCT scan findings were less apparent. Case 2 A 38-year-old white male textile worker had right posterior pleuritic chest pain in March 1998 and, a week later, dyspnea on effort. His chest pain disappeared shortly thereafter, but when his dyspnea persisted for 6 weeks, he was referred for pulmonary evaluation to one of the authors. Two decades earlier, the patient had worked at the index facility in Rhode Island for 2 years. Subsequently, he spent 10 years repairing automobiles and 6 years as a shipyard welder building new submarines. He then returned to the flock manufacturing facility and worked for 6 years as a screen printer on the mezzanine above the cutting and flocking departments before developing the symptoms that prompted his evaluation. An active 50-pack-year smoker, the patient denied medical history of note other than for sinus surgery. Physical examination revealed no abnormalities. Chest radiographs revealed subtle haziness and equivocal reticular infiltrates. FEV1 and FVC were 55% of predicted, and FEV1/FVC was 99% of predicted (Table 1). After remaining out of work for 5 weeks, he felt somewhat better, his FEV1 and FVC increased substantially to 84% of predicted, and his airway responsiveness to methacholine challenge was normal. An HRCT scan revealed striking diffuse ground-glass opacity, assuming a macronodular appearance in some areas, and prominent subpleural interlobular septa (Fig 2, top, A). Rheumatoid factor, ANA, and antinuclear cytoplasmic antibody were negative. Erythrocyte sedimentation rate was 15 mm/h. CBC count and leukocyte differential were normal. Four weeks later, an open lung biopsy revealed a monotonous homogeneous pattern of intra-alveolar macrophages, mild interstitial fibrosis, and occasional lymphoid aggregates in the walls of small airways, compatible with desquamative interstitial pneumonia (DIP; Fig 2, bottom, B). Prednisone therapy, 60 mg qd, was initiated. Two months later, the patient was still smoking, taking prednisone, and experiencing mild dyspnea on effort. Full pulmonary function testing revealed the following: a further improvement in FVC; total lung capacity, 90% of predicted; residual volume, 54% of predicted; and single-breath diffusing capacity, 82% of predicted. Although the patient’s FVC and diffusing capacity measurements by then were both nor254
Figure 2. Case 2. Top, A: HRCT shows striking ground-glass opacity, assuming a macronodular appearance in some areas, and prominent subpleural interlobular septa. Bottom, B: open lung biopsy showing typical histopathology of DIP, alveoli packed with macrophages, and slight thickening of alveolar walls with mild inflammation (hematoxylin-eosin, original 3 150).
mal and essentially the same as those recorded by NIOSH personnel 2 years earlier when the patient was asymptomatic, and although his chest radiographs no longer showed diffuse haziness, a repeat HRCT scan showed extensive diffuse ground-glass opacity without improvement. Six months later, the patient reported no change in symptoms, he was still smoking, prednisone was being tapered, an HRCT scan showed no change, and his pulmonary function remained stable other than for a 20% decline in diffusing capacity. Case 3 A 77-year-old retired white male textile worker was admitted to the Memorial Hospital of Rhode Island in January 1996 for presumed pneumonia and parapneumonic effusion. At the time, he reported a Occupational and Environmental Lung Disease
1- to 2-year history of dyspnea on effort and a minimally productive chronic cough. A former 33pack-year smoker, he had discontinued all tobacco use 36 years earlier. Further evaluation revealed ill-defined synchronous bilateral pulmonary adenocarcinomas detected both by BAL and percutaneous needle biopsies. Other than for 4 years of military service, the patient had worked in the textile industry from 1934 to 1983 and had no known occupational or familial exposures to asbestos. After cancer was diagnosed, the patient received carboplatin, paclitaxel, and vinorelbine for 15 months without evidence of disease progression. Radiation was not administered. In April 1997, on reading in the newspapers about an outbreak of interstitial lung disease at the index plant, he asked to be evaluated by one of the authors and queried whether his illness might have been caused by his 20-year tenure at the Rhode Island plant. He reported working in the cutting and finishing departments from 1964 to 1970, and, subsequently, performing machine maintenance throughout the plant from 1970 to 1983. At the time of his referral, physical examination revealed an elderly deaf man in no apparent distress. Chest auscultation revealed inspiratory crackles over the lower lung fields bilaterally. The patient’s pulmonary function test results of the preceding 15 months revealed mild restriction and a severe diffusion impairment. Review of a previous CT scan without high-resolution imaging raised the possibility of diffuse interstitial lung disease. An HRCT was ordered and showed the previously appreciated illdefined basilar tumor masses but also bilateral peripherally distributed reticular infiltrates and prominent subpleural interlobular septa (Fig 3). Fourteen months later, in July 1998, HRCT scan showed no change. Case 4 A 25-year-old Hispanic white male textile worker presented in February 1998 with a 2- to 3-month history of worsening dyspnea on effort, dry cough, and the more recent onset of substernal burning discomfort on deep inspiration. At the time, he had been working for 2.5 years in the cutting department of a large Massachusetts flock manufacturing plant where a coworker previously had been found to have flock worker’s lung. The patient had never smoked, and denied history of atopic illness, previous respiratory disease, and exposure to agents known to cause hypersensitivity pneumonitis (HP). His mother was reported to have asthma. Chest auscultation revealed clear lung fields. The patient coughed throughout spirometry, making it difficult to interpret the results; FEV1 and FVC were both
Figure 3. Case 3. HRCT shows peripherally distributed reticular infiltrates and prominent subpleural interlobular septa.
found to be approximately 1 L lower than his normal baseline values established 17 months earlier. Chest radiographs were formally interpreted as being normal, but the treating physician detected subtle patchy areas of haziness at both the lung bases and the periphery of the right upper and middle lobes. An HRCT scan revealed definite areas of patchy ground-glass opacity. On the recommendation of his physician, the patient left work and began prednisone. When seen a few weeks later at the University of Massachusetts Medical Center, he reported feeling better. Physical examination revealed no abnormalities. Pulmonary function was reported to be normal other than for borderline-low FEV1 and diffusing capacity; the patient’s FEV1 was 500 mL lower than his normal baseline value, and his diffusing capacity was definitely reduced according to the reference values of Crapo and Morris.7 Mild airway hyperresponsiveness to methacholine challenge was demonstrated (dose provoking a 20% decrement in the FEV1 was 6.14 mmols). A follow-up HRCT scan was formally interpreted as normal other than for a small number of peripheral small densities, raising the possibility of minimal bronchiolitis. Prednisone was discontinued, and 3 weeks later, the patient returned to work. A day or two later, his symptoms CHEST / 117 / 1 / JANUARY, 2000
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Figure 4. Case 4. Top, A: HRCT shows patchy ground-glass opacity and focal areas of frank consolidation. Bottom, B: open lung biopsy shows nodules of lymphocytes (top) and widespread thickening and chronic inflammation of alveolar walls. This is the most common histologic pattern we have seen in flock workers (hematoxylin-eosin, original 3 60).
recurred and then gradually worsened over the following month, prompting him to leave work again. An HRCT scan at the time (Fig 4, top, A) revealed bilateral patchy ground-glass opacity and focal areas of frank consolidation. Rheumatoid factor and ANA were negative. Erythrocyte sedimentation rate, WBC count, and leukocyte differential were normal. Two weeks later, thoracoscopic lung biopsy revealed lymphoplasmacytic bronchiolitis, lymphoid hyperplasia, lymphocytic interstitial infiltrates, and fibroblastic foci (Fig 4, bottom, B). Shortly thereafter, prednisone was resumed, quickly tapered, and discontinued after 6 months of treatment. One month before prednisone was discontinued, pulmonary function testing revealed FEV1 and FVC to be 1 L lower than his normal baseline values and his diffusing capacity to be stable. When last seen, 1 year after first presenting, he reported a stable persistent cough and dyspnea on effort. Case 5 A 37-year-old year white male textile worker presented with severe shortness of breath in January 256
1998 to the Baptist Hospital Medical Center in Winston-Salem, NC. Six years earlier, he had begun working at an area plant (owned by the index Rhode Island company) engaged in the manufacture of flock and flocked fabrics. After a 2-year period in the flock room, he had worked continuously for 4 years in the cutting department. Toward the end of his second year in the flock room, he developed a nonproductive cough and mild dyspnea on effort and was given a symptom-based diagnosis of asthma. After moving to the cutting department, he continued to experience dyspnea, which slowly progressed. Bronchodilators and inhaled corticosteroids provided negligible relief. Six weeks before admission, as his dyspnea intensified, he noticed that he was less short of breath each time he stayed out of work for a few days. A trial of clarithromycin brought no relief. At the time of presentation, the patient also reported a mild nonproductive cough, intermittent cyanosis, mild anorexia, and a 20-lb weight loss over the prior month. A former 20-pack-year smoker, the patient had stopped all tobacco use 5 years earlier. He denied history of atopy, previous respiratory illness, and exposure to potential causes of HP other than a pet ferret. Physical examination revealed a well-nourished cyanotic man in obvious respiratory distress who was afebrile with a heart rate of 122 beats/min, respiratory rate 24 breaths/min, and BP of 111/66 mm Hg. His lungs were clear to auscultation, and the remainder of his examination was normal as well. Chest radiographs revealed bilateral reticulonodular infiltrates. An arterial blood gas on room air revealed pH of 7.42, Paco2 of 36 mm Hg, and Pao2 of 47 mm Hg. The patient was hospitalized, and oxygen was administered. An HRCT scan revealed patchy ground-glass opacity assuming a macronodular appearance in some areas (Fig 5, top, A). Pulmonary function testing (Table 1) revealed moderate restriction, a severe impairment of diffusion, and no obstruction. CBC count and leukocyte differential were normal and rheumatoid factor, ANA, and an HP panel of precipitins were negative. On the fourth hospital day, BAL revealed 35% neutrophils and 7% eosinophils. Transbronchial biopsy revealed modest nodular and diffuse mononuclear cell interstitial infiltrates, moderate interstitial fibrosis, and lesser amounts of intraalveolar macrophages and fibroblastic foci, findings consistent with nonspecific interstitial pneumonia (Fig 5, bottom, B). The patient was discharged on prednisone, 60 mm qd, and supplemental oxygen. Six weeks later, he felt much better, he was no longer using supplemental oxygen, and most of his radiographic infiltrates had resolved. Prednisone was tapered and discontinued within 6 months of its being started. Occupational and Environmental Lung Disease
Figure 5. Case 5. Top, A: HRCT shows ground-glass opacity assuming a macronodular appearance in some areas. Bottom, B: transbronchial biopsy shows moderately severe thickening and mononuclear infiltration of airspace walls and focal epithelial hyperplasia consistent with nonspecific interstitial pneumonia (hematoxylin-eosin, original 3 150).
Near the end of the treatment course, with the patient still out of work, his diffusing capacity had improved from 23% of predicted to 46% of predicted. One year after hospital discharge, the patient remained on inhaled corticosteroids and b-agonists, in an effort to control his intermittent dyspnea. By then, his spirometry and lung volumes had become normal, but his diffusing capacity had improved no further. He currently works in the company’s warehouse. Discussion Each of the five patients described here reported chronic dyspnea and dry cough with or without atypical chest pain, just as did the first eight patients defined to have flock worker’s lung.1 Crackles were all but absent in the current series, despite their presence in all but one of our previous patients. Pulmonary function testing generally revealed restriction and impaired diffusion. Consistent with our previous findings, however, one of the five patients was reported to have normal lung function; notably, another recovered his previously established normal
baseline level of lung function despite the fact that his HRCT scan remained grossly abnormal. Chest radiographs were not reliably informative. HRCT scans, however, if interpreted with a liberal diagnostic threshold, were considered abnormal for all five patients just as they had been for the first eight patients we described. Yet, once again, in disagreement with the treating physicians, hospital radiologists occasionally concluded that an HRCT scan was normal when biopsy would later confirm the presence of disease. The two patients who had BAL cell counts showed an excessive proportion of neutrophils; one also showed a slightly increased proportion of lymphocytes, and the other an increased proportion of eosinophils. As with our initial series, BAL findings were nonspecific. In our previous report,1 we concluded that the observed histopathologic findings of flock worker’s lung were most readily encompassed by the term nonspecific interstitial pneumonia as defined by various authors.10 –12 We noted that whereas all of our patients with biopsies had nodular peribronchovascular lymphocytic infiltrates, and that most also had diffuse lymphocytic interstitial infiltrates, germinal centers, and lymphocytic bronchiolitis, there was considerable variation. In fact, one patient had findings of bronchiolitis obliterans organizing pneumonia, and another had findings consistent with usual interstitial pneumonia. Yet, in both cases, there were a striking number of peribronchovascular lymphoid nodules. The report of a recently convened NIOSH workshop on flock worker’s lung emphasizes the central role of a lymphocytic bronchiolitis and peribronchiolitis with associated lymphoid nodules in the histopathologic recognition of this condition.2 Although the emphasis is deserved, we believe the workshop report underemphasizes the accompanying diffuse interstitial inflammation that is responsible presumably for the severely reduced diffusing capacity and interstitial fibrosis observed in a number of our patients. Furthermore, given the relatively small number of cases described to date, the vagaries of lung biopsy, and the potential for varying host responses, we believe it would be premature to conclude that the causative agents responsible for flock worker’s lung cause but a single stereotypic response pattern. Consequently, for the time being, we continue to prefer our previously articulated case definition, namely: persistent respiratory symptoms, previous work in the flocking industry, and histologic evidence of interstitial lung disease without better explanation. Moreover, in the absence of a tissue specimen, we believe that the triad of an abnormal distribution of cell types on BAL, restrictive lung function, and HRCT findings of diffuse ground-glass CHEST / 117 / 1 / JANUARY, 2000
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opacity or micronodularity (or obvious fibrosis) may serve as a surrogate for the histologic criterion. All five of the cases described herein satisfy this case definition. The severity and acuity of illness in the five patients ranged from minor to severe. The marked subtlety of the radiographic and pathologic findings observed in one patient (case 1) raises the possibility that if asymptomatic flock workers were investigated as intensely, similar findings might be detected. Whether individuals having such minimal abnormalities are less likely to develop clinically progressive disease is unknown. Our one patient with DIP (case 2) is distinctive in being the first flock worker to have such pathologic findings. Canadian investigators previously reported a five-case cluster of what was then believed to be DIP and diffuse alveolar damage among employees manufacturing flock and flocked fabric at the Kingston, Ontario plant.13 However, when we reviewed the Canadian tissue specimens,1 we observed bronchiolocentric lymphocytic interstitial infiltrates and lymphoid nodules comparable to those we were seeing in Rhode Island. Although intra-alveolar collections of macrophages were conspicuous, both their heterogeneity and the presence of other histologic findings were incompatible with a diagnosis of DIP.1 A NIOSH-convened panel of pulmonary pathologists subsequently reached the same conclusion.2 What is particularly interesting about our patient with DIP is that his wedge biopsy specimen revealed a profusion of lymphoid nodules no greater than that typically observed in DIP. Given the previously reported strong association between cigarette smoking and DIP, it is conceivable, then, that the patient’s active smoking habit was solely responsible for his interstitial lung disease.14 This appears unlikely, however, in that a few weeks after the patient left work, before he began corticosteroid therapy, and without changing his smoking practices, his symptoms decreased and his spirometric lung function improved dramatically. Our patient with bilateral synchronous pulmonary adenocarcinoma (case 3), was at low risk of developing tobacco-related lung cancer because he had stopped smoking long ago.15 Presumably, this patient developed flock worker’s lung decades earlier and was left at retirement with subclinical pulmonary fibrosis, the documented fate of a previously described patient.1 Although the prevailing belief is that pulmonary fibrosis is an independent risk factor for lung cancer,16 –19 the results of two recent carefully conducted country-wide studies of death certificates, in the United States20 and England,21 challenge this dogma. The designs of the two studies, 258
however, preclude them from confirming that the mortality rate of lung cancer is increased among patients with pulmonary fibrosis. A well-designed cohort study, which will be necessary to answer this question, is being planned (J. Harris, MSc; personal communication; April 14, 1999). However, the occurrence of cancer in case 3 raises the possibility, and nothing more, that there are carcinogenic exposures in the flocking industry. The patient whose lung biopsy showed the prototypical pathologic features of flock worker’s lung (case 4) is instructive for yet another reason. He improved clinicoradiographically on leaving work only to deteriorate again on returning to the same facility. Although such a temporal pattern might appear to support an occupational nexus, such an interpretation is problematic given the patient’s use of systemic corticosteroids during his time out of work. The patient living with a pet ferret (case 5) raises the possibility of HP. Although exposure to ferrets is not known to cause HP, HP remains a possibility because it has been caused by exposure to rats and gerbils.22,23 Although the patient’s clinical course and pathologic findings are consistent with HP, his BAL findings of marked neutrophilia and modest eosinophilia would be distinctly unusual for this condition.24 –29 Furthermore, both the absence of granuloma from all of the 18 pathologic specimens reviewed to date as well as the marked BAL eosinophilia ($ 25%) in three of our previous patients makes it extremely unlikely that flock worker’s lung is a form of HP.24 –32 Each of the now two dozen reported cases of flock worker’s lung arose among workers exposed to rotary-cut flock; moreover, all but three of the affected workers were employed by one particular company. Whether this tight clustering of cases reflects a specific causative role for rotary-cut nylon flock, relatively high concentrations of air contaminants in the plants of this particular company, or both, currently remains unclear. To date, the results of NIOSH laboratory studies appear to incriminate respirable-sized nylon particulate.3,4 However, much further study will be necessary before it can be conclusively determined that long-term exposure to ambient air concentrations of respirable-sized nylon fragments in the flocking industry is the cause of flock worker’s lung. Additional field and laboratory studies will need to focus on the role of dull cutting blades, heat, mechanical shearing, and alternate current vs direct current flocking in the generation of respirable-sized flock fragments; the relative risk of guillotine-cut vs rotary-cut flock; the air concentrations of respirable dust generated when rotary cutters are used to produce ground flock from nylon Occupational and Environmental Lung Disease
textile waste; the relative toxicity of nylon, rayon, and polyester flock fragments; and whether, within this industry, facilities having higher air concentrations of respirable dust are found to have correspondingly higher rates of interstitial lung disease. In considering the diagnosis of flock worker’s lung, the symptom profile is crucial in raising clinical suspicion. Of the noninvasive tests studied to date, only HRCT with close attention to subtle groundglass attenuation holds promise of being adequately sensitive to detect the condition early. It is conceivable that HRCTs could be interpreted more conservatively without sacrificing sensitivity if workers at risk were studied at baseline and again serially should respiratory symptoms develop. A therapeutic role for corticosteroids and other immunosuppressive agents remains to be demonstrated. Terminating exposure is crucial and is the only intervention that has been shown to be efficacious. Since the submission of this manuscript, we have seen a second worker from the Rhode Island plant with a lung carcinoma, this one an epidermoid carcinoma in a current smoker. ACKNOWLEDGMENTS: The authors thank Drs. Inna Ketsler, Richard S. Irwin, and Marilyn E. Miller for referring patients; Dr. Robert Chin for his clinical observations; Dr. Robert S. Crausman for his careful review of both the radiographic studies and the manuscript; and Mary Martino, Sandra Coppolino, and Mary Lee Nunes for their secretarial skills.
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