showing that installation of these substances induces epithelial damage and airway-associated brotic reactions mimicking brotic obstructive bronchiolitis [196–198].

Frequently radiological signs of airway remodeling leading to mosaic attenuation can be seen. Centrilobular nodules are observed in the parenchyma [199].

Analyses of lung function derived from surveillance programs in food industries demonstrate a restrictive ventilation defect at least as prevalent as obstructive or mixed ventilation patterns [202, 203]. Importantly obstructive ventilatory limitation is higher in non-smokers exposed to diacetyl compared to smokers even though smokers inhale high concentrations of cigarette-released diacetyl [200, 201]. Longitudinal follow-up of spirometry revealed a more pronounced decrease in FeV1 in favoring-exposed workers compared to healthy controls [203]. As a consequence, this results in an elevated rate of chronic obstructive lung disease-related mortality [204].

The lung function assessment of exposed workers demonstrate an association between exposure time and prevalence of lung functional impairment underscoring the need of preventive measures like technical improvement to minimize the occupational exposure to diacetyl and 2,3-pentanedione [202, 205].

Of note in this context is the observation that favors used in electronic cigarette liquids contain high concentrations of diacetyl that exposes consumers to higher diacetyl concentrations than NIOSH limits [206, 207].

Silica-Induced Interstitial Lung Disease

Silicosis is one of the oldest occupational diseases and is caused by inhalation of crystalline silica that triggers abrotic response in the lung parenchyma. Silica (silicon dioxide, SiO2) is one of the most abundant naturally occurring minerals and especially enriched in rocks. Because of the worldwide occurrence of silica, silica-related lung diseases are a concern in developed countries as well as in countries with low incomes [208]. Table 37.4 depicts some of the industries with occupational risk for silica exposure.

Approximately three million workers are exposed to silica-­ containing dusts in Europe, however, preventive measures have reduced morbidity and mortality in Europe and United States [209–212]. In contrast, China reported 500.000 cases between 1991 and 1995 with approximately 24.000 deaths per year [4 ].

With the shift of typical silica-associated industries like mining to countries with lower preventive measures and novel industrial procedures like sandblasting for demim jeans, silica-induced interstitial lung diseases remain an important medical problem [213–218]. Environmental exposure seems to be less important, even though recurrent exposure to sand storms may lead to silicosis [219].

Dose exposure clearly correlates with disease severity and mortality [212, 220–222]: Preventive strategies in reducing silico exposure (e.g. 0.05 mg/m3 in US) have reduced, but not completely abolished the risk of silicosis [222].

Table 37.4  Occupations and industries related to silica dust exposure (modi ed according to [4, 295]

The underlying pathophysiology of silica-associated lung diseases requires the deposition of silica (especially in its crystalline form with a diameter < 10 μm) in the distal airway, where it causes an infammatory and probrotic response. Engulfed silica particles (especially by macrophages) activate the NALP3 infammasome, which is required for the development of silicosis [154, 155, 223]. Additionally, due to its piezoelectric properties, silica may induce the formation of reactive oxygen species, with further contribute to an infammatory and brotic response [224, 225].

Therapeutic options are scare for silicosis. Therapeutic trials like whole lung lavage or corticosteroids have not proven any signi cant bene t [226–228]. Therefore preventive measurements like the avoidance of (ongoing) exposure, smoking cessation and addressing complications like tuberculosis and other infections remain the cornerstones of therapy. Additional bronchodilator therapy and long-term oxygen therapy may be of some help.

Silica-associated lung diseases have a long history in medicine. With the industrialization and machine utilization, e.g., in mining, the silica exposure and prevalence of associated chronic silicosis increased [4, 229, 230]. Novel industries and techniques on the one hand and lacking awareness to preventive measures on the other hand lead to outbreaks of chronic, but also of acute silicosis.

For example, sandblasting has been recognized a procedure with a high risk of silicosis. Outbreaks in Turkey in the recent years have demonstrated that silicosis may arise in young workers (between 20 and 40 years old) after a relatively short exposure period (2-4 years) [214, 231, 232]. Of 50 initial cases 7 had acute and 43 had accelerated silicosis. Similar observations of young age and short exposure period have been made for stonemasons in Iran [233, 234] and workers with arti cial stones (e.g., in benchtops) in other countries [235–237].

Chronic Silicosis

Chronic silicosis typically arises several years after silica dust exposure [4, 238, 239]. The clinical expressions range from asymptomatic forms in the case of the simple chronic form to complicated progressive massive brosing form (PMF). The radiological hallmark of simple chronic silicosis is the presence

of discrete, well-de ned nodules (with a diameter up to 1 cm) that exhibit upper lobe predominance [199, 240]. Additional signs are enlarged mediastinal lymph nodes that may exhibit calci cations [241]. Plain X-ray is mostly used for screening and radiological ndings are classi ed according to the International Labor organization [242], however, computer tomography may be more sensitive and allows more information on lung architecture [243–245]. Lung function in these patients may be normal or demonstrate restrictive or obstructive ventilator defects [246–248].

Histology, when performed, may demonstrate nodules with dust-loaded macrophages, that in later stages has densebrosis in its surrounding [249]. Bronchoalveolar lavage may show a slight lymphocytosis and dust-loaded macrophages with birefringent material may be found.

Simple chronic silicosis may progress to complicated chronic silicosis (or conglomerate, progressive massive brosis) in 20–30% of workers within 5 years, especially ongoing exposure and smoking increase the risk of progression [250–252].

Complicated silicosis is radiologically characterized by conglomerate masses that tend to migrate to the hilar region [199, 253]. These conglomerates consist of hyalinizedbrotic foci. These brotic masses lead to distortion of airways, increase the risk of emphysema and pneumothoraces.

Typically, the diagnosis of chronic silicosis can be made based on the following criteria:

•\ Relevant occupational exposure that could have been occurred even decades prior to the diagnosis.

•\ Typical radiological ndings:

––well-de ned small often symmetric nodules with upper lobe predominance in chronic simple silicosis.

––Conglomerate masses with distortion of the lung architecture in complicated silicosis.

––Calci cations may be present in the masses and/or the mediastinal lymph nodes.

•\ Exclusion of other diseases (e.g. sarcoidosis, (Non-­ Hodgkin) lymphoma, tuberculosis, metastasis, (fungal) infections).

•\ Histology and bronchoalveolar lavage may not be required for the diagnosis, but for the exclusion of differential diagnoses.

Acute and Accelerated Silicosis

In contrast to chronic silicosis, in which long-lasting exposure to silica at low concentrations is the causing culprit, acute and accelerated silicosis arise in cases of short term exposure to dusts with high silica concentrations (1–10 mg/ m3/year) [254].

These acute forms of silicosis develop within few years and may progress von initially ground-glass opacities and pleural thickening to nodules and progressives masses.

The underlying pathophysiology seems to be similar to the chronic silicosis, however, the elevated exposure may lead to a more pronounced infammatory response, as bronchoalveolar lavage in these patients demonstrates high cell count, lymphocytosis, dust-loaded macrophages, and PAS-­ positive milky lavage fuid [255–258].

In line with these observations, radiological ndings demonstrate initially centrilobular nodules and ground-glass opacities and sometimes a crazy-paving pattern [199, 214, 259].

The diagnosis of acute/accelerated silicosis can be made in patients

•\ With recent high exposure to dust with high silica concentrations.

•\ Radiological ndings include typical ndings in chronic silicosis, however ground-glass opacities, crazy-paving and rapidly progressive nodular opacities may be present.

•\ Bronchoalveolar lavage may demonstrate high cellularity, slight lymphocytosis and dust-loaded macrophages.

•\ Histology reveals silicotic nodules with birefringent particles and patchy brosis [236, 237].

Coal Workers Disease—Coal Mine Dust Lung

Disease (CMDLD)

Coal mine dust lung disease describes a sum of different lung diseases that etiologically rise from inhalation of coal mining dusts [260, 261]. In resembles in some pathophysiological and radiological aspects silica-associated lung disease. In contrast to silicosis, CMDLD is caused by mixed dust exposure that normally occurs during coal mining. Importantly, CMDLD can be observed in underground and surface miners, however, prevalence seems to be higher in the former ones [262, 263].

Its prevalence differs between highand low-to-middle income countries. Preventive measures as well as increased mechanization of working processes resulted in a signi - cant reduction of CMDLD prevalence and mortality, with 2% of workers developing CMDLD in the 90s in US [260, 263, 264]. For China, prevalence of CMDLD ranges around 6% in the rst decade of the twentieth century, compared to approximately 3% in US [265]. Nevertheless, in recent years an increase in the prevalence of CMDLD has been noted that goes also along with the more severe phenotype of progressive massive brosis. Notably, prevalence was especially increased in small mines with fewer miners [261, 262, 265].

Inhalation of coal dusts leads to its accumulation in the distal airways leading to airway anthracosis and accumulation in the bronchovascular tissues. Additionally, dust particles are engulfed by macrophages and may thereby trigger a proinfammatory and pro brotic response, engaging TNF and interleukins that are increased in the bron-

choalveolar lavage of coal workers [266–268]. Furthermore, mixed dusts in coal mines may alter (potentially via Fe2+) the redox balance leading to more oxidative stress [269–271]. These cascades trigger the histologically and radiologically observed formation of nodules with dense collagen deposition [272]. Additionally, coal dust inhalation leads to histopathological signs of chronic bronchitis and emphysema that seem to correlate with dust exposure [273, 274].

CMDLD may present in different clinical pictures, the cornerstone of the diagnosis is a convincing work place history with appropriate dust exposure. Roughly, CMDLD may be separated in airway and interstitial lung disease [261], although clinical pictures may overlay.

Chronic Obstructive Disease in CMDLD

Coal dust exposure is able to cause an airway disease leading to a dust dose-dependent decline in FeV1 with signs of chronic bronchitis [275]. Initially, decline in FeV1 is more pronounced, with longer exposure the slope of lung functional decline decreases [276, 277]. The kinetic of FeV1 decline resembles the decline observed in smokers [278]. Additional to airway disease, centriacinar emphysema may develop especially in patients with airway deposition as demonstrated by coal dust macules. Importantly, the airway disease of coal-dust exposed workers contributes to an increased mortality [279].

Simple CMDLD

Simple CMDLD is mostly detected by chest X-ray (Fig. 37.8), as it causes no or only mild clinical symptoms like cough or exertional dyspnea. Classically de ned as nodular, relatively small nodules (<1 cm diameter) with a symmetric distribution in the upper lobe, data from larger cohorts demonstrate, that nodules may be irregular in up to 40% of cases and observed in the lower lung zones as well [280]. These nodular opacities are radiological signs of coal mine dust exposure [281, 282].

Complicated CMDLD

Complicated CMDLD is characterized by a more rapid decline in lung function (FeV1: −60 ml/year), that predisposes to progressive massive brosis (PMF) [283–286]. Radiologically, opacities are of larger size and seem confuent with migration to the hiliar region (Fig. 37.9). Histologically, dense brosis with central coal dust can be found.

Fig. 37.8  Chest X-ray showing upper-lobe opacities, nodules, and reticulation compatible with silicosis in a patient with an appropriate occupational history

Dust Difuse Fibrosis (DDF) in CMDLD

Dust diffuse brosis is a special entity in CMDLD. It describes a more peripheral brosis with lower lobe predominance. It resembles more the radiological and histological picture of idiopathic pulmonary brosis with honeycombing and traction bronchiectasis. The interseptal brosis is often coal dust loaded, which hints towards a causal relation [287–289].

Fig. 37.9  CT scan of a patient with complicated silicosis hiliar masses and calci cations

Because of the aforementioned different phenotypes of CMDLD, the diagnosis of CMDLD relies especially on a detailed and complete work history. It is important to emphasize that CMDLD may develop years and decades after coal dust exposure underpinning the importance of a full working history [290–292]. The diagnosis can be made in patients with

•\ a work history compatible with coal dust exposure

•\ lung function may be normal or present an obstructive, restrictive or mixed ventilatory defect

•\ radiology may demonstrate signs of brosis or emphysema

•\ Bronchoscopy, bronchoalveolar lavage and histology may not be needed to prove the diagnosis, but to rule out differential diagnoses. They may show bronchial anthracosis (Fig. 37.10), coal dust-loaded macrophages or brosis with interstitial coal dust inclusion.