medicina
Case Report Pneumoconiosis with a Sarcoid-Like Reaction Other than Beryllium Exposure: A Case Report and Literature Review
Fumiko Hayashi 1, Takashi Kido 1,*, Noriho Sakamoto 1, Yoshiaki Zaizen 2, Mutsumi Ozasa 1,2, Mitsuru Yokoyama 3, Hirokazu Yura 1, Atsuko Hara 1 , Hiroshi Ishimoto 1, Hiroyuki Yamaguchi 1 , Taiga Miyazaki 4, Yasushi Obase 1, Yuji Ishimatsu 5, Yoshinobu Eishi 6, Junya Fukuoka 2 and Hiroshi Mukae 1
1 Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; [email protected] (F.H.); [email protected] (N.S.); [email protected] (M.O.); [email protected] (H.Y.); [email protected] (A.H.); [email protected] (H.I.); [email protected] (H.Y.); [email protected] (Y.O.); [email protected] (H.M.) 2 Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8520, Japan; [email protected] (Y.Z.); [email protected] (J.F.) 3 Department of Anatomy, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu City, Fukuoka 807-8555, Japan; [email protected] 4 Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; [email protected] 5 Department of Nursing, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8520, Japan; [email protected] 6 Department of Human Pathology, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-95-819-7273; Fax: +81-95-849-7285
Received: 12 October 2020; Accepted: 20 November 2020; Published: 22 November 2020
Abstract: Background: Chronic beryllium disease (CBD) is a granulomatous disease that resembles sarcoidosis but is caused by beryllium. Clinical manifestations similar to those observed in CBD have occasionally been reported in exposure to dusts of other metals. However, reports describing the clinical, radiographic, and pathological findings in conditions other than beryllium-induced granulomatous lung diseases, and detailed information on mineralogical analyses of metal dusts, are limited. Case presentation: A 51-year-old Japanese man with rapidly progressing nodular shadows on chest radiography, and a 10-year occupation history of underground construction without beryllium exposure, was referred to our hospital. High-resolution computed tomography showed well-defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in the middle and lower zones of both lungs. No extrathoracic manifestations were observed. Pathologically, the lung specimens showed 5–12 mm nodules with dust deposition and several non-necrotizing granulomas along the lymphatic routes. X-ray analytical electron microscopy of the same specimens revealed aluminum, iron, titanium, and silica deposition in the lung tissues. The patient stopped smoking and changed his occupation to avoid further dust exposure; the chest radiography shadows decreased 5 years later. Conclusion: The radiological appearances of CBD and sarcoidosis are similar, although mediastinal or hilar lymphadenopathy is less common in CBD and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are also rare. Despite limited evidence, these findings are similar to those observed in pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than of beryllium. Aluminum is frequently detected in patients with pneumoconiosis with a sarcoid-like reaction and is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and may have contributed to the etiology.
Medicina 2020, 56, 630; doi:10.3390/medicina56110630 www.mdpi.com/journal/medicina Medicina 2020, 56, x 630 FOR PEER REVIEW 22 of of 11 12
is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and Additionally,may have contributed our case suggests to the thatetio cessationlogy. Additionally, of dust exposure our case may contributesuggests that to improvement cessation ofunder dust exposurethe aforementioned may contribute conditions. to improvement under the aforementioned conditions.
Keywords: aluminum;aluminum; berylliosis; berylliosis; chronic chronic beryllium beryllium disease; disease; pneumoconiosis; pneumoconiosis; sarcoidosis; sarcoidosis; sarcoid- likesarcoid-like reaction; reaction; X-ray analytical X-ray analytical electronelectron microscopy microscopy
1. Introduction Introduction Studies havehave shown shown that that exposure exposure to industrial to indust dustrial may dust lead tomay the developmentlead to the ofdevelopment granulomatous of granulomatouslung disease. Hardy lung and disease. Tabershaw Hardy have and described Tabershaw a granulomatous have described disease a granulomatous that resembles disease sarcoidosis that resemblesbut is caused sarcoidosis by beryllium, but is caused known by as beryllium, berylliosis known or chronic as berylliosis beryllium or disease chronic (CBD) beryllium [1]. Clinicaldisease (CBD)manifestations [1]. Clinical similar manifestations to those observed similar in to CBD those have observed occasionally in CBD been have reported occasionally in cases been of exposurereported into dustcases of of other exposure metals [to2– 13dust]. However, of other reports metals describing [2–13]. However, the clinical, reports radiographic, describing and pathologicalthe clinical, radiographic,findings of conditions and pathological other than findings beryllium-induced of conditions pneumoconiosis other than beryllium-induced with a sarcoid-like pneumoconiosis reaction, and withdetailed a sarcoid-like information reaction, on mineralogical and detailed analyses information of metal on dusts mineralogical are limited. analyses Herein, of wemetal report dusts a case are limited.of pneumoconiosis Herein, we withreport a sarcoid-likea case of pneumoconiosis reaction other with than a CBD sarcoid-like and review reaction similar other reported than CBD cases and in reviewthe literature. similar reported cases in the literature.
2. Case Case Presentation Presentation A 51-year-old, asymptomatic Japanese man wi withth rapidly progressing nodular shadows, as observed on chest radiography perf performedormed as part of his routine physical examinations, was referred to our hospital. Two Two years ago, hishis chestchest radiographradiograph hadhad revealedrevealed nono abnormalities.abnormalities. Small nodules had appeared a year later, mainly in both the lower lung fields fields (Figure 11A);A); however,however, hehe diddid notnot visitvisit a hospital. Further, Further, he reported a smoking history of 30 pack-years. As As a a civil civil engineer, he had been engaged in underground construction with welding, cutting, and drilling of reinforced concrete and metals for 10 years (between the ages of 41 and 51 years); though he had never used and/or and/or been exposed to beryllium.
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Figure 1. Cont.
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Figure 1. 1. (A(A) )Chest Chest radiograph radiograph 1 year 1 year prior prior to referral to referral to our to ourhospital, hospital, showing showing small small nodules nodules in both in theboth lower the lower lung lungfields. fields. (B) Chest (B) Chest radiograph radiograph on onadmission, admission, show showinging an an increase increase in in the the number number of of nodules in 1 year.
The patient did not not display display clinical clinical respiratory respiratory sy symptomsmptoms such such as as dyspnea, dyspnea, exercise exercise intolerance, intolerance, or any other relevant manifestations upon referral to our hospital. The The patient’s patient’s body body temperature, temperature, pulse rate, and respiratory rate were 36.9 °C,◦C, 58 58 be beatsats/min,/min, and and 20 20 breaths/min, breaths/min, respectively. respectively. On chest auscultation, fine fine crackles were audible in the bilateral lower lung fields. fields. Clubbed fingers fingers were not observed. Laboratory Laboratory data data on on admission admission revealed revealed elevated elevated levels levels of of PR3-ANCA PR3-ANCA (15.4 (15.4 U/mL, U/mL, cutoff cutoff level:level: 3.5 3.5 U/mL). U/mL). Other Other representative representative tests tests for for coll collagenagen disease-related disease-related autoantibodies autoantibodies were were negative. negative. Serum levels levels of of angiotensin-conver angiotensin-convertingting enzyme, enzyme, carcinoembryonic carcinoembryonic antigen, antigen, KL-6, KL-6, and and sIL-2R sIL-2R were were in thein the normal normal range, range, and and the the results results of of interferon interferon-gamma-gamma release release assay assay were were negative. The The chest radiograph on admission showedshowed anan increaseincrease inin thethe numbernumber ofof nodules nodules compared compared with with those those found found 1 1year year previously previously (Figure (Figure1B). 1B). High-resolution computed computed tomography (HRCT) (HRCT) (Figure (Figure 22)) showedshowed well-definedwell-defined multiplemultiple centrilobular andand perilobularperilobular nodules, nodules, and and thickening thickening of theof the intralobular intralobular septa septa in the in middle the middle and lower and lowerzones zones of both of lungs. both lungs. No pleural No pleural effusion effusion or mediastinal or mediastinal lymphadenopathy lymphadenopathy was observed. was observed. Positron emission tomography showed no significant accumulation on the nodules. No extrathoracic manifestations were observed, both clinically and radiologically. The pulmonary function test results revealed the following: total lung capacity, 4.14 L (116.3% of the predicted value); forced vital capacity, 4.00 L (112.4% of the predicted value); forced expiratory volume in 1 s, 3.16 L (109.0% of the predicted value); and carbon monoxide diffusion capacity of the lung, 6.55 mL/min/mm Hg (88.2% of the predicted value). An analysis of the bronchoalveolar lavage fluid obtained from the middle lobe (right B5) showed 2.4 105 cells/mL (88.9% macrophages, 9.9% lymphocytes, 1.0% neutrophils, and × 0.0% eosinophils), with a CD4/CD8 ratio of 0.7. Lung specimens from the anterior basal segment of the right lower lobe, obtained by transbronchial lung biopsy, exhibited non-necrotizing granulomatous inflammation and chronic multinucleated giant cells with marked dust deposition. To confirm the diagnosis, lung specimens from the lateral segment of the right middle lobe and anterior basal segment of the right lower lobe were obtained via video-assisted thoracoscopic surgery. The specimens showed 5–12 mm silicotic nodules with dust deposition (silica- and berlin blue.staining-positive dust), surrounded by fibrotic changes and macrophages on the pleura and around the airways (Figure3A,B). Hemosiderin-ladenFigure 2. High-resolution macrophages computed were tomography observed of in the the lower surrounding lung lobes alveolion admission, of the showing nodules. well- Several non-necrotizingdefined multiple granulomas centrilobular along and the perilobular lymphatic nodule routess, were and alsothickening observed of the (Figure intralobular3C,D). Nosepta asbestos in the middle and lower zones of both lungs.
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Figure 1. (A) Chest radiograph 1 year prior to referral to our hospital, showing small nodules in both the lower lung fields. (B) Chest radiograph on admission, showing an increase in the number of nodules in 1 year.
The patient did not display clinical respiratory symptoms such as dyspnea, exercise intolerance, or any other relevant manifestations upon referral to our hospital. The patient’s body temperature, pulse rate, and respiratory rate were 36.9 °C, 58 beats/min, and 20 breaths/min, respectively. On chest auscultation, fine crackles were audible in the bilateral lower lung fields. Clubbed fingers were not observed. Laboratory data on admission revealed elevated levels of PR3-ANCA (15.4 U/mL, cutoff level: 3.5 U/mL). Other representative tests for collagen disease-related autoantibodies were negative. Serum levels of angiotensin-converting enzyme, carcinoembryonic antigen, KL-6, and sIL-2R were in the normal range, and the results of interferon-gamma release assay were negative. The chest Medicinaradiograph2020, 56on, 630admission showed an increase in the number of nodules compared with those found4 of 12 1 year previously (Figure 1B). bodiesHigh-resolution were observed, computed and immunostaining tomography for(HRCT)Cutibacterium (Figure acnes2) showed, Ziehl–Neelsen well-defined staining, multiple and Grocottcentrilobular staining and were perilobular all negative. nodules, and thickening of the intralobular septa in the middle and lowerMedicina zones 2020 of, 56both, x FOR lungs. PEER REVIEWNo pleural effusion or mediastinal lymphadenopathy was observed.4 of 11
Positron emission tomography showed no significant accumulation on the nodules. No extrathoracic manifestations were observed, both clinically and radiologically. The pulmonary function test results revealed the following: total lung capacity, 4.14 L (116.3% of the predicted value); forced vital capacity, 4.00 L (112.4% of the predicted value); forced expiratory volume in 1 s, 3.16 L (109.0% of the predicted value); and carbon monoxide diffusion capacity of the lung, 6.55 mL/min/mm Hg (88.2% of the predicted value). An analysis of the bronchoalveolar lavage fluid obtained from the middle lobe (right B5) showed 2.4 × 105 cells/mL (88.9% macrophages, 9.9% lymphocytes, 1.0% neutrophils, and 0.0% eosinophils), with a CD4/CD8 ratio of 0.7. Lung specimens from the anterior basal segment of the right lower lobe, obtained by transbronchial lung biopsy, exhibited non-necrotizing granulomatous inflammation and chronic multinucleated giant cells with marked dust deposition. To confirm the diagnosis, lung specimens from the lateral segment of the right middle lobe and anterior basal segment of the right lower lobe were obtained via video-assisted thoracoscopic surgery. The specimens showed 5–12 mm silicotic nodules with dust deposition (silica-. and berlin blue staining-positive dust), surrounded by fibrotic changes and macrophages on the Figure 2. High-resolution computed tomography of the lower lung lobes on admission, showing pleuraFigure and 2. High-resolution around the airways computed (Figure tomography 3A,B). Hemo of thesiderin-laden lower lung macrophages lobes on admission, were observed showing well-in the surroundingwell-defined multiplealveoli of centrilobular the nodules. and Several perilobular non-necrotizing nodules, and granulomas thickening along of the the intralobular lymphatic septa routes in defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in werethe middle also observed and lower (Figure zones of3C,D). both lungs.No asbestos bodies were observed, and immunostaining for the middle and lower zones of both lungs. Cutibacterium acnes, Ziehl–Neelsen staining, and Grocott staining were all negative.
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Figure 3. Cont.
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FigureFigure 3. ( A3.). (A Lung). Lung specimens specimens from from the the laterallateral segment(D) of of the the right right middle middle lobe lobe and and anterior anterior basal basal segment of the right lower lobe, obtained via video-assisted thoracoscopic surgery showing 5–12 mm segmentFigure of 3. the (A right). Lung lower specimens lobe, obtained from the vialateral video-assisted segment of the thoracoscopic right middle surgerylobe and showinganterior basal 5–12 mm sized nodules with dust deposition. The length of the scale bar is 5 mm; (B). Higher magnification of sizedsegment nodules of with the right dust lower deposition. lobe, obtained The length via video-assisted of the scale thoracoscopic bar is 5 mm; surgery (B). Higher showing magnification 5–12 mm of the nodules with dust deposition, surrounded by fibrotic changes and macrophages. The length of the nodulessized nodules with with dust dust deposition, deposition. surrounded The length byof the fibrotic scale bar changes is 5 mm; and (B) macrophages.. Higher magnification The length of of the scale bar is 200 μm; (C). Non-necrotizing granulomas along the lymphatic routes. The length of the scalethe nodules bar is 200withµ m;dust (C deposition,). Non-necrotizing surrounded granulomas by fibrotic changes along the and lymphatic macrophages. routes. The Thelength length of of the scale bar is 500 μm; (D). Higher magnification of the non-necrotizing granulomas. The length of the scalethe scale bar isbar 500 is 200µm; μm (D; ).(C Higher). Non-necrotizing magnification granulomas of the non-necrotizingalong the lymphatic granulomas. routes. The Thelength length of of the scale bar is 100 μm. the scalethe scale bar isbar 100 is 500µm. μm; (D). Higher magnification of the non-necrotizing granulomas. The length of the scale bar is 100 μm. X-ray analytical electron microscopy (S-4500 Hitachi, Japan) of the same specimens detected particlesX-ray analytical containing electron aluminum, microscopy iron, titanium, (S-4500 and silica Hitachi, (Figure Japan) 4). of the same specimens detected particles containingX-ray analytical aluminum, electron iron,microscopy titanium, (S-4500 and Hi silicatachi, (Figure Japan)4 ).of the same specimens detected particles containing aluminum, iron, titanium, and silica (Figure 4).
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(A) Figure 4. Cont. Medicina 2020, 56, 630 6 of 12 Medicina 2020, 56, x FOR PEER REVIEW 6 of 11
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Figure 4. Cont.
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FigureFigure 4. 4. X-rayX-ray microanalysis microanalysis of ofparticles particles in inthe the lung lung specimens. specimens. Particles Particles containing containing aluminum aluminum (Al) ((Al)A–C (),A iron–C), (Fe) iron ( (Fe)A,B, (DA),,B titanium,D), titanium (Ti) ( (Ti)E,F), ( Eand,F), silica. and silica. In Figure In Figure 4B,F,4 backgroundB,F, background peaks peaks are also are observed.also observed.
BasedBased on on his his history history of of occupati occupationalonal exposure exposure and and his his clinical, radiological, and and pathological pathological findings,findings, the the patient patient was was diag diagnosednosed with with pneumoconiosis pneumoconiosis wi withth a a sarcoid-like sarcoid-like reaction. reaction. He He did did not not receivereceive any any medical medical treatment, treatment, such such as as corticoste corticosteroidroid administration; administration; howe however,ver, he he stopped stopped smoking smoking andand changed changed his his occupation occupation to to avoid avoid further further exposure exposure to to dust. dust. Two Two years years later, later, the the HRCT HRCT showed showed an an increaseincrease inin thethe nodular nodular shadows shadows (Figure (Figure5A). However,5A). However, the shadows the shadows were observed were observed to have decreased to have decreasedafter 5 years after (Figure 5 years5B). (Figure 5B).
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Figure 4. X-ray microanalysis of particles in the lung specimens. Particles containing aluminum (Al) (A–C), iron (Fe) (A,B,D), titanium (Ti) (E,F), and silica. In Figure 4B,F, background peaks are also observed.
Based on his history of occupational exposure and his clinical, radiological, and pathological findings, the patient was diagnosed with pneumoconiosis with a sarcoid-like reaction. He did not receive any medical treatment, such as corticosteroid administration; however, he stopped smoking and changed his occupation to avoid further exposure to dust. Two years later, the HRCT showed an increaseMedicina 2020 in, 56the, 630 nodular shadows (Figure 5A). However, the shadows were observed to 8have of 12 decreased after 5 years (Figure 5B).
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Figure 5. (A) High-resolution computedcomputed tomographytomography of of the the chest chest after after 2 years,2 years, showing showing an an increase increase in thein the nodular nodular shadows. shadows. (B ()B High-resolution) High-resolution computed computed tomography tomography (HRCT) (HRCT) ofof thethe chestchest after 5 years, showing a decrease in nodular shadows.shadows.
3. Discussion Non-necrotizing granulomas are observed in several lung diseases, including sarcoidosis, and their causes causes can can be be broadly broadly classified classified into into infectio infectiousus and andnoninfectious noninfectious factor factors.s. Noninfectious Noninfectious factors factorsinclude includethe inhalation the inhalation of organic of organic and inorganic and inorganic agents agents [14,15]. [14 ,15CBD]. CBDis a iswell-known a well-known type type of ofpneumoconiosis pneumoconiosis with with a sarcoid-like a sarcoid-like reaction, reaction, which which is is caused caused by by beryllium beryllium exposure, exposure, and shares several clinical and histopathological features with sarcoidosis [[1,16,17].1,16,17]. Similar manifestations have occasionally been reported in cases of exposure to dust of other metals, such as as aluminum, aluminum, titanium, titanium, silica, and zirconium [[2–13].2–13]. Our patient showed non-necrotizing granulomatous inflammation inflammation with chronic-multinucleated giantgiant cells cells and and marked marked dust dust deposition deposition without without a history a ofhistory beryllium of beryllium exposure; additionally,exposure; additionally, aluminum, aluminum, iron, titanium, iron, andtitanium, silica an wered silica detected were indetected the deposited in the deposited dust in the dust lung in specimens.the lung specimens. Therefore, Therefore, we suspected we suspected the development the development of pneumoconiosis of pneumoconios with ais sarcoid-like with a sarcoid-like reaction inreaction our patient in our due patient to exposure due to exposure to occupational to occu dustpational of metals dust of other metals than other beryllium. than beryllium. The appearance of CBD in the radiological findingsfindings is similar to that of sarcoidosis,sarcoidosis, although mediastinal or hilar lymphadenopathy is less common and is usually seen in the presence of parenchymal opacities [[18,19].18,19]. On On chest CT, multiplemultiple nodules are the most commoncommon finding,finding, often clustered aroundaround the the bronchi bronchi and and interlobular interlobular septa septa or in theor subpleuralin the subpleural region. Ground-glassregion. Ground-glass opacities, bronchialopacities, wallbronchial thickening, wall thickening, and interlobular and interlobul septumar thickening septum thickening may also be may seen also [18 ,be19 ].seen Compared [18,19]. withCompared patients with with patients sarcoidosis, with sarcoidosis, extrathoracic extrathora manifestations,cic manifestations, such as those such observed as those inobserved the eye, in skin, the heart,eye, skin, liver, heart, and liver, nervous and system nervous are system rare in are patients rare in with patients CBD with [18]. CBD Further, [18]. there Further, is little there evidence is little evidence of pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than beryllium dust; however, similar findings have been reported in four out of five cases based on detailed clinical and radiological information [4,8–10,13]. Multiple nodules have also been observed in these four out of five cases [4,8–10,13], and mediastinal and hilar lymphadenopathy was observed in only one case [8]. Extrathoracic manifestations have not been observed. In our case, multiple nodules and thickening of the intralobular septa were the main radiological findings, and lymphadenopathy and extrathoracic manifestations were not observed. These findings correspond to pneumoconiosis with a sarcoid-like reaction. The natural history of CBD has been variable, and the duration from beryllium sensitization to CBD development is reportedly 3.8 years (range, 1.0–9.5 years) [20]. The clinical course varies, and most patients experience a gradual deterioration in their condition; however, improvement may occur with the cessation of beryllium exposure [18,20,21]. Besides beryllium exposure, 18 months of toner dust exposure and 3 years of magnetite iron exposure have been shown to cause pneumoconiosis with a sarcoid-like reaction, without improvement in radiological findings despite administration of corticosteroid therapy [8,13]. By contrast, radiological findings of another individual exposed to aluminum dust for 15 years improved with corticosteroid therapy [4]. Further,
Medicina 2020, 56, 630 9 of 12 of pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than beryllium dust; however, similar findings have been reported in four out of five cases based on detailed clinical and radiological information [4,8–10,13]. Multiple nodules have also been observed in these four out of five cases [4,8–10,13], and mediastinal and hilar lymphadenopathy was observed in only one case [8]. Extrathoracic manifestations have not been observed. In our case, multiple nodules and thickening of the intralobular septa were the main radiological findings, and lymphadenopathy and extrathoracic manifestations were not observed. These findings correspond to pneumoconiosis with a sarcoid-like reaction. The natural history of CBD has been variable, and the duration from beryllium sensitization to CBD development is reportedly 3.8 years (range, 1.0–9.5 years) [20]. The clinical course varies, and most patients experience a gradual deterioration in their condition; however, improvement may occur with the cessation of beryllium exposure [18,20,21]. Besides beryllium exposure, 18 months of toner dust exposure and 3 years of magnetite iron exposure have been shown to cause pneumoconiosis with a sarcoid-like reaction, without improvement in radiological findings despite administration of corticosteroid therapy [8,13]. By contrast, radiological findings of another individual exposed to aluminum dust for 15 years improved with corticosteroid therapy [4]. Further, there was no improvement in radiological findings in an individual exposed to glass wool fibers for 7 years, even after 4 years of exposure cessation [10]. However, in a case of pneumoconiosis with a sarcoid-like reaction in a limestone quarry worker with 8 years of employment, the radiological findings resolved 2 years after the relocation of his workplace [9]. In our case, the patient was engaged in underground construction as a civil engineer, with welding, cutting, and drilling of reinforced concrete and metals for 10 years, and the rapid progression of nodular shadows was observed over 2 years. Improvement in his condition was noted 5 years after exposure cessation. Due to limited evidence for pneumoconiosis with a sarcoid-like reaction, it is difficult to discuss the differences in the clinical course of the patients, and the effect of exposure cessation on the resolution of radiological findings. However, our findings largely suggest that cessation of exposure may improve progression of the disease [9]. In this case, X-ray analytical electron microscopy detected aluminum, iron, titanium, and silica deposition in the lung tissues. In four case reports of pneumoconiosis with a sarcoid-like reaction other than CBD, detailed mineralogical analyses were performed and the following were detected in the lung tissues: aluminum and silica due to limestone exposure; aluminum, silica, and magnesium due to glass wool fiber exposure; silica and iron due to toner dust exposure; and aluminum, magnesium, and silica due to metal reclamation factory exposure [4,8–10,13]. Additionally, aluminum, silica, and titanium were detected in the lung tissues of six patients with pneumoconiosis with a sarcoid-like reaction due to man-made mineral fiber exposure [2]. Other studies have also shown that aluminum and silica are frequently detected in patients with pneumoconiosis with a sarcoid-like reaction [3,7]. We cannot ignore the effects of silica, as it is detected in most lung samples of various lung diseases, regardless of the extent of occupational exposure [22,23]. Aluminum is frequently detected in patients with occupational exposure [22,23] and can cause pulmonary fibrosis, referred to as aluminosis or aluminum lung [24,25]. Pathological findings include interstitial fibrosis and, occasionally, granuloma [24,26]. Aluminum has also been listed as an inorganic agent in the etiology of sarcoidosis [14]. Collectively, we speculate that aluminum may play a particularly important role in the pathology of pneumoconiosis with a sarcoid-like reaction. CBD is diagnosed using the beryllium lymphocyte proliferation test [18]. A recent study has highlighted the utility of the lymphocyte proliferation test called memory lymphocyte immunostimulation assay (MELISA®) in identifying metals causing sarcoid-like reactions; in this test, 9 out of 13 patients (69%) tested positive for at least one of the metal components [27]. However, as this method is not routinely used in Japan and our patient showed a favorable response to avoiding dust exposure, we did not perform this test. Although the specificity of this technique for pneumoconiosis with a sarcoid-like reaction is unclear, it may be used to confirm the pathology or to identify the underlying etiology, particularly in cases with an unfavorable response. Medicina 2020, 56, 630 10 of 12
The detection of mineral components using mineralogical analyses, the beryllium lymphocyte proliferation test, and/or MELISA® is not a convenient option. However, these tests are recommended in all patients with sarcoidosis or sarcoid-like reaction. Based on the presentation of our case, we suggest that these tests may be beneficial for exploring the cause of the condition and the effects of cessation of exposure in patients with a history of occupational exposure, and/or dust deposition in lung tissues. Recently, beryllium sensitization caused by environmental exposure to beryllium-containing concrete dust in a cluster of workers from a non-beryllium-related industry was reported in Germany [28]. While our patient did not have a history of beryllium exposure, we cannot exclude the possibility of CBD in the present case, in addition to the previous reports of pneumoconiosis with a sarcoid-like reaction without beryllium exposure [4,8–10,13]. Further expansion of methods for the diagnosis of CBD is also required.
4. Conclusions The radiological findings of CBD are similar to those of sarcoidosis, although mediastinal or hilar lymphadenopathy is less common and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are rare in patients with CBD. Moreover, besides CBD, the findings observed in pneumoconiosis with a sarcoid-like reaction may be similar to those observed in other dust exposure cases. The findings in our case were compatible with those observed in pneumoconiosis with a sarcoid-like reaction, and suggest that this condition may be improved with the cessation of dust exposure. Aluminum was also detected in this case and may have played an important role in the clinical manifestations. As the information on pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than beryllium is limited, further research is warranted for appropriate diagnosis and management.
Author Contributions: F.H., T.K., and N.S. conceived, designed, and drafted the article. Y.Z., M.O., Y.E. and J.F. contributed to the pathological diagnosis. H.Y. (Hirokazu Yura), A.H., H.I., H.Y. (Hiroyuki Yamaguchi), T.M., Y.O., Y.I. and H.M. made critical revisions. M.Y. contributed to the detection of mineral components in lung tissues. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.
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