not show any effect and eight months after establishment of diagnosis he died due to acute exacerbation.

Symptoms and pulmonary lesions can completely resolve once patients avoid further exposure to fock. Ongoing exposure increases the risk of lung functional deterioration with a decline of 46 ml/year in FeV1 [136]. Re-exposure alters the risk of relapse and progressive disease [131]. Pulmonary function testing often shows a restrictive pattern but also obstructive lung disease was described in some cases. Diagnosis of fock worker’s lung is based on:

•\ persistent respiratory symptoms;

•\ previous work in the focking industry;

•\ histologic evidence of interstitial lung disease compatible with fock worker’s disease [131, 137].

Patients with strong suspicion of fock worker’s disease should strictly avoid any further exposure to fock.

Animal experiments showed similar ndings as observed in humans and demonstrated dose-dependent reversible, infammatory lung lesions induced by fock inhalation [126, 138].

There are no studies evaluating immunosuppressive treatment in fock worker’s disease [131, 137]. Clinicians tend to treat the disease in analogy to other ILDs with similar pathology such as lung involvement in rheumatic diseases; ­however, bene t from immunosuppressive treatment is not unequivocally established.

Asbestosis

Asbestosis is an ILD caused by asbestos inhalation and is subsumed under the group of pneumoconioses [139, 140, 142]. Asbestos is a naturally occurring ber composed of hydrated silicate and metals, such as magnesium. Asbestosbers are classi ed in two different categories of mineralbers: rod-­like amphiboles and serpentine bers. Due to its resistance to heat and degradation as well as its good insulation characteristics, it was ubiquitously used in the past. Asbestos was added to building materials and products used in textile industry, car production, shipbuilding, and electronics [143]. It is well established that there is a dose response relationship between pulmonary lesions and asbestos exposure [144–146]. The cumulative pulmonary burden is crucial for disease development [141]. Cigarette smoking by interfering with mucociliary clearance increases cumulative burden and aggravates asbestos induced pulmonary diseases [147]. Very common are pleural lesions caused by asbestos exposure and pleural plaques are considered as pathognomonic for asbestos exposure [139, 148].

There is a latency period of about 15–30 years between exposure to asbestos and development of asbestosis [140, 149]. Asbestos is of cellular toxicity and deposited in the respiratory bronchiole where it is phagocytosed by alveolar macrophages and alveolar epithelial cells [150] (Fig. 37.7). Alveolar macrophages transport bers to the pleura via lymphatics. Multiple evidence derived from animal experiments documents dose-dependent asbestos induced pulmonary infammation and brosis [151, 152]. Asbestos induces cellular production of radical oxygen species (ROS) and multiple infammatory mediators. Recent evidence indicates that asbestos triggers infammasome activation, a key event of infammatory processes in innate immunity [153, 154]. Noteworthy, infammasome activation results in pulmonary brosis [155]. Interestingly, signs of alveolar infammation in asbestosis (high numbers of alveolar macrophages, elevated neutrophils and eosinophils) and higher numbers of asbestos bodies indicate a worse survival [156]. Asbestos inhalation induces dose-dependent infammatory and consecutive brotic lesions starting from the respiratory bronchiole extending to the adjacent alveolar tissue. The College of American Pathologists [157] has developed histologic criteria for asbestosis and a grading system (I– VI). Alveolar collapse and honeycomb remodeling is the most severe grade (VI), however, histopathological grade I asbestosis does not seem to be a prerequisite for development of grade IV asbestosis [158]. Asbestos bodies can be identi ed in BAL and lung specimens using scanning/ transmission electron microscopy. Noteworthy, this is also the case in specimen of healthy individuals and, therefore, a sole demonstration of asbestos bodies is not suf cient to make a diagnosis.

HRCT often shows bilateral, diffuse brotic changes with subpleural honeycombing, which is more prominent in lower lung elds and frequently resembles the pattern of usual interstitial pneumonia/idiopathic pulmonary brosis (IPF). In most cases subpleural brosis/reticulation is coarser in asbestosis than in IPF [159]. In some cases imaging will not reveal a suf cient evidence and histopathological examination showing lung brosis with peribronchiolar brosis will be required to support a diagnosis of asbestosis [160]. Typical changes are also pleural plaques, pleural thickening, rounded atelectasis, parenchymal bands and curvilinear lines [161– 163] (Fig. 37.6).

Diagnosis of asbestosis requires:

•\ evidence of a diffuse parenchymal lung disease either by HRCT or histology,

•\ evidence of a causal relationship by demonstrating environmental history of asbestos exposure with plausible latency,

•\ markers of exposure such as pleural plaques or recovery of asbestos bodies (BAL, lung specimen) [139, 164–167] (Fig. 37.7), and

•\ exclusion of competing diagnoses.

Patients often present with dyspnea, cough, and pleurodynia. Physical examination may reveal end-inspiratory crackles and nger clubbing. Pulmonary function test often shows restrictive ventilatory dysfunction, but also mixed or sole obstructive patterns have been reported [168].

In some patients asbestosis progresses rapidly, while in others the disease may be stable over years. Patients with a mainly interstitial brotic manifestation of asbestosis have a more rapid decline in lung function (annual decline of approximately 80 ml FVC/year) compared to patients with

pleural manifestation [169]. Co-factors of progression have not been identi ed yet. Total asbestos exposition seems to be an important determinant of disease progression as the cumulative and continuous exposure predisposes to brotic disease rather than malignant disease [170].

There is no evidence based approach for treatment of asbestosis [171]. Smoking cessation and avoidance of further asbestos exposure are strongly recommended. Some patients might bene t from immunosuppressive treatment while others not, which might be dependent on the level of infammatory processes involved. There is no recommendation for the use of immunosuppressive treatment [139]. Of note, one case series reports a bene cial effect of pirfenidone on asbestosis-related interstitial lung disease with UIP pattern [172].

Fig. 37.7  BAL cytospin of a 62-year-old plumber with asbestosis showing four asbestos bers

Nanoparticle Induced ILD

Nanoparticles are de ned as particles sized between 100 and 1 nanometers [127] and can be composed of various organic and inorganic substances. They often contain metals which can lead to enhanced toxicity. They are generated by combustion processes such as diesel exhaust or by any process burning fuel. Worldwide man-made nanostructures are used in multiple and increasing application areas.

Several studies have shown that particle size has huge impact with less toxicity in the micrometer and high toxicity in the nanometer range. Extraordinary harmful are those with a high surface to volume ratio [173, 174]. Animal experiments clearly indicate that distinct nanoparticles induce ILDs. Several studies demonstrated induction of granuloma, infammation, and pulmonary brosis in mice after intratracheal instillation of single wall carbon nanotubes [175, 176]. Single wall carbon nanotubes seem to be even more toxic than quartz [176]. Bonner and colleagues showed that vanadium pentoxide induces pulmonarybrosis in rats [177]. The inhalation of titanium dioxide particles leads to pulmonary brosis in mice and rats and NiO and Co3O4 nanoparticles induce pulmonary delayed type hypersensitivity (DTH)-like responses [178, 179]. Although in animal models the toxicity of several nanoparticles has clearly been demonstrated and occupational exposure to nanoparticles is widespread, the number of reports documenting ILDs caused by nanoparticles is limited. Song and colleagues [180] described seven female workers exposed to spray paint under extreme working conditions without any extraction system. All exposed workers presented with pleural effusion, granuloma, and pulmonary brosis and two died due to progressive pulmonarybrosis. The dust to which all workers were exposed to consisted of multiple substances including polyacrylate nanoparticles. The presence of these nanoparticles was con rmed in histologic specimens and pleural effusions. The authors failed to demonstrate data regarding the type and dose of nanoparticles and possible other substances [180, 181]. Therefore, this report does not proof that nanoparticles caused the described ILD, but it is likely that nanoparticle exposure contributed as one factor to the disease. Recently, Ferri et al. reported in a cohort of patients with systemic sclerosis an association with silica

nanoparticle exposure and more severe disease. Patients exposed to silica nanoparticles had higher serum levels and presented more likely with pulmonary brosis and myositis [182].

In the absence of international agreement on the diagnosis of nanoparticle induced lung disease the following criteria are suggested:

•\ exposure to nanoparticles at the workplace,

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

•\ histological examination of lung specimens demonstrating interstitial lung disease and nanoparticles.

At present it is hard to estimate the hazards of nanoparticles. One major factor contributing to this uncertainty is the variety of nanoparticles. Some authors extrapolate from animal experiments a similar toxicity like asbestos and for some nanoparticle species thresholds have been delineated from animal studies although the differences between rodents and humans in the toxicological response to nanoparticles are not known [183, 184]. Nevertheless, current knowledge suggests that preventive occupational measures to reduce exposure to nanoparticles might be quite effective. There have been no cases reported so far from industrial countries with high safety standards [122, 159, 185].

Sidero brosis

Sidero brosis is a well established but rare interstitial lung disease of occupational origin and is different from the benign welder’s siderosis. It is reported after long term and severe exposure to welding fumes in poorly ventilated workplaces [186]. A recent cross sectional study demonstrated a signi cant effect of welding fume exposure to pulmonary symptoms and lung functional impairment [187]. Interestingly this study found an association between different types of welding and the observed pulmonary impairment. Welding fumes mainly induce obstructive airway diseases especially when smoking is co-factor [188, 189]. However, several case series describe association between welding and pulmonary brosis, which might be a continuous process of infammation, desquamation, and brosis [190]. In this context it is noteworthy that several studies demonstrate an infammatory response leading to epigenetic changes in welding-exposed individuals [191, 192].

There are more than 80 types of welding technology and allied processes in commercial use. Sources of airborne particles are fumes from the base materials, fuxes, andller metals used in powdered form. Relevant gases, which are combined with welding fumes, are ozone, nitrogen dioxide, fuoride, carbon dioxide, and carbon monoxide. Factors that infuence the concentrations of fumes and gases at the workplace are [185]:

•\ Degree of con nement.

•\ Rate of progression of welding. •\ Type of welding process.

•\ Adequacy of ventilation.

Extremely high concentrations of welding fumes occur, when employees work in partly-closed or con ned spaces without using (local) extraction systems. Buerke et al. examined 15 welders with IPF [186]. The duration of work as welder was 28 years and the cumulative dose of welding fumes was 221 mg/m3 (median). Pulmonary function testing showed a pattern of restriction or combined restriction-­ obstruction, lower diffusion capacity, and reduced blood oxygen tension at exercise. Examinations of lung tissue showed brotic reactions in close topographic relationship with deposits of welding fume particles.

Histologically, sidero-pneumoconioses are classi ed into three grades [193]:

•\ Grade I: Mostly alveolar but also interstitial accumulation of macrophages, which contain siderophilic particles, granular black (iron oxide) and minimal mixed dust deposits. Fewer macrophages or mixed dust in perivascular, interstitial, and paralymphatic tissue. Low-grade,brogenic reaction, only seen in microscopy.

•\ Grade II: Rising accumulation of activated alveolar macrophages and mixed dust particles in areas of perivascular, pleural, and septal lymphatic drainage. Fibrotic reactions in areas with mixes dust deposits.

•\ Grade III: Massive ndings of mixed dust deposits. Perivascular pseudogranulomatous pattern with reactivebrillary brosis. Focal deposits of welding fume particles with topographical relationship to interstitial brosis.

As sidero brosis is a rare disease, epidemiological data are limited. The existing data leads to the conclusion that a causal relationship between IPF in welders with a long-term exposure to high concentration to welding fumes exists.

Flavoring-Induced Lung Disease

The favoring-induced lung disease has been described in individuals working in popcorn factories and is therefore also named popcorn lung disease [194]. It is caused mainly by diacetyl (2,3-butanedione) and its substitute 2,3-­pentanedione, that are used for favor intensi cation and naturally occurs, e.g., in butter, caramel, coffee, and honey [195]. It is released as vapor at relatively low temperatures during the process of popcorn favoring, coffee roasting or chocolate manufacturing.

The initial reports describe the disease as an obstructive pulmonary disease with signs of obliterative bronchiolitis. Animal studies mainly in rats emphasize these observations