Pulmonary sarcoid-like granulomatosis induced by aluminum dust: report of a case and literature review

Awide range of pulmonary pathology is attributed to aluminum dust exposure, including interstitial fibrosis,1–5 desquamative interstitial pneumonia,6 and pulmonary alveolar proteinosis.7 To our knowledge, granulomatous lung disease induced by aluminum dust is rare, only two cases were reported in literatures.8,9 We had the opportunity to make a diagnosis of pulmonary sarcoid-like granulomatosis in a patient exposed to aluminum dust. Herein, we report the clinical history, radiographic and histopathological findings in this patient, and the detailed mineralogical analyses performed on lung tissue obtained by open lung biopsy. CASE REPORT A 50-year-old woman presented intermittently with cough, produced white frothy sputum, and dyspnea for 3 years. The doctors in local hospital suspected that the patient got chronic bronchitis, and she was invariably treated with antibacterial agents. Initially, the symptoms of cough and dyspnea were relieved, but easily recurred. However, over the last half month, the aforementioned symptoms significantly progressed. A chest X-ray film was performed in local hospital, and showed diffuse infiltrative opacities in middle and lower lung zones (Fig. 1), therefore the patient was transferred to our hospital for further diagnosis and treatment. The patient had no history of asthma, allergies, or any family history of respiratory disorders. She never smoked cigarettes and denied having tuberculosis, night sweats, fever, chills, or weight loss previously. She had worked in a metal reclamation factory for 15 years, where she was extensively exposed to aluminum dust, and also exposed to iron, to a much less degree, copper, zinc, and nickel. Beryllium was not used. She complained that the work environment was dusty, but she did not wear protective mask. She was still working until she came to medical attention.Fig. 1.: Chest radiograph showing bilateral diffuse infiltrative opacities, predominantly in left middle and lower lung fields.Physical examination revealed a well-developed, well-nourished woman. No evidence of uveitis, cervical or supraclavicular lymphadenopathy. Some crackles on the lower lung field could be heard using stethoscope. There was no enlargement of the liver, kidney, or spleen, and peripheral pulses were normal. Clubbing, cyanosis, and edema were absent, and there were no significant rashes. On admission, she was hypoxemic at room air oxygen levels (pH, 7.43; partial pressure of carbon dioxide 29.9 mmHg; partial pressure of oxygen, 58 mmHg) and had a pulse oximetry reading of 91%. After admission, routine hematological and biochemical blood tests were normal. Purified protein derivative (PPD) skin testing was positive at 10 mm×15 mm of induration. Sputum microscopy and culture for bacteria, acid fast bacilli and fungi were negative. The erythrocyte sedimentation rate was elevated with 28 mm/h. The electrolyte, renal and liver tests were normal. Autoantibodies such as antinuclear antibody, rheumatoid factor, anti-single stranded DNA antibody, anti-double stranded DNA antibody, anti-extractable nuclear antigen antibodies were all negative, and anti-neutrophil cytoplasmic antibodies were also negative. Lung function studies showed a restrictive pattern with a total lung capacity (TLC) by helium dilution of 1.77 L (35.6% of predicted value), a forced vital capacity of 1.34 L (44.1% pred), forced expiratory volume in 1 second 1.24 L (47.7% pred), and a diffusing capacity of the lung for carbon monoxide (DLco) decreased to 10% of predicted value. A high-resolution CT (HRCT) scan findings consisted of bilateral areas of ground-glass attenuation (Figs. 2, 3), and patchy areas of consolidation, extensive reticular hyperattenuating areas and traction bronchiectasis (Fig. 2). Neither evidence of pleural fluid, hilar or mediastinal adenopathy, nor cardiac enlargement was noted.Figs. 2, 3.: High-resolution CT scans (HRCT) showing bilateral areas of ground-glass attenuation, patchy areas of consolidation, extensive reticular hyperattenuating areas and traction bronchiectasis.A diagnosis of interstitial pneumonia was considered. To secure a histopathological diagnosis, open lung biopsy was performed, therefore, wedge biopsies of the lung were taken from the left upper and lower lobes. Histologic sections showed clusters of well-formed nonnecrotizing granulomas with multinucleated giant cells (Fig. 4), mainly along bronchovascular bundles; in some granulomas, multinucleated giant cells of Langerhans or foreign body type were present (Fig. 5). The surrounding parenchyma showed mild chronic interstitial inflammation, but fibrosis and honeycombing were absent. Examination with polarizing light microscopy demonstrated that no foreign bodies and birefringent particles were observed in the granulomas. Grocottmethanamine stains, periodic acid-Schiff stains and acid-fast bacillus (AFB) stains on biopsy specimens were negative.Fig. 4.: Presence of multiple isolated and confluent granulomas in an otherwise normal parenchyma (HE, original magnification ×100).Fig. 5.: In some granulomas, multinucleated giant cells of Langerhans or foreign body type were present (HE, original magnification ×400).Mineralogical analysis After exclusion of infectious agents, based upon this occupational history, and initial pathology, we suspected that exposure to one or more materials resulting from her occupational history may be implicated in the development of granulomatous pulmonary disease. In order to clarify whether or not inorganic particulates identified as aluminum were actually present in the granulomas. Scanning electron microscopy (SEM, JEOL-JSM-6360LV, JEOL Inc., Japan) and energydispersive radiograph analysis (EDXA, EDAXGENESIS 2000 XM analyzer, EDAX Inc., USA) were performed on biopsy specimen. Particulates of lung were measured using morphometric in situ analysis of tissue sections.10–12 Briefly, a 5-micron thick section of paraffinembedded lung tissue was mounted on a glass slide, deparaffinized by thorough washing with xylene, and examined by secondary electron imaging (SEI), backscattered electron imaging (BEI), and EDXA. Areas with the granulomas were readily identified by SEI. With negative BEI, large quantities of bright, round to irregular, particles were seen in the granulomas. Such particles were not apparent in surrounding nongranulomatous tissue. EDXA of the particles yielded discrete peaks (Al, 1.486 keV) for aluminum (Fig. 6). Spectra from lung tissue devoid of particles yielded no trace peaks for aluminum. Elemental maps of the original dust to which this patient exposed were performed using the same procedure described above for the lung tissue. Similar EDXA (Fig. 7) of the particles in tissue was found in the original dust to which the patient exposed. As a control, pulmonary tissue from a case of nonnecrotizing granulomatous inflammation with clinical features consistent with sarcoidosis and a negative aluminum exposure history was subjected to similar analysis. BEI-positive particles were not identified. EDXA of the granulomas did not demonstrate any aluminum peaks. The only other elements identified were carbon and in some areas, oxygen.Fig. 6.: Energy dispersive X-ray analysis (EDXA) spectrum of a particle in granuloma with multinucleate giant cells showing a prominent peak for aluminum (Al, 1. 486 keV).Fig. 7.: Similar EDXA (Fig. 6) of the particles in tissue, showing a prominent peak for aluminum (Al, 1. 486 keV) in the original dust to which the patient exposed.Treatment and follow-up Based upon this occupational history, combined histological and mineralogical studies, the patient was finally diagnosed as pulmonary sarcoid-like granulomatosis induced by aluminum dust. She was treated with prednisolone 80 mg for 10 days, and then, prednisone 40 mg/d. Thirty days later, her cough, sputum and dyspnea obviously improved, and the radiological opacity decreased (Figs. 8, 9). Her pulmonary function showed marked improvement of DLco, and minimal improvement of forced vital capacity (FVC) and TLC, 4 months after therapy (Table). Currently, she remains under follow-up.Figs. 8, 9.: Follow-up HRCT scans at the level similar to those in Figs. 2, 3 obtained a month after therapy showing areas of ground-glass attenuation in upper and lower fields decrease obviously in extent compared with Fig. 2 and Fig. 3, with remaining reticular hyperattenuating areas and traction bronchiectasis.Table: Results of pulmonary function tests (predicted %)DISCUSSION Granulomatous disease of the lung may occur in response to a variety of infectious agents and to the inhalation of both organic and inorganic substances.13 In most instances, a search for a specific agent that results in the granulomatous tissue reaction is very difficult. Occasionally, the specific causal agent has only been identified in a small number of patients. This patient presented with a chronic interstitial granulomatous lung disease. Differential diagnosis includes many possibilities. Infectious diseases could reasonably be excluded because of the absence of the serologic and bacteriologic abnormalities. Against sarcoidosis, there was no extrathoracic involvement or mediastinal adenopathy. After exclusion of infectious agents and sarcoidosis, based upon this occupational history, and initial pathology, we suspected that exposure to one or more materials resulting from her occupational history might be implicated in the development of granulomatous pulmonary disease. With mineralogical analysis, EDXA spectrum of the particles in granuloma with multinucleate giant cells yielded discrete peaks for aluminum (Al, 1.486 keV), meanwhile, similar EDXA of the particles in tissue was found in the original dust to which the patient exposed, suggesting that there was a distinct relation between aluminum deposits and pulmonary sarcoid-like granulomas in this patient. Potroom asthma has been recognized since the 1930s. Parenchymal disease was first described in aluminum refineries by Shaver and Riddell in the 1940s.14,15 Occupational exposure to aluminum while grinding, polishing, and welding has been associated with parenchymal lung disease,16 including chronic bronchitis, pulmonary fibrosis, acute tracheobronchitis, pneumonitis, pulmonary alveolar proteinosis, and pulmonary edema. A number of pulmonary effects have been attributed to aluminum exposure. The respiratory effects depend to some extent on the form of aluminum or stage in processing in which exposure occurs. The mechanisms responsible for aluminum-induced parenchymal disease remain poorly defined. Clusters of interstitial pulmonary fibrosis in aluminum powder and potroom workers have been well documented in Europe, New Zealand, Canada, and the United States.15,16 In most reported cases, histologically, the lung showed diffuse and extensive fibrosis with a variable degree of emphysema.2–5,16,17 However, our case differs from those described in the literature for aluminum related human lung disease.1,15–17 In this patient, the main histological picture was the presence of multiple granulomas in the interstitium. Interestingly, there were two similar cases reported in literature. In 1978, Chen et al8 first reported a 31-year-old patient who was not a worker in an aluminum processing factory, but was a worker in the aircraft industry, heavily exposed to aluminum powder, who developed noncaseating granulomatous lung disease. Histologic examination showed infiltration with foreign body granulomas, and analysis by electron microscopy confirmed the presence of aluminum in the granulomas. Later on, De Vuyst et al9 reported that interstitial lung disease developed in a 32-year-old chemist after working for 8 years in a dirty atomsphere containing aluminum powders, who developed noncaseating granulomatous lung disease with an initial diagnosis of sarcoidosis on biopsy. Transbronchial lung biopsies showed sarcoid-like epithelioid granulomas. These granulomas contained dust identified by mineralogic analyses as consisting mainly of aluminum particles. A recent case of lung granulomatosis attributed to occupational exposure to beryllium and aluminum had also been reported in a dental laboratory technician.18 The diagnosis of sarcoidosis is established when clinical and radiological findings are supported by histological evidence of noncaseating epithelioid cell granulomas, and granulomas of known causes and local sarcoid reactions must be excluded.13,19 Based upon the definition of sarcoidosis, this occupational history, combined histological and mineralogical studies, aluminum dust could account for the development of sarcoid-like pulmonary granulomas in this patient, therefore, we consider the diagnosis of pulmonary sarcoid-like granulomatosis as most likely related to occupational exposure to aluminum dust. Although the causes of sarcoidosis remain unknown, there are lines of evidence supporting the idea that sarcoidosis results from exposure of genetically susceptible hosts to specific environmental agents.13,19 Indeed, some have queried the possibility that sarcoidosis is an environmental disorder due to the inhalation of many antigens capable of sensitizing its host. Therefore, the accurate diagnosis of sarcoidosis depends on a stringent inquiry concerning potential exposures to both organic and inorganic antigens. Recently, Drent et al20 reported that the records of originally diagnosed sarcoidosis patients - who visited their outpatient clinic between 1996 and 1999 - were reviewed, and the occupational history of 50 cases with sarcoidosis revealed exposure to man-made mineral fiber in 14 cases. EDXA of seven biopsy specimen revealed silica, aluminum, and titanium, which are elements of man-made mineral fiber. A distinct relation between fiber deposits and pulmonary sarcoid-like granulomas was found. Therefore, the search for any possible relevant exposure of a patient with suspected sarcoidosis seems mandatory.13,19,20 Acknowledgements: We are grateful to Prof. XUE Ya-jun, Department of Materials Engineering, Nanjing Institute of Technology, for performing the mineralogical analysis. We are also grateful to Prof. TIAN Cheng-gong, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, for manuscript revision.