今日の臨床サポート

じん肺症・アスベスト肺

著者: 原澤寛 獨協医科大学 日光医療センター呼吸器内科

監修: 長瀬隆英 東京大学 内科学専攻器官病態内科学講座

著者校正/監修レビュー済:2020/07/03
患者向け説明資料

概要・推奨   

  1. じん肺は、職業性呼吸器疾患である。
  1. 根治療法は存在せず、合併症に対する治療と予防が中心となる。
  1. じん肺の診断にHRCTを積極的に活用することが勧められる(推奨度1)
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  1. じん肺は肺気腫様病変を合併することが経験される。長時間作用性β2刺激薬(LABA)と長時間作用性抗コリン薬 (LAMA)の合剤投与が勧められる。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
原澤寛 : 特に申告事項無し[2021年]
監修:長瀬隆英 : 講演料(アストラゼネカ),研究費・助成金など(中外製薬)[2021年]

改訂のポイント:
  1. 定期レビューを行い、疾患情報、難治症例の治療、文献について一部加筆を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. じん肺は、職業性呼吸器疾患である。
  1. じん肺は、「粉じんを吸入することによって肺に生じた線維増殖性変化を主体とする疾病」と定義される。
  1. 吸入した原因物質により疾患名が決められる。
 
じん肺の種類

じん肺は起因物質により分類される。
 
参考文献:
滝沢敬夫:図説病態内科講座.メジカルビュー社,1994;271.

出典

img1:  著者提供
 
 
 
  1. 遊離珪酸(結晶性シリカcrystalline silica)吸入による珪肺、アスベスト吸入によるアスベスト(石綿)肺が代表的疾患である。
  1. 珪肺は細気管支周囲に直径数mm~数cmの珪肺結節を形成する[1]
  1. アスベスト肺はアスベスト吸入により細気管支肺胞炎が惹起され、肺のびまん性線維化を来す[2]
 
アスベスト肺

80歳代男性。HRCTで胸膜下線状影(subpleural curvilinear shadow)(b:黒矢印)や胸膜下粒状影(subpleural dotlike opacities)を認める。特発性肺線維症(idiopathic pulmonary fibrosis、IPF)との鑑別にこれらの所見が重要である。胸膜プラークを横隔膜面にも認める(c:白矢印)。
a:胸部X線
b、c:HRCT

出典

img1:  著者提供
 
 
 
  1. 厚生労働省じん肺健康管理実施状況の報告による新規有所見労働者数は、1980年に年間6,842人であった。その後大幅に減少し、2001年以降250人前後で推移していたが2011年からは200人を下回っている。2016年122人、2017年125人2018年91人と、最近3年間は100人前後を推移している。有所見率も2002年以降5.0%を下回り、2016年0.7%、2017年0.6%、2018年0.4%と減少傾向になっている。
  1. 根治療法は存在せず、適切なスクリーニングによる早期診断、合併症に対する治療と予防が中心となる。
問診、診察のポイント  
  1. 粉じん曝露のリスクを識別する。

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文献 

著者: V Castranova, V Vallyathan
雑誌名: Environ Health Perspect. 2000 Aug;108 Suppl 4:675-84.
Abstract/Text Exposure to coal mine dust and/or crystalline silica results in pneumoconiosis with initiation and progression of pulmonary fibrosis. This review presents characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic silicosis by summarizing results of in vitro, animal, and human investigations. These results support four basic mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator release from alveolar macrophages and epithelial cells, which leads to recruitment of polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and in further lung injury and scarring; d) secretion of growth factors from alveolar macrophages and epithelial cells, stimulating fibroblast proliferation and eventual scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend support to these mechanisms.

PMID 10931786  Environ Health Perspect. 2000 Aug;108 Suppl 4:675-84.
著者: American Thoracic Society
雑誌名: Am J Respir Crit Care Med. 2004 Sep 15;170(6):691-715. doi: 10.1164/rccm.200310-1436ST.
Abstract/Text
PMID 15355871  Am J Respir Crit Care Med. 2004 Sep 15;170(6):691-715. ・・・
著者: E Meijer, E Tjoe Nij, T Kraus, J S van der Zee, O van Delden, M van Leeuwen, J W Lammers, D Heederik
雑誌名: Occup Environ Med. 2011 Jul;68(7):542-6. doi: 10.1136/oem.2010.055616. Epub 2011 Feb 25.
Abstract/Text OBJECTIVES: To evaluate the prevalence of HRCT findings in construction workers previously surveyed by chest radiographs classified according to ILO guidelines. To examine the association between HRCT findings and exposure to quartz containing dust, and lung function.
METHODS: The study comprised a questionnaire, dynamic and static lung function measurements, single-breath CO diffusion capacity, chest radiographs and HRCT in 79 individuals. Certified 'B' readers coded radiographs according to the ILO classification. HRCT scans were read according to an international classification system. A qualitative exposure index for cumulative respiratory quartz on a 10-point scale was used.
RESULTS: Agreement between HRCT readers was good (κ>0.60), except for irregular opacities (κ=0.23). In ILO category 0/0, 8% HRCT round, 22% irregular and/or linear opacities and 41% HRCT emphysema was found. HRCT round opacities was associated with high cumulative quartz exposure (OR 7.1; 95% CI 1.3 to 37.8). Emphysema was associated with smoking (OR 10.1; 95% CI 1.2 to 84.2) and showed a reduction in T(L,CO,sb). HRCT round opacities was not associated with lung function. Current smoking was negatively associated with FEV₁/FVC ratio and positively with RV/TLC ratio, and showed a reduction in T(L,CO,sb) (13.4%), adjusted for different HRCT findings.
CONCLUSIONS: Low grade silicosis cannot be excluded in workers with normal chest radiographs (ILO 0/0). In relatively highly exposed construction workers, a sevenfold increased risk of simple (nodular) silicosis was found. Emphysema on HRCT was associated with current or former smokers, but not with exposure, and contributed to reduced diffusion capacity. Airflow limitation was mainly determined by current smoking and was not associated with simple (nodular) silicosis.

PMID 21355064  Occup Environ Med. 2011 Jul;68(7):542-6. doi: 10.1136/o・・・
著者: Masanori Akira, Satoru Yamamoto, Yoshikazu Inoue, Mitsunori Sakatani
雑誌名: AJR Am J Roentgenol. 2003 Jul;181(1):163-9. doi: 10.2214/ajr.181.1.1810163.
Abstract/Text OBJECTIVE: We studied high-resolution CT of asbestosis and idiopathic pulmonary fibrosis to determine whether differences-other than the frequency of associated pleural changes-could be discerned between the two diseases.
MATERIALS AND METHODS: High-resolution CT scans of 80 patients with asbestosis and 80 patients with idiopathic pulmonary fibrosis were retrospectively reviewed. Two chest radiologists assessed the type and distribution of parenchymal and pleural abnormalities on high-resolution CT.
RESULTS: Subpleural dotlike or branching opacities (65/80), subpleural curvilinear lines (55/80), mosaic perfusion (39/80), and parenchymal bands (38/80) were more common in patients with asbestosis (p < 0.0001). Visible intralobular bronchioles (62/80), bronchiolectasis within fibrotic consolidations (47/80), and honeycombing (61/80) were more common in patients with idiopathic pulmonary fibrosis (p < 0.0001). The frequencies of interlobular septal thickening, ground-glass opacities, fibrotic consolidation, and emphysema were similar in both groups. Parenchymal bands and fibrotic consolidation were more commonly seen (p < 0. 05) in patients with asbestosis associated with pleural disease (n = 66) than in patients with asbestosis without pleural disease (n = 14). Also, statistically significant differences were noted between high-resolution CT findings of patients with asbestosis without pleural disease and those of patients with idiopathic pulmonary fibrosis, except for parenchymal bands.
CONCLUSION: Specific combinations of high-resolution CT findings strongly suggest either asbestosis or idiopathic pulmonary fibrosis. We found that CT findings that might have represented bronchiolar obstruction in the subpleural region were more prominent in patients with asbestosis than in those with idiopathic pulmonary fibrosis, whereas bronchiolar dilatation was more prominent in patients with idiopathic pulmonary fibrosis than in those with asbestosis.

PMID 12818850  AJR Am J Roentgenol. 2003 Jul;181(1):163-9. doi: 10.221・・・
著者: Oznur Akkoca Yildiz, Banu Eris Gulbay, Sevgi Saryal, Gulseren Karabiyikoglu
雑誌名: Respirology. 2007 May;12(3):420-6. doi: 10.1111/j.1440-1843.2007.01031.x.
Abstract/Text OBJECTIVE: The aim of this study was to investigate the effect of the radiological evidence of emphysema, and the extent of interstitial involvement, on lung function and pulmonary arterial pressure (PAP) in patients with coal workers' pneumoconiosis (CWP).
METHODS: The records of 48 patients with suspected CWP were evaluated retrospectively. Pulmonary function tests, arterial blood gas analyses and right heart catheterization were evaluated in all patients. Radiological scoring was according to International Labour Organization criteria, and emphysema was scored by CT scanning. Patients were grouped according to the mean PAP (> or =20 mm Hg or < or =19 mm Hg).
RESULTS: All patients showed a mild decrease in FEV(1)/FVC and a mild increase in FRC. Forty-four per cent of patients developed mild to moderate pulmonary hypertension. Emphysema scores correlated significantly with airflow rates, including FEV(1)%, FEV(1)/FVC and FEF(25-75%), and with carbon monoxide diffusing capacity (DLCO)% predicted as well as FRC% predicted and the ratio RV/TLC, which are indices of air trapping. Additionally, profusion and global profusion scores showed significant correlation with FEV(1)/FVC, DLCO% predicted, specific airway conductance and smoking. Mean PAP showed a significant negative correlation with FEF(50%) predicted, DLCO% predicted and profusion score.
CONCLUSIONS: The impairment of pulmonary function (mainly disturbance in airflow rates and air trapping) and pulmonary hypertension may be present, even in a simple form of CWP. The pulmonary function impairment in patients with CWP is likely to be attributable to the occurrence of emphysema. However, pulmonary hypertension was directly related to the profusion of pneumoconiotic nodules, which may result in obliteration of the vascular bed.

PMID 17539849  Respirology. 2007 May;12(3):420-6. doi: 10.1111/j.1440-・・・
著者: S Marchand-Adam, A El Khatib, F Guillon, M W Brauner, C Lamberto, V Lepage, J-M Naccache, D Valeyre
雑誌名: Eur Respir J. 2008 Sep;32(3):687-93. doi: 10.1183/09031936.00149607.
Abstract/Text Chronic beryllium disease (CBD) is a granulomatous disorder that affects the lung after exposure to beryllium. The present study reports short- and long-term evolution of granulomatous and fibrotic components in eight patients with severe CBD receiving corticosteroid therapy. Eight patients with confirmed CBD were studied at baseline, after initial corticosteroid treatment (4-12 months), at relapse and at the final visit. Beryllium exposure, Glu(69) (HLA-DPB1 genes coding for glutamate at position beta69) polymorphism, symptoms, pulmonary function tests (PFT), serum angiotensin-converting enzyme (SACE) and high-resolution computed tomography (HRCT) quantification of pulmonary lesions were analysed. The CBD patients were observed for a median (range) of 69 (20-180) months. After stopping beryllium exposure, corticosteroids improved symptoms and PFT (vital capacity +26%, diffusing capacity of the lung for carbon monoxide +15%), and decreased SACE level and active lesion HRCT score. In total, 18 clinical relapses occurred after the treatment was tapered and these were associated with SACE and active lesion HRCT score impairment. At the final visit, corticosteroids had completely stabilised all parameters including both HRCT scores of active lesions and fibrotic lesions in six out of eight patients. Corticosteroids were beneficial in chronic beryllium disease. They were effective in suppressing granulomatosis lesions in all cases and in stopping the evolution to pulmonary fibrosis in six out of eight patients.

PMID 18757698  Eur Respir J. 2008 Sep;32(3):687-93. doi: 10.1183/09031・・・
著者: Sang Hoon Lee, Seong Tai Hahn, Byung Gil Choi
雑誌名: Acta Radiol. 2008 Feb;49(1):26-31. doi: 10.1080/02841850701675701.
Abstract/Text BACKGROUND: Transcatheter arterial embolization (TAE) is a safe and well-established treatment option to control hemoptysis, but there are few studies focused on treating hemoptysis accompanying coal workers' pneumoconiosis (CWP).
PURPOSE: To evaluate the immediate and long-term efficacy of TAE for control of massive hemoptysis in patients with CWP, and to clarify the factors which influence the frequency of rebleeding.
MATERIAL AND METHODS: This study included 34 CWP patients with massive hemoptysis who were treated with 47 TAE sessions over the last 11 years. Immediate (within 1 month) and long-term outcomes (mean 37 months, range 1 month-11 years) were evaluated retrospectively. The relationships between the frequency of rebleeding and the type of CWP, angiographic findings, and presence of tuberculosis were evaluated.
RESULTS: The immediate success rate was 91.2% (31/34). In 23 patients (68%), hemoptysis did not recur on long-term follow-up. In eight patients who received repeated procedures for recurrent hemoptysis, bleeding was discovered in the non-bronchial systemic artery (n = 13) or bronchial artery (n = 7). The frequency of recurrent hemoptysis was higher in cases with complicated pneumoconiosis (n = 7) than in cases of the simple type (n = 1; P = 0.029). There was no statistical difference between rebleeding and angiographic findings or the presence of tuberculosis.
CONCLUSION: TAE is an effective treatment modality for controlling massive hemoptysis in patients with CWP. However, many non-bronchial systemic collaterals contribute to recurrent hemoptysis. Furthermore, there is a high probability of rebleeding in patients with the complicated type of CWP, and extra care must be taken in the embolization procedure.

PMID 18210312  Acta Radiol. 2008 Feb;49(1):26-31. doi: 10.1080/0284185・・・
著者: J P Singer, H Chen, T Phelan, J Kukreja, J A Golden, P D Blanc
雑誌名: Occup Med (Lond). 2012 Mar;62(2):134-7. doi: 10.1093/occmed/kqr171. Epub 2011 Nov 9.
Abstract/Text BACKGROUND: Information is scant assessing outcomes in lung transplantation (LT) in advanced occupational lung diseases (OLD).
AIMS: To analyse survival after LT for OLD.
METHODS: Using data from the US Organ Procurement and Transplantation Network Registry (OPTN-R), we identified subjects aged ≥ 18 years transplanted for OLD from 2005 to 2010. OPTN-R selected referents of corresponding age, sex and body mass index (BMI) who underwent LT for other diagnoses were also identified. Post-LT survival time was estimated with Cox proportional hazard models. Baseline age, BMI, forced expiratory volume in 1 s, creatinine, lung allocation score, donor age, donor lung ischaemic time and transplant type (single versus bilateral) were included as covariates. Time-dependent covariates were used to model differences in relative risk over time.
RESULTS: Thirty-seven males underwent LT for silicosis (n = 19) or other OLD (n = 18) during the analytic period (0.5% of all LTs). For non-silicotic OLD, 6-month and 1- and 3-year survival estimates were 66, 55 and 55%, compared with the silicotic group (86, 86 and 76%) and referent group (89, 84 and 67%). During the first year post-transplant, those with OLD (silicosis and others combined) manifested an overall 2-fold increased mortality risk [hazard ratio (HR) 2.3, 95% CI 1.3-4.4; P < 0.05] compared to referents. In stratified analysis, this increased risk of death was restricted to those with non-silicotic OLD (HR 3.1, 95% CI 1.5-6.6; P < 0.01). Poorer survival was limited to the first year post-LT.
CONCLUSIONS: Subjects undergoing LT for OLD other than silicosis may be at increased risk of death in the first year post-transplantation.

PMID 22071439  Occup Med (Lond). 2012 Mar;62(2):134-7. doi: 10.1093/oc・・・
著者: Don Hayes, Kaitlyn T Hayes, Hunter C Hayes, Joseph D Tobias
雑誌名: Lung. 2015 Dec;193(6):927-31. doi: 10.1007/s00408-015-9781-z. Epub 2015 Aug 13.
Abstract/Text BACKGROUND: Survival after lung transplantation (LTx) for patients with occupational lung disease (OLD) is not well studied.
METHODS: The United Network for Organ Sharing (UNOS) database was queried from 2005 to 2013 to assess survival after LTx in patients with silicosis and non-silicotic OLD compared to non-OLD patients.
RESULTS: Of 7273 adult LTx recipients, 7227 (24 with silicosis and 29 with non-silicotic OLD) were included in our univariate and Kaplan-Meier function analysis and 6370 for multivariate Cox models. Univariate Cox models did not identify survival differences in silicosis (HR 0.717; 95 % CI 0.358-1.435; p = 0.347) and non-silicotic OLDs (HR 0.934; 95 % CI 0.486-1.798; p = 0.839). Kaplan-Meier function analysis did not identify a survival disadvantage for either silicosis or non-silicotic OLD (log-rank test: χ (2) 0.93, p = 0.627). Patients with non-silicotic OLD were at risk for worse survival for the first 2.5 years post-transplant; however, at the conclusion of the study, this group had the highest survival rate. Multivariate Cox models confirmed no increased risk for mortality for silicosis (HR 1.264; 95 % CI 0.631-2.534; p = 0.509) and non-silicotic OLD (HR 1.114; 95 % CI 0.578-2.147; p = 0.747).
CONCLUSION: Long-term survival for adult patients with silicosis and non-silicotic OLD after LTx is not significantly different compared to the general lung transplant population.

PMID 26267595  Lung. 2015 Dec;193(6):927-31. doi: 10.1007/s00408-015-9・・・
著者: Terence A R Seemungal, Tom M A Wilkinson, John R Hurst, Wayomi R Perera, Ray J Sapsford, Jadwiga A Wedzicha
雑誌名: Am J Respir Crit Care Med. 2008 Dec 1;178(11):1139-47. doi: 10.1164/rccm.200801-145OC. Epub 2008 Aug 21.
Abstract/Text RATIONALE: Frequent chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation. Macrolides have airway antiinflammatory actions and may reduce the incidence of COPD exacerbations.
OBJECTIVES: To determine whether regular therapy with macrolides reduces exacerbation frequency.
METHODS: We performed a randomized, double-blind, placebo-controlled study of erythromycin administered at 250 mg twice daily to patients with COPD over 12 months, with primary outcome variable being the number of moderate and/or severe exacerbations (treated with systemic steroids, treated with antibiotics, or hospitalized).
MEASUREMENTS AND MAIN RESULTS: We randomized 109 outpatients: 69 (63%) males, 52 (48%) current smokers, mean (SD) age 67.2 (8.6) years, FEV1 1.32 (0.53) L, FEV1% predicted 50 (18)%. Thirty-eight (35%) of the patients had three or more exacerbations in the year before recruitment, with no differences between treatment groups. There were a total of 206 moderate to severe exacerbations: 125 occurred in the placebo arm. Ten in the placebo group and nine in the macrolide group withdrew. Generalized linear modeling showed that the rate ratio for exacerbations for the macrolide-treated patients compared with placebo-treated patients was 0.648 (95% confidence interval: 0.489, 0.859; P = 0.003) and that these patients had shorter duration exacerbations compared with placebo. There were no differences between the macrolide and placebo arms in terms of stable FEV1, sputum IL-6, IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein, or serum IL-6 or in changes in these parameters from baseline to first exacerbation over the 1-year study period.
CONCLUSIONS: Macrolide therapy was associated with a significant reduction in exacerbations compared with placebo and may be useful in decreasing the excessive disease burden in this important patient population. Clinical trial registered with www.clinicaltrials.gov (NCT 00147667).

PMID 18723437  Am J Respir Crit Care Med. 2008 Dec 1;178(11):1139-47. ・・・
著者: Marc Decramer, Bartolome Celli, Steven Kesten, Theodore Lystig, Sunil Mehra, Donald P Tashkin, UPLIFT investigators
雑誌名: Lancet. 2009 Oct 3;374(9696):1171-8. doi: 10.1016/S0140-6736(09)61298-8. Epub 2009 Aug 27.
Abstract/Text BACKGROUND: The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD.
METHODS: The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339.
FINDINGS: 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (pINTERPRETATION: Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV(1) in patients with GOLD stage II COPD. This finding and the other improvements in outcomes suggest that treatment of COPD should begin at an early stage of the disease.
FUNDING: Boehringer Ingelheim and Pfizer Pharmaceuticals.

PMID 19716598  Lancet. 2009 Oct 3;374(9696):1171-8. doi: 10.1016/S0140・・・
著者: Louise Restrick, Myra Stern, Noel Baxter
雑誌名: N Engl J Med. 2011 Jun 30;364(26):2552; author reply 2553-4. doi: 10.1056/NEJMc1104617.
Abstract/Text
PMID 21714657  N Engl J Med. 2011 Jun 30;364(26):2552; author reply 25・・・
著者: Donald P Tashkin, Bartolome Celli, Stephen Senn, Deborah Burkhart, Steven Kesten, Shailendra Menjoge, Marc Decramer, UPLIFT Study Investigators
雑誌名: N Engl J Med. 2008 Oct 9;359(15):1543-54. doi: 10.1056/NEJMoa0805800. Epub 2008 Oct 5.
Abstract/Text BACKGROUND: Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy.
METHODS: In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality.
RESULTS: Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure.
CONCLUSIONS: In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)

2008 Massachusetts Medical Society
PMID 18836213  N Engl J Med. 2008 Oct 9;359(15):1543-54. doi: 10.1056/・・・
著者: Jadwiga A Wedzicha, Donald Banerji, Kenneth R Chapman, Jørgen Vestbo, Nicolas Roche, R Timothy Ayers, Chau Thach, Robert Fogel, Francesco Patalano, Claus F Vogelmeier, FLAME Investigators
雑誌名: N Engl J Med. 2016 Jun 9;374(23):2222-34. doi: 10.1056/NEJMoa1516385. Epub 2016 May 15.
Abstract/Text BACKGROUND: Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear.
METHODS: We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations.
RESULTS: A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02).
CONCLUSIONS: Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).

PMID 27181606  N Engl J Med. 2016 Jun 9;374(23):2222-34. doi: 10.1056/・・・
著者: Jin-Ping Zheng, Jian Kang, Shao-Guang Huang, Ping Chen, Wan-Zen Yao, Lan Yang, Chun-Xue Bai, Chang-Zheng Wang, Chen Wang, Bao-Yuan Chen, Yi Shi, Chun-Tao Liu, Ping Chen, Qiang Li, Zhen-Shan Wang, Yi-Jiang Huang, Zhi-Yang Luo, Fei-Peng Chen, Jian-Zhang Yuan, Ben-Tong Yuan, Hui-Ping Qian, Rong-Chang Zhi, Nan-Shan Zhong
雑誌名: Lancet. 2008 Jun 14;371(9629):2013-8. doi: 10.1016/S0140-6736(08)60869-7.
Abstract/Text BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD.
METHODS: We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233.
FINDINGS: 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated.
INTERPRETATION: Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.

PMID 18555912  Lancet. 2008 Jun 14;371(9629):2013-8. doi: 10.1016/S014・・・
著者: T Hirano, T Yamagata, M Gohda, Y Yamagata, T Ichikawa, S Yanagisawa, K Ueshima, K Akamatsu, M Nakanishi, K Matsunaga, Y Minakata, M Ichinose
雑誌名: Thorax. 2006 Sep;61(9):761-6. doi: 10.1136/thx.200X.058156.
Abstract/Text BACKGROUND: Reactive nitrogen species (RNS) are thought to be one of the important factors in the pathogenesis of chronic obstructive pulmonary disease (COPD). A study was undertaken to examine the effects of theophylline and fluticasone propionate (FP) on RNS production in subjects with COPD.
METHODS: Sixteen COPD subjects participated in the study. Theophylline (400 mg/day orally) or FP (400 mug/day inhalation) were administered for 4 weeks in a randomised crossover manner with a washout period of 4 weeks. Induced sputum was collected at the beginning and end of each treatment period. 3-nitrotyrosine (3-NT), which is a footprint of RNS, was quantified by high performance liquid chromatography with an electrochemical detection method as well as by immunohistochemical staining.
RESULTS: Theophylline significantly reduced the level of 3-NT in the sputum supernatant as well as the number of 3-NT positive cells (both p<0.01). FP also reduced 3-NT formation, but the effect was smaller than that of theophylline. Theophylline also significantly reduced the neutrophil cell counts in the sputum (p<0.01), while FP treatment had no effect on the number of inflammatory cells in the sputum, except eosinophils.
CONCLUSIONS: Theophylline reduces nitrative stress and neutrophil infiltration in COPD airways to a larger extent than inhaled corticosteroid.

PMID 16936236  Thorax. 2006 Sep;61(9):761-6. doi: 10.1136/thx.200X.058・・・
著者: Paul A Ford, Andrew L Durham, Richard E K Russell, Fabiana Gordon, Ian M Adcock, Peter J Barnes
雑誌名: Chest. 2010 Jun;137(6):1338-44. doi: 10.1378/chest.09-2363. Epub 2010 Mar 18.
Abstract/Text BACKGROUND: Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD.
METHODS: To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L).
RESULTS: In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD.
CONCLUSIONS: Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD.
TRIAL REGISTRATION: clinicaltrials.gov; Identifier NCT00241631.

PMID 20299628  Chest. 2010 Jun;137(6):1338-44. doi: 10.1378/chest.09-2・・・
著者: Eduardo Mello De Capitani, Marcelo Schweller, Cristiane Mendes da Silva, Konradin Metze, Elza Maria Figueiras Pedreira de Cerqueira, Manoel Barros Bértolo
雑誌名: J Bras Pneumol. 2009 Sep;35(9):942-6.
Abstract/Text Although rare, rheumatoid pneumoconiosis, also known as Caplan's syndrome, can occur in workers exposed to silica, as well as in patients with silicosis, coal workers' pneumoconiosis or asbestosis. Prevalence is higher among patients with silicosis, despite the fact that it was originally described in coal workers with pneumoconiosis. The classical finding that defines this syndrome is that of rheumatoid nodules in the lungs, regardless of whether there are small rounded opacities suggestive of pneumoconiosis or large opacities consistent with massive pulmonary fibrosis, with or without clinical rheumatoid arthritis. We describe the case of a female patient with rheumatoid arthritis, diagnosed 34 years after 7 years of occupational exposure to silica at a porcelain plant. A chest X-ray showed circular opacities of 1-5 cm in diameter, bilaterally distributed at the periphery of the lungs. A CT-guided thoracic punch biopsy of one of those nodules revealed that it was rheumatoid nodule surrounded by a palisade of macrophages, which is typical of Caplan's syndrome. Aspects of diagnosis, classification and occurrence of this syndrome are discussed, emphasizing the importance of the occupational anamnesis of patients with rheumatoid arthritis and lung opacities on chest X-rays.

PMID 19820822  J Bras Pneumol. 2009 Sep;35(9):942-6.
著者: K D Rosenman, M Moore-Fuller, M J Reilly
雑誌名: Am J Ind Med. 1999 Apr;35(4):375-81.
Abstract/Text BACKGROUND: To determine the prevalence of connective tissue disease in a cohort of individuals with silicosis, we reviewed the medical records and questionnaires from individuals reported from 1987 to 1995 to a state surveillance system for silicosis. Reporting of individuals with silicosis is required by state law. Cases were reported by hospitals, physicians, the state workers' compensation bureau, or from death certificates. Only individuals who met the criteria for silicosis developed by the National Institute for Occupational Safety and Health (NIOSH) were included in the analysis.
RESULTS: A questionnaire was completed for all 583 cases. Medical records were available for 463. There were 24 people with rheumatoid arthritis, one with scleroderma, and one with systemic lupus erythematosus. All were men. The prevalence of rheumatoid arthritis was 5.2% (relative risk (RR) 2.73, 95% confidence limit (CL) 1.75-4.06). The prevalence of scleroderma was 0.2% (RR 15.65, 95% CL 0.21-87.03) and the prevalence of systemic lupus erythematosus was 0.2% (RR 11.37, 95% CL 0.15-63.23). This is an approximately 2.5-15-fold increased risk for these connective tissue diseases compared to estimated prevalences in the general population. Individuals with silicosis and connective tissue disease did not differ from individuals with silicosis but without connective tissue disease by race, age, type of industry where exposed to silica, history of tuberculosis, whether or not they had applied for workers' compensation, and whether or not they had progressive massive fibrosis on chest x-ray.
CONCLUSION: Although the association between scleroderma and silicosis has been more widely reported in the literature, the prevalence of rheumatoid arthritis was greater than the prevalence of scleroderma or systemic lupus erythematosus among a cohort of individuals with silicosis.

PMID 10086214  Am J Ind Med. 1999 Apr;35(4):375-81.
著者: Gabriel Zaghi, Fábio Koga, Renato M Nisihara, Thelma L Skare, Antonieta Handar, Shirley R Rosa Utiyama, Marilia Barreto Silva
雑誌名: Rheumatol Int. 2010 Jun;30(8):1071-5. doi: 10.1007/s00296-009-1116-z. Epub 2009 Aug 25.
Abstract/Text The aim of this study was to evaluate the prevalence of autoantibodies in silica-exposed patients with and without silicosis and without any known rheumatic disease. We studied 61 males exposed to silica for a mean time of 12.2 +/- 10.2 years of exposure. A total of 72.1% (44/61) of them presented with pulmonary silicosis. As control group we included 62 healthy males. In all samples we screened for rheumatoid factor (latex agglutination), antinuclear antibodies (indirect immunofluorescence), anti Scl-70 (ELISA) and ANCA (indirect immunofluorescence technique). One patient (1.6%) of the silica group had weakly positive ANA (titer 1:80, centromeric pattern); one (1.6%) had atypical ANCA and seven patients (11.4%) presented positive rheumatoid factor (values range from 8 to 32 UI/ml). One control patient had a positive RF and none of them had positive ANA or ANCA. All patients and controls were negative for anti-Scl-70. The finding of positive RF was higher in the silica-exposed patients (p = 0.032; Fisher). All patients with positive RF had pulmonary silicosis. In the silica-exposed group we could not find a relationship between the presence of RF and age (p = 0.21; Mann-Whitney), smoking habits (p = 0.25; Fisher) but a positive relationship was found with exposure time to silica dust (p = 0.005; Mann-Whitney). We conclude that there was 11.4% prevalence of low titer RF in the silica-exposed patients without known rheumatic disease. RF was more common in patients with longer exposure to silica dust and appeared only in those with silicosis. The presence of ANA, Scl-70 and ANCA was the same as in the control population.

PMID 19705119  Rheumatol Int. 2010 Jun;30(8):1071-5. doi: 10.1007/s002・・・
著者: Hiroaki Arakawa, Koichi Honma, Hisao Shida, Yoshiaki Saito, Hiroshi Morikubo
雑誌名: J Comput Assist Tomogr. 2003 Sep-Oct;27(5):758-60. doi: 10.1097/00004728-200309000-00013.
Abstract/Text We report a case of Caplan syndrome complicated with tuberculosis, which was clinically followed up for 18 years and underwent autopsy. Initial chest radiograph showed 2 large nodules against the background of smaller pneumoconiotic nodules. One of the large nodules showed cavitation during follow-up. Computed tomography (CT) was helpful in identifying calcification in another large nodule. Autopsy confirmed the 2 large nodules as burned-out rheumatoid nodules and revealed additional rheumatoid nodules that were indistinguishable from silicotic nodules by CT.

PMID 14501367  J Comput Assist Tomogr. 2003 Sep-Oct;27(5):758-60. doi:・・・

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