taken to protect workers from beryllium sensitization and CBD. In order to recognize diseases at an early stage, it is important to perform regular occupational health checks. After diagnosing CBD responsible authorities have to be informed to take action for the prevention of other workers at this particular workplace, their family members, and habitants in the neighborhood of the workplace. A Be-LPT screening program may be appropriate to identify beryllium sensitization and latent CBD in those cohorts although the high variability of Be-LPT makes its use dif cult in cohorts with low prevalence [73]. However, with careful epidemiologic guidance this type of program can yield clinical and occupational important results but several positive tests might be required for a de nite diagnosis [53, 74, 75].

Although genetic factors determining susceptibility for beryllium sensitization and the risk for progression to CBD are known [28], a genetic counseling cannot be suggested in primary or secondary prevention because the expected postintervention CBD prevalence rates might not be low enough in the light of serious ethical, social, or legal concerns [66]. The hypersensitivity nature of the CBD implies that a complete eradication by industrial hygiene measures will not be possible as long as the use of beryllium is maintained. However, primary prevention by mandatory exclusion of individuals testing positive for certain genetic markers from workplaces with potential beryllium-exposure is no practical approach since the predictive value of the known markers is too low to enable an ethically correct verdict [66]. Voluntary genetic counseling of sensitized workers may be a cost-­ effective way of preventing CBD, however, suf cient data to do so is only available for the Caucasian ethnicity and therefore ethical and legal implications may prevent implementation [28, 66].

Indium–Tin Oxide-Lung Disease

Indium–tin oxide (ITO) is a sintered alloy containing a large portion (≈90%) of indium oxide and a small portion (≈10%) of tin oxide. It is used in the production of thinlm transistor liquid crystal displays (LCDs) for fat-panel displays used in television screens, touch screens, solar cells, and architectural glass. The use of ITO containing compounds in the electronics and semiconductor industry has risen by 500% over the last two decades. Little is known about the potential health hazard induced by occupational exposure to indium compounds. However, pulmonary toxicity has been demonstrated in experiments with hamsters.

In 2003 the rst case of ITO interstitial pneumonia was identi ed by demonstrating indium and tin in intra-alveolar

particles by energy dispersive X-ray analysis of a patient suffering from interstitial lung disease [76]. Chest CT-scan showed ground glass opacities all over the lung and subpleural honeycombing. Exposure time was three years but exposure dose could not be estimated. Therapy with prednisolone was initiated but no improvement was observed. The patient died from bilateral pneumothorax 7 years afterrst exposure [76].

Following this initial report, further indium–tin oxide-­ exposed worker were identi ed with interstitial lung disease, mainly with subpleural reticulation, honeycombing and bronchiectasis on the one hand, and centrilobular emphysema on the other hand. Lung function showed a mainly restrictive pattern [77]. The typical histopathological changes were foamy macrophages with cholesterol clefts, which can be pathophysiologically interpreted as an altered surfactant metabolism induced by indium–tin-oxide [77, 78]. In line with this hypothesis, case reports mention pulmonary alveolar proteinosis (PAP) in indium–tin-oxide-exposed workers [78, 79] and also PAS-positive material in lung biopsies emphasizing a role of disturbed surfactant handling a part of indium–tin-oxide lung disease [77]. Animal studies in rats and mice with inhaled indium support this hypothesis demonstrating alveolar proteinosis and infammation preceding pulmonary brosis [80, 81].

Cross-sectional studies identi ed a substantial proportion of tin oxide-exposed persons exhibited pulmonary phenotypes, e.g., 21% of exposed persons with interstitial abnormalities and 13% with emphysema [82]. Workers exposed to higher indium–tin oxide concentrations exhibit higher plasma indium levels, and higher cumulative doses of inhaled indium–tin oxide correlate with higher pulmonary symptoms and serum biomarkers of lung disease [83, 84]. Notably several reports point towards a dose-depen- dency between indium–tin oxide exposition and pulmonary symptoms. However, also low indium–tin oxide exposition and plasma concentrations infuence pulmonary symptoms, spirometric parameters, and lung disease biomarkers [83].

Indium–tin oxide-related lung disease has no uniform diagnostic criteria, however, should be suspected in patients with:

––Exposition to indium–tin oxide, which can be further ver- i ed by elevated plasma levels of indium.

––Restrictive or obstructive ventilatory defect in spirometry.

––Signs of interstitial lung disease (e.g., reticular and/or nodular alterations) on HRCT; alternatively also emphysematous changes may be present as sign of indium–tin oxide lung disease.

––Giant cells, foamy macrophages and/or cholesterol clefts in bronchoalveolar lavage or lung biopsy.

Cornerstone of the therapy is avoidance of ongoing exposition to indium–tin oxide, which might lead to amelioration of interstitial changes. However, long-term surveillance observations demonstrate progression of emphysema [85, 86]. The use of half-mask respirators that lter >99.95% of airborne particles reduced the serum levels of indium and Krebs von den Lungen-6 (KL-6) signi cantly in a cohort of indium-reclaiming plant workers despite ongoing exposition [87]. The role of steroid treatment of indium–tin oxide lung is a matter of debate [78]. Finally, lung transplantation remains a therapeutic option in patients with deteriorating lung function despite stopped exposition [88].

Animal models demonstrate an additional carcinogenic effect of indium [81, 89]. One case report of lung cancer in an indium-exposed worker demonstrated an accumulation of indium within the tissue by factor 1000 compared to serum, arguing for a causal relationship [90], however, another report demonstrated the nascent of cancer within the ­subpleural brosis zone [85], which is also the preferential localization of lung cancer in pulmonary brosis [91]. Even surveillance programs could not verify or deny the risk of indium-exposition for lung cancer nascent. Surveillance of indium-exposed workers identi ed four cases of lung cancer in 381 exposed persons. Standardized incidence ratio was elevated to 1.89, however, lacking statistical signi cance [90]. Therefore it remains unclear, whether indium–tin oxide exerts a direct carcinogenic or an indirect brosis-related effect in humans.

Hard Metal Lung

The term “hard metal” must not be confused with “heavy metals” such as lead, cadmium, and mercury. Hard metal consists to 90–94% of a tungsten carbide structure (also named Wolfram) which is blended with 6–10% cobalt as a binder and compressed into a polycrystalline material [92, 93]. It is heat and corrosion resistant and has an extraordinarily mechanical strength almost that of diamond. It is used in tools for drilling, cutting, or grinding [92–94]. Workers exposed to hard metals are toolmakers, blacksmiths, diamond polisher, and workers processing steel alloys containing hard metal [92, 95]. Abraham and colleagues were the rst to publish that many cases described by Liebow as giant cell interstitial pneumonitis (GIP) were related to hard metal exposure [96]. Later, Ohori and colleagues con rmed the nding that GIP is almost pathognomonic for hard metal or cobalt exposure [97].

Animal experiments and case reports suggest that cobalt is the key agent inducing ILD by hard metal [98–101] with bound cobalt being even more toxic [102, 103]. Hard metal lung disease develops only in a small proportion of exposed individuals after a variable period and a dose-dependency cannot be observed [94, 104]. Therefore, an immunological mechanism with similarities to hypersensitivity pneumonitis is postulated [105, 106]. Genetic variants of the HLA-DP gene might confer to hard metal lung and being involved in the immunological process leading to interstitial lung disease [105, 107]. Another pathophysiological explanation of hard metal lung is increased oxidative stress that can be induced by cobalt an even more pronounced by tungsten carbide [102, 103, 108].

Clinically, cobalt related lung disease may manifest in acute /subacute or chronic form. The acute/subacute form presents during exposure to cobalt with constitutional and respiratory symptoms including cough, dyspnea, fever, and weight loss [94, 109]. The clinical presentation of the chronic form resembles more the presentation of interstitial lung disease, i.e., cough and dyspnea that arise without a temporal relation to exposure [104, 110].

Pulmonary function tests in hard metal lung generally reveal a restrictive pattern and reduction in diffusion capacity, however, in parallel with other occupational lung diseases (e.g., silicosis), obstructive pattern may occur [111–113]. There are no established laboratory tests to establish the diagnosis of hard metal lung, even though determination of cobalt in blood or urine samples may help to establish the diagnosis by proving exposition with urine concentration after working being relevant for occupational diagnostic steps in Germany [114]. Bronchoalveolar lavage may help to establish the diagnosis, if multinucleated giant cells (“cannibalistic cells,” Fig. 37.3) are found in bronchoalveolar lavage, otherwise lavage has a lymphocytic pattern [115]. Histopathologically, interstitial giant cell pneumonitis (Fig. 37.3) is the prototypic nding for cobalt-related interstitial lung disease [116]. Nevertheless, a broad range of interstitial abnormalities can be found with patterns of organizing pneumonia, usual interstitial pneumonia or desquamative interstitial pneumonia [97, 117, 118]. In doubtful cases BAL or tissue can be used for detection of cobalt or tungsten to unequivocally establish the diagnosis [116].

Radiological ndings in plain chest X-ray typically show nodular and/or reticular alterations that can be observed without gradients in distribution [113]. Fibrotic changes generally progress if exposition is ongoing [119]. In HRCT hard metal lung may present as NSIP pattern with ground-glass opacities and consolidations correlating to cellular in ltra-

tion in histology [115]. Besides NSIP pattern other radiological patterns are possible in hard metal lungs [120].

Unfortunately, criteria for the diagnosis of hard metal induced lung disease which are generally agreed on are missing. Thus, in view of the literature [121, 122] the following criteria are suggested:

•\ evidence of a diffuse parenchymal lung disease by HRCT, •\ evidence of pulmonary function defects, and

•\ histological examination of lung specimens demonstrating giant cell interstitial pneumonitis.

In our outpatient clinic, we established the diagnosis of giant cell interstitial pneumonia (GIP) in an 82 year old, never-smoking, retired woman. HRCT revealed subpleu-

ral honeycombing combined with diffuse ground glass lesions (Fig. 37.2). She had been working for 20 years in a spinning mill and exposed to cobalt containing paints. This lead to the diagnosis of occupational hard metal lung. An example of giant cell pneumonitis is shown in Fig. 37.3.

Thus, even minimal exposure can cause hard metal lung disease. Course of the disease is variable: some patients might recover completely after avoiding further exposure, while others progress to irreversible pulmonary brosis. Older patients tend to have chronic and progressive disease. Several authors reported that patients bene t from ­prednisolone and other immunosuppressive treatment, but multicenter, placebo-controlled studies are lacking [95, 105, 123–125].

Fig. 37.2  HRCT scan of a 82-year-old patient with giant cell interstitial pneumonitis after Cobalt exposure at yarn factory. Histological diagnosis was obtained by transbronchial biopsy and con rmed by wedge biopsy. HRCT shows diffuse severe lesions, predominately in

the right lung. There is severe subpleural honeycombing on both sides. Besides honeycombing, there are ground glass lesions at the left lung. Right lung shows coarse reticular lesions in the lower central areas and ground glass lesions in the upper regions

Flock Worker’s Disease

Short bers (fock) cut from cables of synthetic micro laments bound to adhesive fabric build a velvet-like surface used to produce upholstery, textiles, lters, coated fabrics such as feeces and other materials. Flock can be derived from polyamide (nylon), cellulose acetate (rayon), polyester, polypropylene, polyethylene, and other ole ns [126]. The diameter of the bers ranges from 0.3 to 2.0 mm [127]. Depending of the cutting process, very small, breathablebers might be generated [128]. First reports described ILDs in textile workers [129, 130]. The term fock worker`s disease was introduced 1998 by Kern and colleagues [128] who studied a case series in a fock plant in the U.S. In their initial article the authors described that all their patients had very similar lymphoproliferative lesions such as follicular bronchiolitis and lymphocytic interstitial pneumonitis. Further

studies revealed that other pulmonary lesions such as desquamative interstitial pneumonitis (DIP) and non-speci c interstitial pneumonitis (NSIP) as well as bronchiolitis obliterans organizing pneumonitis (BOOP) may be associated with exposure to fock [131–133]. Granuloma formation has not been described [132, 133]. An increase in lymphocytes can frequently be found in BAL, which might be accompanied by an increase in eosinophils and neutrophils. Most patients suffer from a subacute type of the disease presenting with dyspnea, dry cough, and chest pain [128, 134, 135]. The acute type of the disease can be associated with fever, fatigue, and weight loss. A substantial number of patients progress and require long-term oxygen treatment [131].

We observed one patient with a fatal course of fock worker`s disease, otherwise not reported. The 58-year-old patient, ex-smoker, worked in a plant producing nylon and rayon fock for cigarette lters and other products. One of his

daily jobs was to clean machines cutting fock and he did not use any respirator mask. He presented with dyspnea and dry cough. Pulmonary function test revealed severe restrictive

lung disease. HRCT scan (Fig. 37.4) and histology of wedge biopsy were consistent with non-speci c interstitial pneumonia (NSIP, Fig. 37.5). High dose prednisolone treatment did

Fig. 37.4  HRCT scan of a 58-year-old patient with severe, subacute fock worker`s disease after exposure in a lter factory. Patient died because of acute exacerbation. HRCT shows severe diffuse ground

glass lesions in both lungs and reticular bands. There is also some honeycombing in the lower subpleural regions and considerable pleural thickening

Fig. 37.5  Microphotographs from the lungs of the 58-year-old patient with fock worker`s disease who died because of acute exacerbation. Panel (a) and (b): Autopsy revealed morphology predominately consis-

tent with NSIP and diffuse alveolar damage. Intra-alveolar edema and alveolar desquamation is due to respiratory failure and subsequent death