tis, granulomatous lung diseases, and other interstitial lung diseases (Table 37.1). As depicted in Table 37.1 numerous toxic compounds and bioaerosols generated at workplaces are capable of inducing ILDs. In this chapter we will exemplary discuss a number of pulmonary disorders caused by the inhalation of metallic and organic chemical dusts at the workplace without claiming to be comprehensive. The ­diseases discussed in this chapter are either of immunologic origin or can be subsumed under pneumoconiosis. However, hypersensitivity pneumonitis, silicosis, and coal workers lung are discussed elsewhere in this monograph.

In the clinical context described for CBD above we will discuss CBD and the following disorders in this chapter: indium–tin oxide-lung disease, hard metal lung, fockworker’s disease, asbestosis, sidero brosis, popcorn worker’s lung, and nanoparticle induced interstitial lung disease.

Acute Berylliosis

Even though safety measures in industrial countries reduced the risk of acute beryllium disease, acute berylliosis deserves a mention. It clinically manifests shortly after exposure to high dose of Beryllium exposure, as it can still accidentally happen [14, 15]. It shares clinical characteristics of acute sarcoidosis and toxic alveolitis with similarities to hypersensitivity pneumonitis [16]. Biopsy specimens of the lung show

a lymphocytic interstitial pneumonitis indistinguishable from chemical pneumonitis due to other causes. Approximately one third of these acute cases progresses into chronic granulomatous lung disease [17].

Chronic Beryllium Disease

De nition

Chronic beryllium disease (CBD) is in general an occupational hypersensitivity disorder elicited by exposure to beryllium containing dusts and fumes. It phenocopies sarcoidosis with identical clinical, radiological, and histological ndings (Table 37.2). Generally, chronic beryllium disease affects more likely organs with contact to beryllium-containing dusts (e.g., skin, lungs, and eyes). In the diagnostic work-up, chronic beryllium disease is characterized by (i) the exposition of the affected person to beryllium (which occurs in general at the working place) and (ii) tests demonstrating beryllium-sensitization. This sensitization is the only known difference between these two disorders. Beryllium sensitization is most frequently documented by the ex vivo beryllium-­ lymphocyte proliferation test (Be-LPT), which can be performed with lymphocytes from peripheral blood or from bronchoalveolar lavage. The latter one in our hands is more sensitive.

Table 37.2  Workplaces, components, and products with potential beryllium-exposure

Exposure

Beryllium-exposed individuals may be unaware of their exposure and physicians may be unaware of beryllium-­related health effects leading to non-recognized beryllium sensitization and CBD. Therefore, an occupational case history covering the entire professional life is mandatory in the diagnostic workup of granulomatous disorders. Typical industries with use of beryllium and the hazard of occupational beryllium dust exposition are depicted in Table 37.3. Beryllium sensitization is usually recognized in occupational monitoring programs of exposed workers or in the diagnostic workup of granulomatous disorders. Asymptomatic individuals without any evidence for granulomatous disease and documented beryllium sensitization must not be diagnosed as CBD but are at risk to develop CBD and require counseling whether a change of workplace is appropriate to terminate exposure [18].

Beryllium is a metallic processed into beryllium oxide, beryllium metal, beryllium alloys, and composite materials. The addition of beryllium improves the electrical and thermal conductivity of alloys and increases the mechanical strength of alloys. The most important product is copper alloy containing 0.15 to 2.0% beryllium. More than 80% of the world’s beryllium ore mining and processing is done in the United States. Beryllium is frequently used in electronic and microelectronic applications, in nuclear indus-

Table 37.3  Clinical, radiographic, and laboratory differences between CBD and sarcoidosis

tries, as an additive to glass or plastics and found in gems. Workers potentially exposed to beryllium are miners, beryllium alloy fabricators, phosphor manufacturers, ceramic workers, missile technicians, nuclear reactor workers, electric, electronic, and optical equipment workers, and jewelers. Noteworthy, workers in down-stream industries and crafts using beryllium-­containing parts may be exposed. Past exposure of workers involved in fuorescent powder manufacture and in the manufacture and salvage of fuorescent lamps may still cause disease. The recycling of electronic parts is a relatively new business with implied beryllium exposure.

Of note, several nonoccupational cases of CBD have already been diagnosed [12, 19, 20] and most cases masquerade as sarcoidosis [21, 22]. Those cases may be caused by indirect or paraoccupational beryllium exposure at the workplace such as secretaries or security guards [22], by exhaust air of beryllium utilizing industries endangering residents in their vicinity [23] or by contaminated clothing brought to the home affecting family members [24, 25]. The latter is of practical relevance since a genetic background de ning susceptibility for [26, 27] and progression of CBD [28] is known

and this background is shared by family members, so that an extended occupational history in the diagnostic workup is mandatory/highly required.

Epidemiology

Soon after industrial utilization of beryllium started in the 1930s, acute beryllium disease was recognized, leading to register acute and chronic beryllium diseases by the Atomic Energy Commission of the United States of America. The distribution of the chronic disease did not follow a linear exposure-response model which led to the hypothesis that CBD is a hypersensitivity disease with a genetic background de ning susceptibility and in 1949 a workplace airborne exposure limit of 2 μg/m3 averaged over an 8-h period was established that was later reduced to a Threshold Limit Value (TLV) of 0.05 μg/m3 for an average 8-h period by the National Institute for Occupational Safety and Health of the United States into effect to prevent beryllium sensitization and subsequent CBD. However, reports on community acquired CBD indicate that low level exposure is suf cient to induce CBD in susceptible individuals [23] and preventive programs are able to reduce but not to eliminate sensitization [29].

Exact numbers of current or previous exposure of workers to beryllium are not known in any nation. Estimates for the United States name up to 135.000 current and up to 800.000 former beryllium exposed workers [30]. Downstream exposure (i.e., handling of beryllium-containing alloys) could not be included in this estimate and may increase the number of exposed, sensitized, and diseased individuals. Furthermore, CBD may be misdiagnosed as sarcoidosis. In a binational study in Germany and Israel obtaining a detailed occupational history in the diagnostic workup of suspected sarcoidosis in more than 500 patients, 84 disclosed a potential beryllium exposure and underwent beryllium lymphocyte proliferation testing, which demonstrated beryllium sensitization in 34 patients leading to the diagnosis of CBD [21], although all diagnostic criteria for sarcoidosis have been satis ed according to actual standards [31]. On the other hand, a Canadian study using a similar approach, even employing two different tests to check for beryllium sensitization, could not identity latent CBD in 34 sarcoidosis patients with exposure to metal dusts or fumes from whom 17 had documented beryllium exposure [32]. Non-recognized CBD will respond to corticosteroid therapy aimed to control sarcoidosis but due to persistent beryllium exposure relapses will occur resulting in a clinical phenotype of relapsing and therapy resistant sarcoidosis. Only the diagnosis of CBD entails termination of beryllium exposure, which is, although not formally proven, the rst recommended step of therapy [3].

Immunopathogenesis and Pathology

When CBD was originally described it was demonstrated that patients developed a delayed-type cutaneous response to beryllium salts. Bronchoalveolar lavage and peripheral blood mononuclear cells of these patients proliferate ex vivo in response to a beryllium challenge which demonstrates the immunologic hypersensitivity nature of CBD. In contrast, no proliferation is detectable after beryllium-stimulation of cells from healthy controls or from patients with other granulomatous disorders. Thus, this reaction can be used to identify beryllium sensitization and is recommended as a diagnostic test for CBD in current guidelines [3]. A recent epidemiologic study showed that T cell sensitization depends on the peak concentration of exposure and progression to CBD on the cumulative exposure [33]. This demonstrates that CBD is a hypersensitivity disease in which beryllium is the speci c antigen [34]. Beryllium induces conformational changes of the MHC-peptide complex inducing an oligoclonal T cell response [35]. These activated cells are then compartmentalized to the lung inducing an infammatory response similar to sarcoidosis within the lung [36].

Although not pathognomonic or speci c for CBD, the characteristic pathologic lesion in CBD is the non-­ necrotizing granuloma as it is seen in sarcoidosis, which consists of epithelioid histiocytes and multinucleated giant cells with a collar of predominantly CD4+ T lymphocytes. As in sarcoidosis, their distribution follows lymphatics, bronchovascular bundles, and interlobular septae down to subpleural space. Histology of berylliosis is indistinguishable from that of sarcoidosis, but detection of beryllium within the granulomas may increase con dence to the diagnosis of berylliosis. Because of a missing generally accepted Beryllium threshold in histological specimen in surgical biopsies [37], this way of demonstrating exposure is not used in routine diagnostic workup. Furthermore, the absence of beryllium in tissue analysis and the fact that biorelevant tissue concentrations are below detection limits do not exclude the diagnosis [37, 38].

Genetics

The susceptibility to acquire beryllium sensitization progressing to CBD is linked to the individual genetic background. The presence of HLA-DPB1 alleles positive for glutamate at position 69 is the most powerful, known genetic risk factor [26] that has been con rmed in multiple studies. However, the question whether any or certain glutamate 69 positive alleles or allele combinations are required is not yet settled [39, 40]. Depending on ethnicity, a large minority of beryllium sensitized individuals and CBD patients do not

carry a glutamate 69 positive HLA-DPB1 allele. In Caucasian cohorts around a quarter of CBD patients are glutamate 69 negative [28], which demonstrates that genetic testing is futile in the diagnostic workup of CBD. In particular, gene– environment interactions may reduce or increase the risk of CBD. High exposure may devaluate a protective genetic background and genetic susceptibility may be irrelevant at low exposure workplaces [28]. Genetic testing is a politically sensitive matter in many countries and the high frequency of susceptibility gene variants would cause more cases of suspicion than identify real cases. For these reasons a genetic testing is discouraged.

Clinical Description and Natural History

Among metals capable to cause diseases mimicking sarcoidosis, beryllium is the most prominent [41]. It commonly produces granulomas in the lungs and in some cases also in liver, spleen, and heart muscle. In addition, it can cause skin nodules, contact dermatitis, poor wound healing, and symptomatic hypercalcemia. It develops insidiously with symptoms of dyspnea on exertion, cough, fatigue, chest pain, weight loss, night sweats, fever, and anorexia. In rare cases liver, spleen, myocardium, skeletal muscles, salivary gland, and bone involvement may imitate a systemic chronic infammatory disease (Table 37.3). The link between this granulomatous disorder and beryllium exposure can be elusive because the latency from time of rst beryllium exposure to the development of clinical disease ranges from a few months to several decades, and exposure dose and time may be minimal [42]. As in sarcoidosis, patients with early disease typically have a normal physical exam and patients with advanced disease report unspeci c complaints, have unspeci c ndings in physical examination, and suffer from restrictive lung disease with distortion of gas exchange but obstructive lung disease is also frequently observed [42, 43]. In advanced cases clubbing and pulmonary hypertension with fatal courses may be seen [44]. Isolated extrathoracic manifestations of CBD other than dermatologic manifestations and fatigue are rarely observed. These and further differences between CBD and sarcoidosis are listed in Table 37.3.

Radiographic appearance of CBD on chest X-ray or CT-scan is identical to that of sarcoidosis, although mediastinal or hilar lymphadenopathy is less common. Chest radiographs range from small nodular opacities, with an upper level predominance, to the formation of conglomerate masses or can be normal. Moreover, even HRCT and pulmonary function tests can be normal in patients with granulomatous lung disease and therefore the diagnosis CBD must not be excluded on the basis of those negative results [45]. Mediastinal and hilar lymphadenopathy are present in approximately a third of

individuals examined by chest radiograph or computed tomography. Further radiographic features are listed in Table 37.3. In aggregate, there are no radiographic ndings differentiating CBD from sarcoidosis.

Beryllium sensitization is the rst immunologic event leading to CBD but it does not result in any physical impairment. A clear dose dependency exposure could be established [33]. At present there is no medical therapy to prevent progression to CBD. However, theoretical considerations and epidemiological studies suggest that termination of exposure may remit sensitization [46]. Further exposure and its cumulative dose de ne progression to CBD [33], which can take place after a short time or after a latency of years or decades. Precipitating cofactors are not known [18, 46]. Overall, under continued exposure a progression rate of 6 to 8% per year of sensitized is reported [18]. After manifestation of CBD, many patients suffer from slow progression of symptoms and defects of pulmonary function, which can precede radiographic abnormalities [47]. However, next to those protracted courses, rapid ones are observed [44]. According to CBD registry data and epidemiological studies from the United States of America, mortality rates of CBD patients vary widely from 6 to 38%. In addition to CBD excess mortality rates for chronic obstructive pulmonary disease, lung cancer, urinary tract cancer, and nervous system cancer are reported [46, 48, 49]. Whether advances in diagnosing early disease and consecutive termination of exposure have lowered this number seems likely, however, is not known.

Diagnosis and Diferential Diagnosis

The diagnosis is made in the setting of a granulomatous disease (typically with non-necrotizing granuloma) with a documented occupational (or in rare cases ambient) beryllium-exposure and proven beryllium hypersensitivity by a beryllium lymphocyte-proliferation assay. Granulomatous disease of other origin such as bacterial, fungal, viral, helminthic, or metallic need to be excluded in a diagnostic workup. Beryllium hypersensitivity differentiates between sarcoidosis and berylliosis, additional clinical clues are listed in Table 37.3. None of these clinical features, however, is adequately sensitive or speci c to reliably distinguish between sarcoidosis and berylliosis in individual patients.

The pivotal step in the diagnosis of CBD is the demonstration of beryllium sensitivity by beryllium-lymphocyte proliferation test (Be-LPT) [3]. At present Be-LPT with blood or bronchoalveolar lavage mononuclear cells is the only routine laboratory test available to prove beryllium hypersensitivity [50]. Patch test (on skin) or intracutaneous injections of beryllium salts should be avoided because of

lacking clear diagnostic criteria and the risk of sensitization. There is a considerable risk of inducing sensitization by intracutaneous application of beryllium salts and clear ­diagnostic readout criteria are not de ned. Originally, bronchoalveolar lavage cells have been employed in the Be-LPT [50] but for practicability reasons it has been adopted for the use of peripheral blood mononuclear cells [51], even though in our hands lavage Be-LPT seems to be more sensitive. In uncertain cases we recommend to use lavage cells for Be-LPT.

Blood Be-LPT measures the proliferation of viable cells under stimulation with beryllium-salts and use mitogens as positive controls [51, 52]. The mean plus two standard deviations is usually taken for the upper limit but other limits are also in use. To obtain a reliable value, multiple cell cultures should be performed. Generally, tests with at least two elevated proliferation values are considered abnormal. Since a speci c positive control is not available, some authors demand two independent tests to accept the clinical consequence [53]. A test speci cation released by the Department of Energy of the United States of America in 2001 (Speci cation 1142-2001) to standardize Be-LPT for epidemiological purposes can be used as guideline to evaluate or to establish the test. In the United States of America laboratories offering Be-LPT are accredited according to the Clinical Laboratory Improvement Amendments. Similar procedures have to be established in most other countries.

It has to be noted that the sensitivity of Be-LPT from peripheral blood is under debate. Reported sensitivities comparing multiple testings to identify false negatives range between 38% [52] and 100% [51] with low interlaboratory reproducibility [54]. Consequently, there are cases of berylliosis which have not been diagnosed due to false negative test results. Thus, in those cases with negative Be-LPT results and doubtless exposure, the tentative diagnosis of CBD has to be either excluded or veri ed with multiple independent tests. The high speci city of Be-LPT, however, is generally accepted since positive test results have not been reported in non-exposed controls or patients suffering from other granulomatous disorders [51, 52, 55]. Its positive predictive value is comparable to other accepted medical tests with a sensitivity of 0.683, a speci city of 0.969, and a positive predictive value of one abnormal test of 0.253 [53]. In case of any doubt the test can be repeated with cells from bronchoalveolar lavage, which has been demonstrated to be more sensitive due to an higher proliferation capacity of these cells in response to beryllium [50] (see Fig. 37.1).

Importantly, Be-LPT should ideally be performed before starting therapy, because immunosuppressive drugs (includ-

Fig. 37.1  Beryllium-lymphocyte proliferation tests with peripheral blood mononuclear cells (MNC, top) and bronchoalveolar lavage cells (BAL, bottom) of a patient with chronic beryllium disease are shown demonstrating the higher sensitivity of BeLPT using BAL-cells. The test with MNCs reveals a negative and the one with BAL cells a positive result. C: stimulation index (SI) of non-stimulated cells yields the background DNA replication and is set 1.0, PHA, ConA (phytohemagglutinin, concanavalin A): stimulation with lectins causes a high SI demonstrating the viability of the cells in in vitro culture. From the variation of the SI in C individual thresholds are calculated which are indicated by horizontal dotted lines. MNCs exhibit SIs below the threshold in all beryllium sulfate concentrations but cultures with BAL cells disclose SIs above the threshold in 4 out of 6 concentrations indicating the sensitization of this patient. The gure depicts the means of octuplet cultures for every concentration

ing corticosteroids) can dampen the proliferation. In our experience, positive results for Be-LPT can be obtained in patients with a low-dose steroid therapy, but it is generally recommended to pause immunosuppressive therapy 3 weeks before performing Be-LPT.

Not every individual with a positive Be-LPT suffers from CBD [56]. Some beryllium exposed individuals have repeatedly positive results demonstrating sensitization without pul-