今日の臨床サポート

慢性進行性肺アスペルギルス症

著者: 谷直樹 諏訪中央病院 呼吸器内科

監修: 具芳明 東京医科歯科大学大学院医歯学総合研究科 統合臨床感染症学分野

著者校正/監修レビュー済:2020/11/19
参考ガイドライン:
  1. 深在性真菌症のガイドライン作成委員会:深在性真菌症の診断・治療ガイドライン 2014
患者向け説明資料

概要・推奨   

  1. 慢性進行性肺アスペルギルス症は、陳旧性肺結核、COPD、間質性肺炎などの呼吸器系基礎疾患、糖尿病、アルコール依存、低栄養、ステロイド治療などの免疫不全を背景にもつ患者に多い。
  1. 慢性進行性肺アスペルギルス症の診断において、沈降抗体検査が最も有用である。
  1. 慢性進行性肺アスペルギルス症の治療薬の第一選択はMCFGとVRCZである。
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:
谷直樹 : 未申告[2021年]
監修:具芳明 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 呼吸器にアスペルギルスが起こす慢性感染を、慢性肺アスペルギルス症(chronic pulmonary aspergillosis、CPA)と呼ぶ。わが国のガイドライン[1][2]では、治療方針を決定する上で、CPAを、病変が単一の空洞内に限定される単純性肺アスペルギローマ(simple aspergilloma:SPA)と、慢性進行性肺アスペルギルス症(chronic progressive pulmonary aspergillosis:CPPA)に大別している。
  1. CPPAは、慢性空洞性肺アスペルギルス症(chronic cavitary pulmonary aspergillosis:CCPA)、慢性壊死性肺アスペルギルス症(chronic necrotizing aspergillosis:CNPA)の2つを包括する概念である。
  1. 慢性空洞性肺アスペルギルス症(CCPA)は、呼吸器症状や全身症状、炎症反応の亢進を伴い、複数の空洞(菌球を伴うこともある)が増大、周囲に拡大する病態である。病理学的に組織侵襲を伴わない。
  1. 慢性壊死性肺アスペルギルス症(CNPA)は、アスペルギルスの組織侵襲を伴うもので、緩徐進行性に肺の破壊が進行する病態である。
  1. CCPA、CNPAが更に進展、増悪し、肺の線維化と破壊が2葉以上の広範囲に及んだ病態を、慢性線維性肺アスペルギルス症(chronic fibrosing pulmonary aspergillosis、CFPA)という。
  1. CCPAとCNPAの厳密な鑑別には病理学的所見が必要であり、臨床的には困難であること、しかし、これらの2つの疾患は治療方針に大きな差異が認められないことから、わが国のガイドライン[1][2]では、これらを包括した概念として、慢性進行性肺アスペルギルス症(chronic progressive pulmonary aspergillosis、CPPA)という名称を提唱している。
  1. IDSAやERSなどの海外のガイドラインでは、CPAを、SPA、aspergillus nodule(画像所見上結節影を呈するまれなアスペルギルス病変)、CCPAに大別し、CNPAはsubacute IPAとして、CPAと区別している。わが国のガイドラインでいうところのCPPAは、海外のガイドラインでいうCCPAと同義と考えられる。
問診・診察のポイント  
  1. 陳旧性肺結核、肺非結核性抗酸菌症、肺嚢胞、気管支拡張症、COPD、間質性肺炎、胸部術後、サルコイドーシス、塵肺などの呼吸器系の基礎疾患を持つ患者は、CPPAのリスクが高い。

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文献 

著者:
雑誌名: 2020 Mar 17;15(3):e0222738.
Abstract/Text
PMID 32182249  2020 Mar 17;15(3):e0222738.
著者: Shigeru Kohno, Koichi Izumikawa, Kenji Ogawa, Atsuyuki Kurashima, Niro Okimoto, Ryoichi Amitani, Hiroshi Kakeya, Yoshihito Niki, Yoshitsugu Miyazaki, Japan Chronic Pulmonary Aspergillosis Study Group (JCPASG)
雑誌名: J Infect. 2010 Nov;61(5):410-8. doi: 10.1016/j.jinf.2010.08.005. Epub 2010 Aug 24.
Abstract/Text Chronic pulmonary aspergillosis (CPA) is slowly progressive inflammatory pulmonary syndrome due to Aspergillus spp. The evidence regarding CPA treatment is limited. We conducted a randomized, multicenter, open-label trial comparing intravenous micafungin (MCFG) of 150-300 mg once daily with intravenous voriconazole (VRCZ) of 6 mg/kg twice on Day 1 followed by 4 mg/kg twice daily for the treatment of 107 in patients with CPA to compare the efficacy and safety of both drugs as initial treatment in Japan. Treatment effectiveness was defined by clinical, mycological, radiological and serological responses 2 weeks after the initial administration and at the end of therapy. The total of 50 and 47 patients were assigned to the MCFG and VRCZ groups, respectively. The difference in efficacy rates between MCFG and VRCZ was not significant, either after 2 weeks [68.0% vs. 58.7%; the absolute difference, 9.3% with a 95% confidence interval (CI), -9.97 to 28.58, P = 0.344] or at the end of therapy (60.0% vs. 53.2%; the absolute difference, 6.8% with a 95% CI, -12.92 to 26.54, P = 0.499). In the safety evaluation, fewer adverse events occurred in the MCFG than VRCZ group (26.4% vs. 61.1%, P = 0.0004). MCFG was as effective as VRCZ and significantly safer than as an initial treatment of CPA. (UMIN Clinical Trials Registry number, UMIN000001786.).

Copyright © 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
PMID 20797407  J Infect. 2010 Nov;61(5):410-8. doi: 10.1016/j.jinf.201・・・
著者: Yasuhiko Kitasato, Yoshiaki Tao, Tomoaki Hoshino, Kousuke Tachibana, Naoko Inoshima, Makoto Yoshida, Shohei Takata, Kan Okabayashi, Masayuki Kawasaki, Tomoaki Iwanaga, Hisamichi Aizawa
雑誌名: Respirology. 2009 Jul;14(5):701-8. doi: 10.1111/j.1440-1843.2009.01548.x.
Abstract/Text BACKGROUND AND OBJECTIVE: The usefulness of two tests in the serodiagnosis of chronic pulmonary aspergillosis (CPA) was compared. The tests were the serum Aspergillus galactomannan antigen test (Platelia (R) Aspergillus) by enzyme-linked immunoassay (EIA) using old and new cut-off indexes, and the Aspergillus precipitating antibody test.
METHODS: Both Aspergillus-precipitating antibody and Platelia Aspergillus EIA positivity were measured in the sera of 28 patients at the time of diagnosis of CPA.
RESULTS: Serum Aspergillus precipitating antibody positivity was 89.3% (25/28) in CPA patients. Serum Platelia Aspergillus EIA positivity was 21.4% (6/28) using the old cut-off index (> or =1.5) and 50% (14/28) using the new cut-off index (> or =0.5)-still less than that for Aspergillus precipitating antibody. Three of the 28 CPA patients had positive reactions in the Platelia Aspergillus EIA using the old cut-off index but not in the Aspergillus precipitating antibody test. Positivity for (1,3) beta-d glucan was 15.4%, and that for culture on CHROMagar Candida was 17.9%. One patient with pulmonary actinomycosis had a false-positive reaction in the Platelia Aspergillus test with the new cut-off index.
CONCLUSIONS: For the diagnosis of CPA, Aspergillus precipitating antibody testing is more sensitive than the Platelia Aspergillus EIA, even with the new cut-off index. False-positive reactions are observed with the Platelia Aspergillus EIA in patients with conditions such as pulmonary actinomycosis. Results should be interpreted with care when patients are positive for the Platelia Aspergillus EIA but negative for Aspergillus precipitating antibody.

PMID 19659648  Respirology. 2009 Jul;14(5):701-8. doi: 10.1111/j.1440-・・・
著者: Wouter Meersseman, Katrien Lagrou, Johan Maertens, Alexander Wilmer, Greet Hermans, Steven Vanderschueren, Isabel Spriet, Eric Verbeken, Eric Van Wijngaerden
雑誌名: Am J Respir Crit Care Med. 2008 Jan 1;177(1):27-34. doi: 10.1164/rccm.200704-606OC. Epub 2007 Sep 20.
Abstract/Text RATIONALE: Invasive aspergillosis (IA) is an important cause of mortality in patients with hematologic malignancies. However, IA appears to be gaining a foothold in the intensive care unit (ICU) in patients without classical risk factors. A recent study described 89 cases of IA in patients in a medical ICU without leukemia or cancer. The diagnosis of IA remains difficult and is often established too late. Galactomannan (GM) is an exo-antigen released from Aspergillus hyphae while they invade host tissue.
OBJECTIVES: This prospective single-center study was conducted to investigate the role of GM in bronchoalveolar lavage (BAL) fluid as a tool for early diagnosis of IA in the ICU.
METHODS: All patients with risk factors identified in our earlier study were evaluated. BAL for culture and GM detection, serum GM levels, and computed tomography scan were obtained for all included patients with signs of pneumonia. Patients were classified as having proven, probable, or possible IA.
MEASUREMENTS AND MAIN RESULTS: A total of 110 patients out of 1,109 admissions were eligible. There were 26 proven IA cases. Using a cutoff index of 0.5, the sensitivity and specificity of GM detection in BAL fluid was 88 and 87%, respectively. The sensitivity of serum GM was only 42%. In 11 of 26 proven cases, BAL culture and serum GM remained negative, whereas GM in BAL was positive.
CONCLUSIONS: IA is common in immunocompromised, critically ill patients. GM detection in BAL fluid seems to be useful in establishing or excluding the diagnosis of IA in the ICU.

PMID 17885264  Am J Respir Crit Care Med. 2008 Jan 1;177(1):27-34. doi・・・
著者: Koichi Izumikawa, Yoshihiro Yamamoto, Tomo Mihara, Takahiro Takazono, Yoshitomo Morinaga, Shintaro Kurihara, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Tomoya Nishino, Misuzu Tsukamoto, Hiroshi Kakeya, Katsunori Yanagihara, Mariko Mine, Akira Yasuoka, Takayoshi Tashiro, Shigeru Kohno
雑誌名: Med Mycol. 2012 Nov;50(8):811-7. doi: 10.3109/13693786.2012.682228. Epub 2012 May 9.
Abstract/Text Diagnosing chronic pulmonary aspergillosis (CPA) is complicated, and there are limited data available regarding the identification of galactomannan (GM) in clinical specimens to assist the detection of this infection. The purpose of this study was to evaluate the detection of GM in bronchoalveolar lavage fluid (BALF) and serum and to assess its utility for diagnosing CPA. We retrospectively reviewed the diagnostic and clinical characteristics of 144 patients, with and without CPA, in Nagasaki University Hospital, Japan, whose BAL and serum specimens were examined for the presence of GM. The Platelia Aspergillus enzyme immunoassay (PA EIA) was performed according to the manufacturer's instructions. The mean values of BALF GM antigen were 4.535 (range, 0.062-14.120) and 0.430 (range, 0.062-9.285) in CPA (18) and non-CPA (126) patients, respectively. The mean values of serum GM antigen were 1.557 (range, 0.232-5.397) and 0.864 (range, 0.028-8.956) in CPA and non-CPA patients, respectively. PA EIA of BALF is superior to the test with serum, with the optimal cut-off values for BALF and serum of 0.4 and 0.7, respectively. The sensitivity and specificity of PA EIA in BALF at a cut-off of 0.4 were 77.2% and 77.0%, respectively, whereas with serum at a cut-off of 0.7, they were 66.7% and 63.5%, respectively. GM testing using BALF showed reasonable sensitivity and specificity as compared to that using serum. Thus, assessing GM levels in BALF may enhance the accuracy of diagnosing CPA.

PMID 22568603  Med Mycol. 2012 Nov;50(8):811-7. doi: 10.3109/13693786.・・・
著者: Hae-Seong Nam, Kyeongman Jeon, Sang-Won Um, Gee Young Suh, Man Pyo Chung, Hojoong Kim, O Jung Kwon, Won-Jung Koh
雑誌名: Int J Infect Dis. 2010 Jun;14(6):e479-82. doi: 10.1016/j.ijid.2009.07.011. Epub 2009 Nov 11.
Abstract/Text OBJECTIVES: Chronic necrotizing pulmonary aspergillosis (CNPA) is uncommon, and the optimal therapeutic regimen has not been established. In a retrospective cohort study, we investigated the clinical characteristics and treatment outcomes of patients with CNPA.
METHODS: We reviewed the medical records of all patients who had been diagnosed with CNPA at our institution over the last 10 years.
RESULTS: Forty-three patients were identified. Their median age was 60 years (interquartile range (IQR) 45-65 years), and 34 (79%) of the patients were men. The most common underlying lung disease was pulmonary tuberculosis (n=40, 93%). After CNPA was diagnosed, all patients were treated with antifungal drugs, including oral itraconazole (n=39, 91%) or intravenous amphotericin B (n=4, 9%). Seventeen (40%) patients discontinued therapy early (<3 months), 14 patients due to death and three to loss of follow-up. Twenty-six (60%) patients received oral itraconazole at a daily dose of 200-400mg for more than 3 months. The median treatment duration was 6 months (IQR 6-12 months). In these 26 patients, clinical improvement was observed in 15 (58%) and radiological improvement was observed in 11 (42%). Ten (38%) patients showed no improvement. Twenty-two (51%) patients died, including 18 (42%) CNPA-related deaths, during a median follow-up of 15 months (IQR 2.5-32 months). The median survival time was 62 months.
CONCLUSIONS: CNPA is difficult to treat and often has a poor outcome. Further studies with more patients are needed to identify the optimal therapy for patients with CNPA.

Copyright 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
PMID 19910234  Int J Infect Dis. 2010 Jun;14(6):e479-82. doi: 10.1016/・・・
著者: J Cadranel, B Philippe, C Hennequin, A Bergeron, E Bergot, A Bourdin, V Cottin, T Jeanfaivre, C Godet, M Pineau, P Germaud
雑誌名: Eur J Clin Microbiol Infect Dis. 2012 Nov;31(11):3231-9. doi: 10.1007/s10096-012-1690-y. Epub 2012 Jul 11.
Abstract/Text Early evidence suggests the efficacy of voriconazole for chronic pulmonary aspergillosis (CPA). We conducted a prospective, open, multicenter trial to evaluate the efficacy and safety of voriconazole for proven CPA in minimally or non-immunocompromised patients. Patients had CPA confirmed by chest computed tomography (CT) and/or endoscopy, positive Aspergillus culture from a respiratory sample, and positive serologic test for Aspergillus precipitins. Patients received voriconazole (200 mg twice daily) for a period of 6-12 months and were followed for 6 months after the end of therapy (EOT). The primary endpoint was global success at 6 months, defined as complete or partial (≥50 % improvement) radiological response and mycological eradication. Forty-one patients with confirmed CPA were enrolled. All patients had A. fumigatus as the etiologic agent. By EOT, five patients had died from comorbidities and seven had discontinued voriconazole due to toxicity. The global success rate at 6 months was 13/41 (32 %): 10/19 (53 %) for chronic necrotizing aspergillosis and 3/22 (14 %) for chronic cavitary aspergillosis (p = 0.01). The respective success rates at EOT were 58 and 32 %. Clinical symptoms and quality of life also improved during treatment. Voriconazole is effective for CPA, with acceptable toxicity. The response rate is higher and obtained more rapidly in necrotizing than cavitary forms.

PMID 22782438  Eur J Clin Microbiol Infect Dis. 2012 Nov;31(11):3231-9・・・
著者: David W Denning, Kostantinos Riniotis, Richard Dobrashian, Helen Sambatakou
雑誌名: Clin Infect Dis. 2003 Oct 1;37 Suppl 3:S265-80. doi: 10.1086/376526.
Abstract/Text We describe 18 nonimmunocompromised patients with chronic pulmonary aspergillosis. Duration of the disease ranged from several months to >12 years. All 18 patients had prior pulmonary disease. Weight loss, chronic cough (often with hemoptysis and shortness of breath), fatigue, and chest pain were the most common symptoms. All 18 patients had cavities, usually multiple and in 1 or both upper lobes of the lung, that expanded over time, with or without intraluminal fungal balls. All had detectable Aspergillus precipitins and inflammatory markers. Elevated levels of total immunoglobulin E were seen in 78% of patients and of Aspergillus-specific immunoglobulin E in 64%. Directed lung biopsies showed chronic inflammation, necrosis, or granulomas without hyphal invasion. Antifungal therapy with itraconazole resulted in 71% of patients improved or stabilized, with relapse common. Interferon-gamma treatment was useful in 3 patients. In azole nonresponders, modest responses to intravenous amphotericin B (80%) followed by itraconazole were seen. Surgery removed disease but postoperative pleural aspergillosis was inevitable. Indicators of good long-term medical outcomes were mild symptoms, thin-walled quiescent cavities, residual pleural fibrosis, and normal inflammatory markers.

PMID 12975754  Clin Infect Dis. 2003 Oct 1;37 Suppl 3:S265-80. doi: 10・・・
著者: Keitaro Nakamoto, Noboru Takayanagi, Tetsu Kanauchi, Takashi Ishiguro, Tsutomu Yanagisawa, Yutaka Sugita
雑誌名: Intern Med. 2013;52(7):727-34. Epub 2013 Apr 1.
Abstract/Text OBJECTIVE: The prognostic factors of chronic necrotizing pulmonary aspergillosis remain unclear. We assessed the prognostic factors of all-cause mortality in patients with chronic necrotizing pulmonary aspergillosis, focusing especially on underlying pulmonary disease, first-line treatment and host predisposition.
METHODS: We retrospectively analyzed the medical records of 194 patients negative for HIV who had chronic necrotizing pulmonary aspergillosis treated at our institution in Saitama, Japan.
RESULTS: The patients (median age, 68.5 years) were followed over a median follow-up time of 2.6 years. The underlying pulmonary diseases consisted of previous pulmonary tuberculosis in 59 (30.4%) patients, emphysema in 39 (20.1%) patients, interstitial lung disease in 32 (16.5%) patients, nontuberculous mycobacteriosis in 29 (14.9%) patients and other diseases in 35 (18%) patients. The first-line treatments included observation in 65 (33.5%) patients, itraconazole in 56 (28.9%) patients, micafungin in 46 (23.7%) patients, voriconazole in 22 (11.3%) patients and amphotericin B (including liposomal amphotericin B) in five (2.6%) patients. The overall cumulative mortality rate was 50.2% at five years and 67.4% at 10 years. Multivariate Cox proportional hazard modeling found an older age, the presence of systemic comorbidities, baseline corticosteroid use, a body mass index of <18.5 kg/m(2) and a C-reactive protein level of ≥5.0 mg/dL to be negative prognostic factors for all-cause mortality.
CONCLUSION: The 5-year mortality rate of chronic necrotizing pulmonary aspergillosis was 50.2%. When clinical trials are designed and implemented to test effective drug therapies in patients with chronic necrotizing pulmonary aspergillosis, the trial patients should be stratified according to these prognostic factors prior to randomization.

PMID 23545666  Intern Med. 2013;52(7):727-34. Epub 2013 Apr 1.
著者: Stefan Pabst, Michael Krüger, Dirk Skowasch, H Zhou, Jens Bürmann, Marcel Kaminski
雑誌名: Adv Exp Med Biol. 2013;755:225-36. doi: 10.1007/978-94-007-4546-9_29.
Abstract/Text Twenty three patients of the University Hospital Bonn were reviewed following surgical procedures for pulmonary aspergilloma, including the choice of antifungal therapy, diagnostic findings, decision-making in treatment, and treatment outcomes of the past 16 years. We used pathological records to identify aspergilloma patients. A review of patients' records and follow-up phone calls to patients, families, or general practitioners were done. Data collected from 1995 to 2011 included patients with aspergilloma (n = 15), multiple aspergillomas (n = 2) and chronic necrotizing pulmonary aspergillosis (n = 6). Classification and diagnosis were based on pathological records. The decision to use systemic antimycotic therapy was based on perioperative findings suspecting parenchymal involvement of the fungal infection. Seventeen patients received systemic antimycotic chemotherapy. Compared with the use of Amphotericin B, newer drugs such as voriconazol, caspofungin, or posaconazol showed no better result in the morbidity and mortality of the patients. Postoperative complications requiring extended therapy and/or prolonged ICU stay (>48 h) were seen in 12 (52.2%) patients. During follow-up there were ten deaths; one death (4.4%) from aspergillus-associated sepsis, nine deaths from patients' underlying diseases (n = 4 within <3 months, n = 6 within >3 months of follow-up). In conclusion, in our cohort, immunocompromised patients with no documented preexisting lung-cavities were most likely to develop pulmonary aspergilloma. Postoperative morbidity (52.2%) was high, but related mainly to patient co-morbidity; postoperative mortality was reasonably low. Patients showing classical symptoms or immunocompromised patients should be considered for surgery. Encapsulated Aspergilloma without invasion of surrounding parenchyma requires no antifungal chemotherapy.

PMID 22826071  Adv Exp Med Biol. 2013;755:225-36. doi: 10.1007/978-94-・・・

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