Aluminum Lung
A 56 year old woman presented with a history of chronic troublesome unproductive cough. Physical examination was normal as were pulmonary function tests. The chest radiograph showed diffuse reticulonodular infiltrates in both lungs. The CT scan showed a larger nodule with eccentric calcification in the right upper lobe. An open thorascopic lung biopsy showed multiple discrete non necrotizing granulomas. Many of the granulomas contained globular birefringent particles. Energy dispersive

X ray elemental analysis (EDXEA) conducted on tiny particles carved directly out of the granulomas showed major peaks of aluminum and silicon. She had been employed for several years at a New England Plant manufacturing deodorants and toothpaste. Powder bags of "aluminum sulfate" and "sodium aluminum lactate" were usually in her immediate surrounding areas at work. High dose prednisone therapy and later low dose methotrexate therapy, along with departure from her job provided symptomatic relief.

Diagnosis
Metalloconiosis (aluminum lung, aluminosis)

Discussion
Aluminum is a durable, light weight metal used extensively in industrial processes. Exposure to aluminum may occur during aluminum smelting, manufacturing of aluminum abrasives, aluminum polishing and aluminum arc-welding.

Clinically, asthma and chronic obstructive lung disease have been described in individuals exposed to aluminum. At the tissue level, diffuse fibrosis (with an upper lobe distribution) is a major manifestation of exposure (Roggli). Granulomatous inflammation mimicking sarcoid (perhaps on basis of hypersensitivity), alveolar proteinosis and DIP-like reactions are other forms of tissue response to aluminum. Macrophages can be numerous in cases of aluminosis and found to contain fine gray to brown cytoplasmic dust. The aluminum particles themselves appear as electron dense spheres 0.1 um to 1 um in diameter, by electron microscopy (Roggli). An illustrative case of aluminosis characterized by granulomatous interstitial lung disease in a 32 year old chemist was reported by De Vuyst. The disease developed after working 8 years in a dusty atmosphere containing aluminum powders. Bronchoalveolar lavage disclosed a helper T-lymphocyte alveolitis and a transbronchial biopsy showed sarcoid-like epithelioid granulomas. Peripheral blood lymphocytes showed blastic transformation in the presence of soluble aluminum (De Vuyst).

How is the diagnosis made ? Documentation of exposure to aluminum is important but actual diagnosis can only be made with the use of ancillary techniques in combination with one or more of the histopathologic changes (such as sarcoid like granulomas or interstitial fibrosis) that are known to occur in aluminosis. An important diagnostic tool, particularly in patients showing sarcoid or beryllium like granulomatosis is the helper T-cell lymphocytosis test in BAL fluid. An alternate way is to perform in-vitro blastogenic response of peripheral blood lymphocytes to soluble aluminum compounds (Roggli). Confirmation can also be achieved by electron microscopy and/or demonstration of elemental aluminum in lung tissue sections by EDXEA. In the absence of these specialized tests, the Irwin's aluminum stain may be a helpful alternate diagnostic tool. With this technique, aluminum will appear as globules and mulberry like aggregates of dark red material lying in the center of fibrous nodules or granulomas, after treatment of tissues with a 2% aurine tricarboxylic acid solution (Lillie).

Popcorn Lung
A 46 year old woman employed for 18 months at a US microwave popcorn production plant developed shortness of breath and cough. Her FEV₁, varied from 20 – 25% of predicted. A CT scan of the chest showed pulmonary interstitial changes. A thoracoscopic lung biopsy showed focal bronchiolar fibrosis and fibroblastic proliferation compressing bronchiolar lumina. There was no intersitial pneumonia. She did not respond to steroids but showed partial (symptomatic) relief to a 3 month course of cyclophosphamide. Later, she was accepted for a lung transplant and needed up to 3 L of oxygen per minute (Kreiss) (Parmet).

Diagnosis
Popcorn lung (Popcorn workers lung)

Discussion
In May 2000, the above cited index patient and seven other former workers at the microwave popcorn production plant were recognized as having clinical evidence of severe bronchiolitis obliterans (Kreiss). All but one of the eight workers were non-smokers. The suspected offending agent appeared to be a work place toxin.

The histopathologic changes reported in the index patient are those of constrictive bronchiolitis. Two forms of bronchiolitis have been described, bronchiolitis obliterans (BO) and constrictive bronchiolitis (CB). Non idiopathic BO may result from infectious agents, connective tissue disease and complications form heart, lung or bone transplants. BO also occurs after inhalation of chemical agents such nitrogen dioxide, and sulfur dioxide. Constrictive bronchiolitis (CB) refers to syndrome of airflow limitation due to bronchiolar and peribronchiolar inflammation and fibrosis. Clinical syndromes associated with CB include allograft recipients (bone marrow, heart and lung); collagen vascular diseases (rheumatoid arthritis, systemic lupus erythematosus); post infectious conditions (RSV, adenovirus); inhaled toxins (nitrogen dioxide, sulfur dioxide), drugs (penicillamine) and ulcerative colitis. Vapors of butter flavoring may now be added to this list.

What is the responsible agent(s) for the airway damage seen in popcorn factory workers ? Obvious suspected agent or agents are the vapors of butter flavoring. To test the hypothesis that vapors of butter flavoring are noxious agents to the lung, Hubbs and associates exposed rats to heated butter flavorings. Rats were exposed for 6 hours by inhalation and autopsied a day later. By gas chromatography, the vapors consisted of a complex of various organic gases with major peaks corresponding to diacetyl (2,3 butanedione), acetic acid, acetone and butyric acid, among others. DIACETYL was used as a marker of exposure concentration. In the lung, vapors containing containing 285-370 ppm diacetyl caused multifocal necrotizing bronchiolitis. In the nasal passages vapors containing 200-270 ppm diaceytl caused necrotizing rhinitis.

How is the diagnosis made ? Clearly, history of current or past exposure to vapors of butter flavoring is critical. Most cases reported thus far have been diagnosed as bronchiolitis on basis of clinical, spirometric and radiographic findings. Histopathologic responses described thus far include 1) non necrotizing granulomas, 2) constrictive bronchiolitis and 3) focal bronchiolar fibrosis and fibroblastic proliferation compressing bronchiolar lumina". The case illustrated in this session (contributed by Bill Travis) showed findings of constrictive bronchiolitis.

Flock Lung
A 26 year old man first presented with increasing shortness of breath associated with exercise and minimal but persistent dry cough. His O₂ saturation at rest was 97% but decreased to 93% upon walking 1200 ft in 5 minutes. The chest X ray showed patchy densities bilaterally in the upper lung fields. The high resolution CT of the chest showed a pattern consistent with bronchiolitis, most prominent in the upper lobes. The clinical differential diagnoses included hypersensitivity pneumonitis, bronchial asthma, idiopathic interstitial pneumonitis and an infectious process.

He was a machine operator at a Massachusetts synthetic flock factory and was primarily responsible for mixing and loading machines with raw flock material. He denied smoking or family history of tuberculosis or other chronic respiratory diseases. Therapy with a short course of prednisone provided only temporary relief of his symptoms. An open, video assisted open lung biopsy was performed.

Diagnosis
Flock lung (lymphocytic bronchiolitis and peribronchiolitis with multifocal lymphoid hyperplasia) (LBP-BLH)

Discussion
Kern and associates first called attention (1997) to the occurrence of chronic interstitial lung disease among workers in the nylon flocking industry. Flocking is a process in which continuous synthetic fibers (mainly nylon) are chopped into short segments and then applied to an adhesive-coated backing fabric to produce a plush finish such as in fabrics used to upholster seating in the automotive industry. Although the cut fibers, or flock, are of non-respirable size, smaller respirable nylon shards may be produced during processing Two other young men employed at a nylon flocking plant in Rhode Island developed interstitial lung disease of unknown etiology. This led to identification of four additional cases for a total of seven cases. In six of seven patients who had a biopsy, a picture of non specific interstitial pneumonitis was noted. The seventh had bronchiolitis obliterans organizing pneumonia. All seven had peribronchovascular interstitial lymphoid nodules, with germinal centers and most had lymphocytic bronchiolitis and interstitial fibrosis. All of these patients improved symptomatically after leaving work for variable periods of time.

To investigate the problem, the National Institute of Occupational Safety and Health (NIOSH) of the Centers for Disease Control hosted a clinical-pathological workshop to review additional accumulated case load of patients with interstitial lung disease associated with the flocking industry. In all, biopsies from fifteen patients (eight open, seven transbronchial) were reviewed at the workshop by a panel of pathologists led by Tom Colby. In this group of flock workers the main histopathologic findings was a peribronchiolar lymphocytic interstitial inflammation with associated lymphoid hyperplasia.

The histopathologic features in the group of 15 cases were classified as prominent, variable and not found. Prominent features included peribronchiolar lymphocytes interstitial (BLH); Bronchiolar mural lymphocytic inflammation and peribronchiolar alveolar macrophages. Variable features included Type II hyperplasia; non-lymphocytic interstitial inflammatory cells, bronchiolar mural fibrosis and organizing air space processes such as BOOP. Features not identified included granulomas, smooth muscle hyperplasia, honeycombing, vascular changes and severe interstitial fibrosis.

How is the diagnosis of flock lung made? In the proper clinical setting, a diagnosis can be made in biopsy material that shows LBP-BLH, bronchiolar mural lymphocytic infiltration and peribronchiolar accumulation of macrophages.

The rest of the story: More recent cases of workers employed in a North Carolina nylon producing plant reported in 2000 by Kern et al had differing histopathology, with one worker showing DIP on lung biopsy and one showing mild acute inflammation on BAL fluid. Of two other workers one had marked acute inflammation and the other, malignant cells in his BAL fluid. In one other recent case from Nova Scotia, a 60 year old nylon flock worker also showed a different pattern of lung injury in his biopsy with a less prominent lymphoid hyperplasia and a rather distinct histiocytic component to the inflammatory infiltrate (Alex Boag, personal communication, October 2003). These additional cases suggest a pathologic spectrum of disease broader than that first described at the NIOSH conference and further support the likelihood that flock workers lung is caused by inhaled fragments of nylon fibers (Kern).

Summary
The putative (or confirmed) work-related toxins, clinical manifestations, principal pulmonary function abnormalities, main histopathology and key references for aluminum, popcorn and flock lungs are summarized in the following table:

ALUMINUM LUNG, POPCORN LUNG AND FLOCK LUNG

Lung Lesion	# of cases	Toxic agent	Signs and symptoms	Respiratory function	Pathologic findings	Main refs
Aluminum lung	1	Elemental aluminum	Cough Dyspnea	Normal in this case	Diffuse fibrosis, granulomas, aggregates of histiocytes	Hull Roggli Corrin
Popcorn lung	8	Butter flavoring ketones. Diacetyl and other vapors ?	Cough Dyspnea	¯Fev1	Non-necrotizing granulomas, Constrictive bronchiolitis	Kreiss Hubbs Parmet
Flock lung	15	Respirable shard-like nylon fibers	Cough Dyspnea	O2 desaturation on exercise	LB PB LH	Boag Kern

LB = Lymphocytic bronchiolitis
PB = Peribronchiolitis
LH = Lymphoid Hyperplasia

Aluminum Lung

1. Shaver CG, Ridell AR. Lung changes associated with the manufacture of alumina abrasives. Am J Med Sci 29:145-157, 1947.
2. Hull MJ and Abraham JL. Aluminum welding fume – induced pneumoconiosis. Human Pathol 33:819-825, 2002.
3. Bomans DM, Van Suylen RT, Lamers RJ et al. Association of man made natural fiber exposure and sarcoid-like granulomas. Resp. Med. 94:815-820, 2000.
4. Newman LS. Metals that cause sarcoidosis (review). Seminars in Respiratory Infections 12:212-220, 1998.
5. Herbert A, Sterling G, Abraham J, Corrin B. Desquamative interstitial pneumonia in an aluminum welder. Human Pathol 13:694-699, 1982.
6. Corrin B. Aluminium pneumoconiosis I. In vitro comparison of stamped aluminium powders containing different lubricating agents and of a granular aluminium powder. Br J Ind Med 20:268-276, 1963.
7. Corrin B. Aluminium pneumoconiosis II. Effect on the rat lung of intratracheal infection of stamped aluminium powders containing different lubricating agents and of a granular aluminium powder. Br J Ind Med 20:268-276, 1963.
8. De Vuyst P, Dumortier P, Scharden é L. Estenne M, Verherst A and Yernault JC. Sarcoid-like granulomatosis induced by aluminum dusts. Am Rev Resp Dis 135:493-497, 1987.
9. Roggli VL. Rare pneumoconiosis (metalloconiosis) Chapter 37, pp 411-422, In Saldana MJ ed Pathology of Pulmonary Disease The JB Lippincott Co., Philadelphia, 1994.
10. Lillie RD. Histopathologic technique and practical histochemistry. Third Ed, McGraw Hill, New York, Toronto, 1965 pp 433-434.

Popcorn Lung

11. Kreiss K, Gomma A, Kullman G et al. Clinical bronchiolitis obliterans at a microwave popcorn plant. NEJM 347:330-338, 2002.
12. Parmet AJ and Von Essen S. Rapidly progressive fixed airway obstructive disease in popcorn workers: a new occupational pulmonary illness ? J. Occup Environ Med 44:216-218, 2002.
13. Akpinar-Elci M, Kanwall R and Kreiss K. Bronchiolitis obliterans syndrome in popcorn plant workers. Amer J Resp Crit care Med 163:A526, 2002.
14. Hubbs AF, Batteli LA, Goldsmith WT et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicology and Applied Pharmacology 185:128-135, 2002.
15. Myers JL, Colby TV. Pathologic manifestations of bronchiolitis obliterans, constrictive bronchiolitis, cryptogenic organizing pneumonia and diffuse peribronchiolitis. Clin Chest Med 14:611-622, 1993.

Flock Lung

16. Kern DG, Durand KTH, Crausman RS, et al. Nonspecific interstitial pneumonia in the synthetic textile industry. American Journal of Respiratory & Critical Care Medicine 155:A810 (Abstract), 1997.
17. Kern DG, Crausman RS, Durand KTH, et al. Flock Worker's Lung: Chronic Interstitial Lung Disease in the Nylon Flocking Industry. Annals of Internal Medicine 129;261-272, 1998.
18. Eschenbacher WL, Kreiss K, Lougheed MD, Pransky GS, Castellan RM. Clinical Pathology Workshop Summary on Nylon-Flock Associated Interstitial Pneumonitis. Amer Rev. Resp. Crit Care Med 159:2003-2008, 1998.
19. Boag AH, Colby TV, Fraire AE, Kuhn CH, Roggli, VL, Travis WD and Vallyathan V. The pathology of interstitial lung disease in nylon flock workers. Amer J Surg Path 23:1539-1545, 1999.
20. Lougheed MD, Roos JO, Waddell WR, et al. Desquamative interstitial pneumonitis and diffuse alveolar damage in textile workers. Potential role of mycotoxins. Chest 108:1196-1200, 1995.
21. Kern DG, Kuhn C, Wesley E, Pransky GS, Mello CJ, Fraire AE and Muller J. Flock workers lung, broadening the spectrum of clinico-pathology, narrowing the spectrum of suspected etiologies. CHEST 117:251-259, 2000.