Lesson 8, Volume 16—Metal-induced Granulomatous Lung Disease

By Karin A. Pacheco, MD; and Lee S. Newman, MD, MA

Objectives

1. Identify the metals that cause granulomatous lung disease.
2. Describe two models that explain the pathophysiology of metal-induced granulomatous lung disease.
3. List the occupations that are associated with exposure to metals causing granulomatous lung disease.
4. Describe the latency and clinical presentation of different metal-induced granulomatous lung diseases.
5. Describe the treatment and long-term prognosis of metal-induced granulomatous lung disease.

Key words

aluminum; barium; beryllium; cobalt; copper; gold; granulomatous lung disease; metals; rare earths; titanium; zirconium

Abbreviations

BeLPT=beryllium lymphocyte proliferation test; CBD = chronic beryllium disease; HLA = human lymphocyte antigen

Exposure to metal dusts and fumes occurs in many occupational settings. This article discusses the etiology and clinical presentation of metal-induced parenchymal lung diseases that manifest as granulomatous inflammation. The lung can respond to the inhalation of such metals in a variety of other ways. Although not the focus of this lesson, those responses should be kept in mind. Metal fume fever is an acute, short-lived response mediated by the release of specific cytokines, typically in response to zinc oxides. Airways disease such as asthma occurs in response to the inhalation of antigenic metals, eg, chromium, nickel, or cobalt. Parenchymal lung diseases such as lung fibrosis and granulomatous lung disorders are another consequence of metal inhalation.

Etiology

A variety of different metals possess antigenic or physicochemical properties that promote the development of granulomas in the lung. These metals and their associated pathology are listed in Table 1, and include aluminum, barium, beryllium, cobalt, copper, gold, rare earths, titanium, and zirconium. In the case of beryllium, such granulomas can also be found in the liver, spleen, myocardium, skeletal muscles, salivary gland, bone, and the skin. In aluminum- and zirconium-exposed individuals, noncaseating granulomas have also been detected in the lung and skin, although not in the viscera.

Epidemiology

The rates of disease and levels of exposure that lead to granulomatous lung disease have been the most carefully characterized for beryllium. From 2 to 16% of workers exposed to beryllium, depending on the industrial process, will become sensitized, ie, will develop a specific immune response to the metal.¹ Over time, the majority of the sensitized subgroup will develop a granulomatous lung disease at a rate of 7 to 11% per year. CBD continues to occur, in part, because exposures below the US Occupational Safety and Health Administration's permissible exposure limit of 2 mg/m³ can cause disease.^2,3 The Department of Energy has lowered the action level for beryllium exposure to 0.1 mg/m³. On average, CBD develops 6 to 10 years after exposure,² but it has been reported in as little as 50 days⁴ and more than 30 years after initial exposure.⁵ Disease often occurs even decades after work with beryllium has ceased. Recently, Kelleher et al⁶ reported a higher median cumulative exposure of 2.9 mg/m³-years in CBD cases from a beryllium machining plant, compared with 1.7 mg/m³-years of total exposure in the control group. Cases also have higher exposure to respirable size particles (ie, < 6 mm in diameter).⁷

The rate of granulomatous lung disease in workers exposed to the other metals is unknown. Only case reports describe disease in affected workers. Because of the relative paucity of reports on these other metals, disease incidence can be inferred to be low. Several factors may contribute to the lower rates, including lower exposure to respirable and ultrafine particulates, particle deposition and clearance in the upper airway that protects the lower airway from exposure, as well as lower inherent immunogenicity of the metal.

Pathophysiology

All the metals discussed in this article are capable of inducing granulomas in the lung. Varying degrees of fibrosis are found with aluminum, beryllium, cobalt, copper, and rare earth exposure. Histologically, the pathologic lesion is comprised of a cluster of immune effector cells, predominantly lymphocytes, macrophages, epithelioid cells, multinucleated giant cells, mast cells, and fibroblasts.⁸ While there may be subtle histologic differences among these disorders, the major effector cell populations are consistent. It is likely that resident epithelial and endothelial cells contribute to the inflammatory lesions observed. The rim of the mature granuloma contains large numbers of mast cells that produce and release basic fibroblast growth factor (bFGF, FGF-2). Macrophages express platelet-derived growth factor and insulin-like growth factor-1, which, together with tumor necrosis factor and other locally derived cytokines, may promote fibroblast proliferation and secondary fibrosis.⁹ The cellular immune response triggered by the inhalation of these metals may be grouped into three categories—immune-mediated, foreign body, and unknown—listed in Table 2.

The immune response to beryllium serves as a model for immunologically driven granulomatous lung disease. Beryllium-specific T cell clones appear early in the course of the disease. The clones are predominantly CD4+ CD45RO+ memory T helper cells that express the AB T cell antigen receptor and are class II major histocompatibility complex restricted.^10,11 Evidence from several laboratories suggests that human lymphocyte antigen (HLA)-DP is needed to present antigen to the beryllium-reactive T lymphocyte. An allelic substitution of glutamic acid in position 69 of the HLA-DPB1 gene is associated with increased risk for beryllium sensitization, and suggests that the substitution improves the ability of the HLA molecule to present the beryllium-containing epitope to responder cells.¹² CBD T cells produce a T helper 1–type pattern of cytokines that help drive the immune response to the metal. These include high production of gamma interferon, as well as interleukin 2 and interleukin 6.^13,14 Whereas typical protein and polysaccharide antigens are processed and degraded following antigen presentation, metals are unique in that the antigenic metal is frequently retained in the lung and may be detected in the center of the surrounding granuloma. It is possible that retention of the antigen contributes to the formation of a noncaseating granuloma, as well as to the eventual progression to fibrosis. The specificity of the immune response is reflected in the ability of beryllium salts to stimulate T cells to proliferate, and forms the basis for the beryllium lymphocyte proliferation test (BeLPT).^15,16

Other metals can trigger a specific immune response. Aluminum, cobalt, gold, and zirconium have stimulated a delayed-type hypersensitivity response to intradermal injection, analogous to the purified protein derivative, in certain susceptible individuals. Aluminum, cobalt, gold, and titanium can also trigger in vitro lymphocyte proliferation.¹⁷ These findings suggest that the granulomatous lung disease found in response to these metals reflects an antigen-driven process in certain susceptible individuals.

The inflammatory response to barium, in contrast, is more consistent with a foreign body–type granuloma, and specific cellular immune responses to the metal appear to be absent.¹⁸ The histologic response to copper sulfate exposure is similar to foreign body–type granulomas in some cases, and to noncaseating granulomas in others.¹⁹ Rare earth elements, or lanthanides (lanthanum, cerium, yttrium, and others), have been detected in lung granulomas previously diagnosed as sarcoidosis, although whether this reflects an immune-specific or foreign body response is unknown.²⁰

Sources of Exposure to Metals

For most metals, exposure is occupational, and related to the manufacture and machining of metal parts. Machining and lathing, in particular, generate large amounts of small particles in the respirable range that may be particularly pathogenic. Among beryllium machinists, for example, > 50% of the beryllium machining particles in the breathing zone are < 10 mm in aerodynamic diameter.⁷ This small particle size may result in beryllium deposition into the deepest portion of the lung and may explain elevated rates of sensitization among beryllium machinists. Use of metalworking fluids does not necessarily reduce exposures. In a recent study of workers in a beryllium precision machining facility, 18 of 20 sensitized employees reported work as a machinist in the plant,⁶ although some bystanders also developed disease. Table 3 lists the industries in which workers may be exposed. Gold is the exception, in that exposure typically occurs in patients treated with gold as a pharmaceutical agent and not occupationally. While most cases of CBD occur in industry (ie, nuclear weapons manufacturing, electronics, and aerospace), nonoccupational cases of CBD continue to occur due to secondhand exposure to contaminated clothing as well.²¹ Community cases of CBD have occurred in the neighborhoods adjacent to beryllium manufacturing plants.^22,23

Sarcoid-like lung granulomatosis was reported in a 32-year-old chemist after working for 8 years in a workplace dusty with aluminum powder.²⁴ In another worker with similar disease, aluminum was identified in the lung biopsy specimen by electron probe microanalysis.²⁵ The inadvertent aspiration of barium sulfate during radiologic procedures involving the lung has caused foreign-body granulomas.¹⁸ The dense, discrete nodular opacities seen on chest radiograph appear to be due to the radiopacity of the barium sulfate itself. Tungsten carbide contains cobalt that is released into air during grinding and tool manufacture. Chronic cobalt exposure among hard metal workers can result in a number of respiratory diseases, including a granulomatous hypersensitivity pneumonitis with multinucleated giant cells on biopsy or in BAL. Once thought to be idiopathic, giant cell interstitial pneumonitis is often caused by cobalt.^26,27 Vineyard workers who spray an antimildew agent referred to as Bordeaux mixture containing 1 to 2.5% copper sulfate have developed both foreign body–type as well as more typical noncaseating granulomas on lung biopsy.^19,28 A cell-mediated hypersensitivity to gold treatment for rheumatoid arthritis has been implicated in the development of hypersensitivity pneumonitis.²⁹ Granulomatous pneumonitis has been documented in workers exposed to rare earths as photoengravers,³⁰ and in lens polishing and glass manufacture. Diffuse granulomas on lung biopsy, with titanium particles found in the granulomas, have been described in titanium-exposed workers,³¹ including a furnace feeder in a titanium production plant³² and a worker exposed to abrasion-generated titanium dioxide particles.³³ Granulomatous interstitial pneumonitis with mild fibrosis has been described in several workers exposed to zirconium silicates. Pulmonary particle analysis of the biopsy specimen from a nonsmoking ceramic tile worker demonstrated a dust burden 100 times the normal background level, consisting of clay minerals and zirconium silicate.³⁴ The interstitial noncaseating granulomas with epithelioid and giant cells from another lung biopsy contained weakly birefringent particles in interstitial histiocytes typically found in zirconium skin lesions.³⁵

Clinical Presentation and Diagnosis

The acute pneumonitis seen in response to high-dose exposures (eg, copper sulfate solution, beryllium) has largely disappeared in the United States and other developed economies as a result of improved workplace controls. Disease symptoms typically begin with the subtle onset of dyspnea on exertion, nonproductive cough, fatigue, and weight loss. In the case of beryllium-, cobalt-, and copper-associated disease, systemic symptoms such as fever and night sweats may also occur. Arthralgias, chest pain, and fever are present in some beryllium sensitized persons. Vineyard sprayers may present with cough, shortness of breath, recurrent respiratory infections, fever, purulent sputum, or hemoptysis.²⁷ The chest examination may demonstrate fine or dry rales, or it may be normal. The chest radiograph demonstrates different patterns of irregular or reticulonodular infiltrates in response to different metals, as summarized in Table 4. Of note, one third of patients with CBD demonstrate mediastinal and hilar lymphadenopathy that is easily confused with sarcoidosis. Patients with suspected disease should undergo pulmonary function tests. These typically show airflow obstruction early in the disease process, with subsequent mixed patterns of obstruction and restriction, and pure restriction in advanced or end-stage disease. Gas exchange abnormalities during exercise are notable in patients with CBD, and hypoxemia can occur with advanced fibrosis in parenchymal disease associated with beryllium, copper, and rare earth (lanthanide) metals. Pulmonary function tests and blood gases may also be normal, as in the few reported cases of zirconium-associated lung disease.

Diagnosis

A careful occupational and environmental history may implicate the etiologic metal involved. Table 3 lists some of the most common industries in which clinicians should suspect exposures to occur related to granulomatous inflammation. The history should include a listing of jobs that entailed metal dust or fume exposures, metals used, and conditions of exposure (ie, use of respiratory protection, availability of exhaust ventilation).³⁶

The diagnosis of granulomatous lung disease is usually made by lung biopsy. Linking the pathology to the metal exposure presents the clinical challenge. Typical histologic findings include poorly formed noncaseating granulomas frequently indistinguishable from those found in sarcoid or hypersensitivity pneumonitis.¹ Other histologic features may include an interstitial mononuclear cell infiltrate, multinucleated giant cells, T-lymphocytes, and varying degrees of fibrosis.

Detection of metal in the lavage fluid, in the granuloma, or by lung tissue particle analysis helps make the association of disease with metal exposure, but does not necessarily prove causation. It may be possible to demonstrate a specific immune reaction to the metal by patch testing, as in aluminum, beryllium, cobalt, gold, or zirconium exposure. Tests of in vitro lymphocyte proliferation to the metal in question, as has been demonstrated with aluminum, beryllium, cobalt, gold, and titanium, also help establish the presence of a specific immune response. Such immunologic tests help make the causal link.

A diagnostic algorithm has been best worked out for beryllium, to evaluate patients in whom CBD is suspected.⁴ Patients or exposed workers are screened for beryllium disease on the basis of known exposure, or are screened because they have been diagnosed with granulomatous lung disease and have an exposure history suggestive of beryllium. Patients are first evaluated for beryllium sensitization using the blood BeLPT,³⁷ which compares the ability of peripheral blood mononuclear cells to incorporate tritiated thymidine in response to media alone, to mitogens such as phytohemagglutinin or Candida, and to concentrations of beryllium sulfate. A stimulation index is calculated as the highest thymidine uptake for any concentration of beryllium compared to uptake of unstimulated cells. The presence of circulating lymphocytes that proliferate and incorporate thymidine in response to beryllium is indicative of sensitization to beryllium. If the BeLPT results are negative and the patient is asymptomatic and has normal chest radiographs, he or she is considered not sensitized and not further evaluated. If the patient has two abnormal BeLPTs, is symptomatic, or has an abnormal chest radiograph or proven granulomatous lung pathology, then he or she should undergo bronchoscopy with biopsy and BAL BeLPT. At the same time, infectious causes of granulomatous pathology can be excluded with culture. Occasionally, beryllium-reactive lymphocytes are limited to the lung, and a BAL BeLPT will be positive in the context of a negative peripheral blood cell BeLPT. In CBD, BAL fluid demonstrates a lymphocytosis, principally CD4+ T cells. The biopsy in CBD may show noncaseating granulomas and/or a mononuclear cell interstitial infiltrate that accumulate primarily in the interstitium and submucosa, often tracking along the bronchovascular bundle. If the peripheral blood or BAL BeLPT is reactive to beryllium salts but the biopsy findings are normal, the individual is considered sensitized only. He or she should be followed for progression to CBD, which occurs at a rate of approximately 10% per year in sensitized individuals.⁸

As an adjunct to the diagnosis of granulomatous disorders due to metals, it can be useful to perform mineral analysis on lung tissue specimens. Most metal particles can be identified using energy dispersive X-ray microanalysis with scanning electron microscopy or related techniques. Discovery of metals within affected tissues raises the probability of metal-induced granuloma formation, although such data must be viewed in context with the clinical and exposure data as well.¹⁷

Prevention and Treatment

The natural history of metal-induced granulomatous lung disease varies by type of metal, the dose received, and the kind and extent of the inflammatory response. Removal from exposure is the key therapeutic intervention for most patients. However, removal from all exposure may be impossible in those patients with retained metal antigen in the lung. There are limited data establishing that reducing future exposure to metals can positively affect the course of illness, but doing so is nonetheless considered medically prudent. Medical treatment is indicated in symptomatic patients, and is largely aimed at reducing lung inflammation and palliating the secondary consequences of hypoxemia, pulmonary hypertension, and right heart failure. In patients with CBD, a complete cure with or without treatment is rare, and therapy is aimed at controlling the disease. Symptomatic patients with CBD are typically treated with 40 mg of oral prednisone every day or every other day for 3 to 6 months. Prednisone is then tapered to the lowest alternate-day dose needed to maintain symptomatic and physiologic improvement. Inhaled steroids may be effective in treating milder disease and airways involvement, or as maintenance therapy following oral steroids. Methotrexate may be used as a steroid-sparing, not steroid-replacing, agent in those who do not respond to prednisone, or respond only at a dose associated with intolerable side effects. Patients receive an initial oral dose of 2.5 to 5 mg/wk, increasing up to 10 to 15 mg/wk. Prednisone may then be tapered to the lowest dose that maintains improvement. Of seven methotrexate-treated individuals with CBD to date, four improved (with a reduction in steroid dose in three), two did not improve, and one individual worsened.³⁸ Treatment was halted in one patient because of infection. Treatment with other immunosuppressive agents, such as cyclophosphamide or azathioprine, infliximab, or etanercept, has not been reported in patients with metal-induced granulomatous disorders. Cytokine therapy, such as with anti–tumor necrosis factor-a receptor blockers, may be used in the future to inactivate those mediators that participate in the development of fibrosis. Supplemental oxygen, limited use of diuretics, calcium-channel blockers, and angiotensin-converting enzyme inhibitors are well-used second-line therapy for pulmonary hypertension and right-sided heart failure. Pulmonary rehabilitation can help patients function with their impairment.

Primary prevention is the best treatment, given our limited ability to halt or reverse the progression of disease once the patient has progressed to end-stage fibrosis and persistent granulomatous inflammation. The best hope for prevention is to substitute safer working materials, limit the number of exposed workers, and introduce tighter industrial hygiene controls. In the case of beryllium, exposed workers should be screened and followed for sensitization or disease.⁴

References

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