In the past decade, the demand for indium has grown worldwide, driven by the popularity of LCDs (7
). Although ITO substitutes that provide the dual functions of transparency and conductivity are available, they are regarded as technically inferior (zinc-tin oxide) or untested for mass production (carbon nanotubes) (7
). Thus, an understanding of the health effects of ITO production is imperative.
We describe two cases of pulmonary alveolar proteinosis in workers involved in the production and recycling of ITO. Pulmonary alveolar proteinosis is a rare disease, characterized by an intraalveolar accumulation of surfactant components and resultant impaired gas exchange (8
). Progressive dyspnea and cough are common presenting symptoms, and chest imaging typically shows alveolar infiltrates, although interstitial patterns are seen (10
). Since the introduction of whole lung lavage, in which saline is used to physically remove excess alveolar material, survival has improved, but the therapy is not curative and residual impairment and recurrence are observed (9
). Although most cases of adult pulmonary alveolar proteinosis traditionally have been considered idiopathic, a minority is classified as secondary to another disease, such as a hematological disorder (8
). Cases of pulmonary alveolar proteinosis also have been reported in association with occupational exposures, including silica, titanium, aluminum, cement, and tin (11
). Recent investigations into the pathophysiology of idiopathic pulmonary alveolar proteinosis have implicated autoantibodies against GM-CSF that lead to impaired alveolar macrophage function and decreased surfactant clearance (8
Previous reports have provided evidence that exposure to indium can result in pulmonary pathology. Animal studies have demonstrated that exposure to indium oxide, indium phosphide, and ITO results in a spectrum of lesions including alveolar proteinosis and interstitial fibrosis (17
). Lison and colleagues recently suggested that ITO is particularly reactive (21
). In rats, a single administration of ITO, indium oxide, tin oxide, or a nonsintered mixture of indium oxide and tin oxide resulted in alveolitis that persisted at 60 days, accompanied by proteinaceous material in the alveolar lumen; the response to ITO appeared more marked than the responses to its components or the nonsintered mixture (21
). The authors also reported that ITO was cytotoxic to cultured alveolar macrophages but not cultured lung epithelial cells (21
), which is notable given the role of macrophage impairment in the pathogenesis of pulmonary alveolar proteinosis.
In the two cases of lung disease in Japanese ITO workers, the pathology was described as interstitial pneumonia in the first worker, who ultimately died of bilateral pneumothorax (1
), and pulmonary fibrosis in the second (2
). Both of those workers were engaged in surface grinding of ITO, each had elevated serum indium levels, and the presence of indium in their lungs was confirmed (1
). A subsequent investigation found interstitial changes on high-resolution computed tomography scans of the chest in 23 (21%) of 108 tested current and former workers from the same workplace and a positive correlation between serum indium concentration and degree of radiographic changes (22
). More recently, a cross-sectional study of 93 indium-exposed and 93 nonexposed workers in ITO manufacturing and recycling plants in Japan did not find an association between radiograph changes and indium exposure but did demonstrate exposure–response relationships between serum indium concentrations and serum markers of lung inflammation (23
We were unable to find other reports of pulmonary alveolar proteinosis in ITO workers. In addition to the corroborative results of animal exposure studies and previous reports of lung pathology, several lines of evidence suggest that these cases resulted from workplace exposures. Pulmonary alveolar proteinosis is an exceedingly uncommon disease: there have been fewer than 800 cases reported in the literature since its first description in the 1950s (8
). Estimates of the disease's annual incidence and prevalence vary from 0.24 to 0.49 and 2.0 to 6.2 per million population, respectively (8
). Thus, the occurrence by chance of two cases in a single facility's small workforce is highly unlikely. The temporal relationship to employment is also compelling: neither worker had a history of respiratory symptoms or disease before being hired, and each became symptomatic months into employment. Furthermore, the finding of indium particles within their lungs, although not irrefutable evidence of causation, confirms occupational respiratory exposure and is consistent with a case-control study that found higher concentrations of inorganic particles in the lung tissue of patients with pulmonary alveolar proteinosis than in the lung tissue of control subjects (25
). Finally, we are aware of two additional young workers from the same facility who had diffuse abnormalities on chest imaging studies detected through a workplace medical surveillance program; whereas their subsequent work-ups were insufficient to establish a diagnosis, the overall burden of lung disease in this small group of workers serves to implicate shared workplace exposures.
There are several challenges to be addressed. The worker in Case 1 had previous occupational experience installing cellulose insulation, and pulmonary alveolar proteinosis related to household exposure to cellulose insulation dust has been reported (26
). However, his work with insulation preceded the symptom onset by years, he reported consistent use of respiratory protection in that job, and pathological examination did not reveal fibrous material, all which indicates that his prior occupational experience is likely noncontributory. In addition, early in his employment at the facility he worked with cadmium, which has been found to cause pathological changes similar to pulmonary alveolar proteinosis in animals (27
). Yet cadmium is an unlikely cause of his disease, given the relatively short period he worked with the substance and the minimal exposure expected with packing finished product. In Case 2, the worker's diagnosis was prompted by an inhalational exposure to ammonium hydroxide, which raises questions about that compound's role in his development of pulmonary alveolar proteinosis. However, it is difficult to reconcile his brief exposure to ammonium hydroxide, a well-recognized irritant that damages the respiratory epithelium through chemical and thermal mechanisms (28
), with his earlier onset of respiratory symptoms and the diffuse interstitial changes on chest radiograph detected within a day of the exposure. Far more plausible is the notion that the ammonium hydroxide exposure served to bring an underlying condition to medical attention. Another issue is that this worker did not have a detectable blood indium level when tested, in contrast to the Japanese experience (1
). Whether technical differences, such as use of plasma or serum, significantly affect results remains to be determined. Nonetheless, the detection of indium in his lung tissue confirms his exposure.
Why some ITO-exposed workers appear to have developed interstitial lung disease and others pulmonary alveolar proteinosis is unclear. Both of the Japanese case reports described histopathological features suggestive of pulmonary alveolar proteinosis (30
): intraalveolar accumulation of cholesterol clefts and particle-laden alveolar macrophages (1
). Furthermore, although the abnormalities in pulmonary alveolar proteinosis are classically confined to the alveolar spaces, interstitial infiltration and fibrosis have been described (9
). Thus, the Japanese cases may represent pulmonary alveolar proteinosis with associated interstitial involvement. Given the possible variations in disease manifestions, pulmonary alveolar proteinosis should be considered in the differential diagnosis of unexplained interstitial lung disease generally (31
) and in patients with ITO exposure specifically.
Pulmonary alveolar proteinosis associated with occupational exposure has traditionally been categorized, along with that associated with hematological disorders and other conditions, as secondary disease (8
). Whereas autoantibodies to GM-CSF have been found to be absent in secondary pulmonary alveolar proteinosis, the secondary cases studied have been limited to those with implicated comorbid diseases (24
). Inoue and colleagues recently described a large pulmonary alveolar proteinosis cohort with autoantibodies to GM-CSF (24
). The observation that 26% of this group reported a history of inhalational dust exposure (24
) raises the possibility that autoimmunity plays a role in the pathophysiology of exposure-related pulmonary alveolar proteinosis and highlights the limitations of the conventional categorizations of this disease. The concept of a chemical exposure triggering an autoimmune response is not new; indeed, a growing literature links heavy metals and other xenobiotics to immune activation and loss of self-tolerance (36
). We were unable to find other reports of GM-CSF antibody testing in patients with exposure-related pulmonary alveolar proteinosis. Although the test was not performed in the first case we describe, the presence of autoantibodies to GM-CSF in Case 2 serves to tie the ITO exposure to an autoimmune disease mechanism. Yet this intriguing finding prompts many further questions: for instance, do all cases of ITO-related disease involve autoimmunity; what is the pathophysiologic relevance of the direct macrophage toxicity of ITO (21
); and what is the role of exposures, more generally, in autoimmune pulmonary alveolar proteinosis? Ultimately, an investigation into how exposure to ITO and other compounds might lead to the development of GM-CSF autoantibodies would shed needed light on disease mechanism.
In conclusion, these cases, as well as previous experimental and clinical reports, suggest that inhalational exposure to ITO causes pulmonary alveolar proteinosis. Clinicians and public health officials should be alert to the potential for pulmonary toxicity with ITO exposure, and effective control measures should be determined and implemented in workplaces where ITO is used. The role of autoantibodies to GM-CSF in ITO-related pulmonary alveolar proteinosis specifically, and exposure-related pulmonary alveolar proteinosis more generally, should be explored further.