今日の臨床サポート

肺胞出血

著者: 坂東政司 自治医科大学 呼吸器内科

監修: 久保惠嗣 信州大学名誉教授・地方独立行政法人 長野県立病院機構理事長

著者校正/監修レビュー済:2020/05/14
参考ガイドライン:
  1. 厚労省難治性疾患政策研究事業 難治性血管炎に関する調査研究班:ANCA関連血管炎 診療ガイドライン 2017
  1. 日本呼吸器学会:気管支肺胞洗浄(BAL)法の手引き 第3版
  1. 日本呼吸器学会:薬剤性肺障害の診断・治療の手引き 2018
患者向け説明資料

概要・推奨   

  1. 肺胞出血の診断は、病歴や血液検査所見、画像所見などを総合的に評価することが重要であるが、非特異的所見のことも多い。
  1. 臨床的に肺胞出血が疑われる場合には、早急に気管支肺胞洗浄(BAL)を行うことが推奨される(推奨度1)
  1. BALでは、徐々に濃くなる血性の洗浄液の回収と、ヘモジデリン貪食マクロファージの確認が重要である。
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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:
坂東政司 : 特に申告事項無し[2021年]
監修:久保惠嗣 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、最新の総説文献の追加を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 肺胞出血はびまん性肺胞出血(diffuse alveolar hemorrhage、DAH)症候群とも呼ばれ、さまざまな原因で生じる。
  1. 原因の相違にかかわらず共通の病態を呈し、肺胞毛細血管レベルで血管の破綻により、びまん性に肺胞内に出血を来す。
  1. 喀血、血痰を認める多種多様な疾患群の中で、気管支拡張症や肺癌、肺結核、肺内血管病変などの気管支・肺局所からの出血は含めない。
  1. 原因疾患は、肺胞毛細血管炎を伴う群と伴わない群に大別される。
  1. 肺胞毛細血管炎を伴う群では、顕微鏡的多発血管炎などの抗好中球細胞質抗体(anti-neutrophil cytoplasmic antibody、ANCA)関連血管炎や全身性エリテマトーデス(SLE)などの膠原病、Henoch-Schönlein紫斑病などが含まれる。
  1. 肺胞毛細血管炎を伴わない群では、急性呼吸窮迫症候群や骨髄移植後に起こるびまん性肺胞損傷、抗血栓薬(抗凝固薬、抗血小板薬など)の使用中、凝固異常、化学物質の吸入、僧帽弁狭窄などの循環器疾患、薬剤誘発性などが含まれる。
  1. 呼吸器にのみ病変を認める原因不明のDAHは、特発性肺血鉄症と呼ばれる。
  1. 重症度や予後は原因疾患によりさまざまであるが、いずれの場合にも早期の診断、治療が生命予後の改善に重要である。
問診・診察のポイント  
  1. 詳細な病歴聴取および系統的な身体診察が重要であるが、これらのみでは正確に診断することは困難である。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

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文献 

著者: Abigail R Lara, Marvin I Schwarz
雑誌名: Chest. 2010 May;137(5):1164-71. doi: 10.1378/chest.08-2084.
Abstract/Text Diffuse alveolar hemorrhage (DAH) is often a catastrophic clinical syndrome causing respiratory failure. Recognition of DAH often requires BAL as symptoms are nonspecific, hemoptysis is absent in up to one-third of patients, and radiographic imaging is also nonspecific and similar to other acute alveolar filling processes. Once the diagnosis is established, the underlying cause must be established in order to initiate treatment. This review discusses the diagnosis of the underlying histologies and the clinical entities that are responsible for DAH as well as treatment options.

PMID 20442117  Chest. 2010 May;137(5):1164-71. doi: 10.1378/chest.08-2・・・
著者: John P Lichtenberger, Subba R Digumarthy, Gerald F Abbott, Jo-Anne O Shepard, Amita Sharma
雑誌名: Curr Probl Diagn Radiol. 2014 May-Jun;43(3):128-39. doi: 10.1067/j.cpradiol.2014.01.002.
Abstract/Text Diffuse pulmonary hemorrhage (DPH) refers to an uncommon but significant condition of bleeding into the alveolar space. Anemia and hemoptysis are important clinical features, but they may be absent. Although the radiographic and computed tomography findings are often varied and nonspecific, the imaging manifestations of pulmonary hemorrhage and the associated findings in the thorax often provide important diagnostic information that may lead to a specific diagnosis. DPH significantly influences patient management and has important prognostic implications. This review article explores the imaging findings in DPH and its differential diagnosis, highlighting important clues to this diagnosis and to its underlying etiology. DPH is an uncommon condition characterized by bleeding into the alveolar space that, when recognized on imaging, provides important diagnostic and prognostic information.

Published by Mosby, Inc.
PMID 24791616  Curr Probl Diagn Radiol. 2014 May-Jun;43(3):128-39. doi・・・
著者: Rodrigo Cartin-Ceba, Luis Diaz-Caballero, Mazen O Al-Qadi, Stavros Tryfon, Fernando C Fervenza, Steven R Ytterberg, Ulrich Specks
雑誌名: Arthritis Rheumatol. 2016 Jun;68(6):1467-76. doi: 10.1002/art.39562.
Abstract/Text OBJECTIVE: To identify predictors of respiratory failure and to evaluate the therapeutic efficacy of plasma exchange (PE) and of rituximab versus cyclophosphamide in a cohort of patients with diffuse alveolar hemorrhage (DAH) secondary to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with or without respiratory failure.
METHODS: We performed a single-center historical cohort study of all consecutive patients with AAV-associated DAH who were evaluated over a 16-year period. Logistic regression models were developed to examine the predictive role of the baseline clinical characteristics for the development of respiratory failure, and for the effect of PE and remission induction therapy on the main outcome (complete remission at 6 months).
RESULTS: Seventy-three patients with DAH were identified, and 34 of them experienced respiratory failure. The degree of hypoxemia upon initial presentation, a higher percentage of neutrophils in the bronchoalveolar lavage fluid cell count, and higher C-reactive protein levels were independently associated with the development of respiratory failure. PE was not associated with achieving complete remission at 6 months, with an odds ratio (OR) of 0.49 (95% confidence interval [95% CI] 0.12-1.95) (P = 0.32). Rituximab treatment was independently associated with achieving complete remission at 6 months (OR 6.45 [95% CI 1.78-29], P = 0.003).
CONCLUSION: Our findings indicate that the most important predictor of respiratory failure in patients with DAH secondary to AAV is the degree of hypoxemia upon presentation. No clear benefit of the addition of PE to standard remission induction therapy was demonstrated. Complete remission by 6 months was achieved at a higher rate with rituximab than with cyclophosphamide in patients with DAH secondary to AAV, including those needing mechanical ventilation.

© 2016, American College of Rheumatology.
PMID 26713723  Arthritis Rheumatol. 2016 Jun;68(6):1467-76. doi: 10.10・・・
著者: I D Lewis, T DeFor, D J Weisdorf
雑誌名: Bone Marrow Transplant. 2000 Sep;26(5):539-43. doi: 10.1038/sj.bmt.1702546.
Abstract/Text Diffuse alveolar hemorrhage (DAH) is a non-infectious pulmonary complication of bone marrow transplantation (BMT) with resultant high mortality. It reportedly occurs primarily in autologous recipients. We examined the incidence of DAH in our center in order to assess potential risk factors and develop preventive strategies. Between 1991 and 1997, 23 cases of DAH occurred in 922 adult patients (2.5%) receiving BMT for hematological malignancy. Strikingly, 12 cases occurred in 1997 with the majority in recipients of allogeneic matched sibling donor stem cells. Treatment with high-dose steroids, 250 mg to 2 g/day, in 15 patients led to transient improvement in 10 patients, but 21 of the 23 patients required mechanical ventilation. Mortality was high with 17 patients (74%) dying a median of 39 days (range 22-47) post transplant; a median of 17 days post onset of DAH (range 5-34). Six patients are alive with a median follow-up of 18 months (range 12-60). No recognizable alteration in supportive care, conditioning regimen, GVHD prophylaxis or cytokine usage was associated with this striking increase in the frequency of DAH after allografting. Further follow-up is required to establish whether this increase in the incidence of DAH in allogeneic transplantation is an isolated occurrence or an ongoing problem. If indeed there is a real increase in the incidence of this complication, then efforts need to be directed towards elucidating a possible cause or risk factors. We offer the possibility that a new unidentified infection, undetected by current microbiological tests might contribute to this striking increase in DAH. These data, while not establishing a cause, suggest a markedly augmented risk of DAH in allogeneic BMT. In addition, high-dose corticosteroids have only limited efficacy as therapy for DAH after allotransplantation. Further investigation into the pathogenesis of this syndrome is essential as is prompt and immediate consideration of DAH in all patients with respiratory compromise early after BMT.

PMID 11019844  Bone Marrow Transplant. 2000 Sep;26(5):539-43. doi: 10.・・・
著者: Bekele Afessa, Ayalew Tefferi, Mark R Litzow, Steve G Peters
雑誌名: Am J Respir Crit Care Med. 2002 Nov 15;166(10):1364-8. doi: 10.1164/rccm.200208-792OC. Epub 2002 Sep 25.
Abstract/Text Previous studies have reported mortality rates of about 80% in hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage. This retrospective study describes the clinical course of 48 such patients: mean age 47.7 years, 52% autologous transplant and 67% peripheral stem cell source. The hemorrhage occurred within one month of transplant in 28 patients. Symptoms included dyspnea in 92%, fever in 67%, cough in 56%, and hemoptysis in 15%. Intensive care unit admission was required in 85% and mechanical ventilation in 77%. Most of the patients were treated with intravenous methylprednisolone 1 g daily for 3 days and then tapered off after a median of 22 days. The hospital mortality was 48%. The cause of death was respiratory failure in 15 of the 23 deaths. Mortality was 28% in autologous compared with 70% in allogeneic transplant recipients (p = 0.0040). The mortality rate of patients whose hemorrhage occurred within the first 30 days of transplant was 32% compared with 70% of those with late hemorrhage (p = 0.0096). This study shows that survival rate of hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage is better than previously reported, and that early onset and autologous transplant are favorable prognostic indicators.

PMID 12406834  Am J Respir Crit Care Med. 2002 Nov 15;166(10):1364-8. ・・・
著者: O C Ioachimescu, S Sieber, A Kotch
雑誌名: Eur Respir J. 2004 Jul;24(1):162-70.
Abstract/Text Idiopathic pulmonary haemosiderosis is a rare cause of diffuse alveolar haemorrhage of unknown aetiology. It occurs most frequently in children, has a variable natural history with repetitive episodes of diffuse alveolar haemorrhage, and has been reported to have a high mortality. Many patients develop iron deficiency anaemia secondary to deposition of haemosiderin iron in the alveoli. Examination of sputum and bronchoalveolar lavage fluid can disclose haemosiderin-laden alveolar macrophages (siderophages), and the lung biopsy shows numerous siderophages in the alveoli, without any evidence of pulmonary vasculitis, nonspecific/granulomatous inflammation, or deposition of immunoglobulins. Contrary to earlier reports, corticosteroids alone or in combination with other immunosuppressive agents may be effective for either exacerbations or maintenance therapy of idiopathic pulmonary haemosiderosis.

PMID 15293620  Eur Respir J. 2004 Jul;24(1):162-70.
著者: Megan L Krause, Rodrigo Cartin-Ceba, Ulrich Specks, Tobias Peikert
雑誌名: Immunol Allergy Clin North Am. 2012 Nov;32(4):587-600. doi: 10.1016/j.iac.2012.08.001. Epub 2012 Sep 28.
Abstract/Text Diffuse alveolar hemorrhage is a clinical syndrome that can be a manifestation of multiple different causes. Identification of the underlying etiology is of utmost importance and dictates treatment. Pulmonary vasculitis including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a common cause of diffuse alveolar hemorrhage. For AAV, treatment includes induction followed by maintenance therapy. Rituximab has an increasing role in the treatment of AAV.

Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 23102067  Immunol Allergy Clin North Am. 2012 Nov;32(4):587-600. ・・・
著者: Stephen West, Nishkantha Arulkumaran, Phillip W Ind, Charles D Pusey
雑誌名: Intern Med. 2013;52(1):5-13. Epub 2013 Jan 1.
Abstract/Text Diffuse alveolar haemorrhage (DAH) is a serious complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A literature review was performed to ascertain the diagnostic features, treatment, and outcome of this rare but serious condition. Haemoptysis and dyspnoea are common but non-specific features. Chest radiography is usually abnormal, and high-resolution computerised tomographic scanning is more sensitive. Increased uptake of inhaled carbon monoxide and reduced clearance of C(15)O on lung function testing is suggestive of intra-alveolar blood. Fiberoptic bronchoscopy and bronchoalveolar lavage are useful when a super-added infection is suspected. Concurrent renal disease is common and contributes to the morbidity and mortality. Treatment should be individualised, and it is based on glucocorticoid and cyclophosphamide induction with azathioprine maintenance. The role of plasmapheresis is unclear, and is currently being evaluated. Patients are at risk of disease and treatment-related long-term complications. Ongoing research into the most efficacious therapeutic regimens associated with the least side effects is especially important.

PMID 23291668  Intern Med. 2013;52(1):5-13. Epub 2013 Jan 1.
著者: Toshiro Sugimoto, Naoko Deji, Shinji Kume, Norihisa Osawa, Masayoshi Sakaguchi, Keiji Isshiki, Daisuke Koya, Atsunori Kashiwagi
雑誌名: Intern Med. 2007;46(1):49-53. Epub 2007 Jan 1.
Abstract/Text We present a case of a 38-year-old Japanese man with Wegener's granulomatosis complicated with pulmonary-renal syndrome, i.e., diffuse pulmonary hemorrhage and rapidly progressive renal glomerulonephritis. As this is a life-threatening condition, we promptly initiated plasma exchange with intravenous methylprednisolone therapy. Diffuse pulmonary hemorrhage and renal failure were markedly improved. This case merits presentation because there are few clinical studies of the treatment of Wegener's granulomatosis with pulmonary-renal syndrome, particularly with pulmonary hemorrhage.

PMID 17202734  Intern Med. 2007;46(1):49-53. Epub 2007 Jan 1.
著者: Thong Nguyen, Meri King Martin, Alexander J Indrikovs
雑誌名: J Clin Apher. 2005 Dec;20(4):230-4. doi: 10.1002/jca.20069.
Abstract/Text We present a case of a 20-year-old male with Wegener's Granulomatosis involving the upper respiratory tract, lungs, and kidneys. In his fourth hospital admission, the patient presented with diffuse alveolar hemorrhage and poor pulmonary function: FiO2 of 100% and PEEP of 17cm H2O on intubation. Due to a fast clinical deterioration while receiving drug therapy (cyclophosphamide and methylprednisolone), we performed nine daily 1-volume therapeutic plasma exchanges (TPE) using 5% albumin as replacement fluid. TPE resulted in a decrease in cytoplasmic anti-neutrophil cytoplasm antibodies (c-ANCA) titer from 1:1,024 to 1:16. On the ninth day of plasmapheresis, his pulmonary status was markedly improved with FiO2 of 60% and PEEP of 8 cm H2O. The patient was later extubated and discharged home in stable condition. Wegener's Granulomatosis with pulmonary hemorrhage is not included in the current guidelines for therapeutic apheresis; therefore, we report this case and, if warranted, propose this condition to be included in the guidelines.

(c) 2005 Wiley-Liss, Inc.
PMID 16265628  J Clin Apher. 2005 Dec;20(4):230-4. doi: 10.1002/jca.20・・・
著者: A S Santos-Ocampo, B F Mandell, B J Fessler
雑誌名: Chest. 2000 Oct;118(4):1083-90.
Abstract/Text AIM: To describe our experience with alveolar hemorrhage (AH) in systemic lupus erythematosus (SLE).
METHODS: Review of medical records and pertinent medical literature using MEDLINE and reference lists from retrieved publications.
PATIENTS: Seven patients with SLE admitted with episodes of AH (n = 11).
RESULTS: Six patients were female, and one was male. Mean age at the time of AH was 31.1 years. Mean duration of SLE was 4.5 years. AH occurred within 3 weeks of SLE onset in two patients. Recurrent AH was observed in four patients. Six patients were already receiving treatment for SLE at the time of AH. All patients presented with dyspnea and new pulmonary infiltrates. Hemoptysis occurred in only 54%. All patients had BAL within 48 h of presentation. Temperature > or =39 degrees C (102.2 degrees F) accompanied 82% of episodes. Glomerulonephritis was the most common nonpulmonary SLE manifestation (74%). Treatment with empiric IV antibiotics was initiated in 10 episodes. Initial treatment included high-dose corticosteroids (prednisone, 1 to 3 mg/kg/d [n = 2]; or IV methylprednisolone, 1 g/d [n = 9], with or without oral cyclophosphamide, 2 to 3 mg/kg/d [n = 7]). Plasmapheresis (three to four sessions) was added in five episodes for persistent AH. All patients survived.
CONCLUSIONS: AH may mimic pneumonia. Hemoptysis may not be evident. Infection must be aggressively excluded, especially since many patients with AH are already receiving immunosuppressive therapy. AH frequently recurs despite ongoing immunosuppression. Although high mortality rates have been reported with AH in SLE, we observed 100% survival.

PMID 11035681  Chest. 2000 Oct;118(4):1083-90.
著者: Ken-ichi Hoshi, Masayuki Matsuda, Mariko Ishikawa, Shigeaki Mitsuhashi, Takahisa Gono, Takao Hashimoto, Shu-ichi Ikeda
雑誌名: Clin Rheumatol. 2004 Jun;23(3):252-5. doi: 10.1007/s10067-003-0859-2. Epub 2004 Mar 6.
Abstract/Text We report a patient with systemic lupus erythematosus (SLE) who developed fulminant pulmonary hemorrhage. This patient also showed liver dysfunction, bicytopenia and hyperferritinemia, with an increase in serum levels of interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) at the onset of pulmonary symptoms, probably indicating an associated hemophagocytic syndrome. Despite an acute progressive course temporarily requiring mechanical ventilation the patient was successfully treated with continuous drip infusion of tacrolimus, plasmapheresis and intravenous high-dose immunoglobulin and corticosteroid. In this patient increased inflammatory cytokines ascribable to activation of macrophages and/or helper T cells were considered to play an important role in the pathogenesis of the pulmonary hemorrhage. Because this complication is frequently fatal in SLE, intensive therapy, including immunosuppressants and plasmapheresis, should be actively considered as early as possible after onset.

PMID 15168157  Clin Rheumatol. 2004 Jun;23(3):252-5. doi: 10.1007/s100・・・
著者: Felipe Mussi von Ranke, Gláucia Zanetti, Bruno Hochhegger, Edson Marchiori
雑誌名: Lung. 2013 Feb;191(1):9-18. doi: 10.1007/s00408-012-9431-7. Epub 2012 Nov 6.
Abstract/Text Diffuse alveolar hemorrhage (DAH) represents a syndrome that can complicate many clinical conditions and may be life-threatening, requiring prompt treatment. It is recognized by the signs of acute- or subacute-onset cough, hemoptysis, diffuse radiographic pulmonary infiltrates, anemia, and hypoxemic respiratory distress. DAH is characterized by the accumulation of intra-alveolar red blood cells originating most frequently from the alveolar capillaries. It must be distinguished from localized pulmonary hemorrhage, which is most commonly due to chronic bronchitis, bronchiectasis, tumor, or localized infection. Hemoptysis, the major sign of DAH, may develop suddenly or over a period of days to weeks; this sign may also be initially absent, in which case diagnostic suspicion is established after sequential bronchoalveolar lavage reveals worsening red blood cell counts. The causes of DAH can be divided into infectious and noninfectious, the latter of which may affect immunocompetent or immunodeficient patients. Pulmonary infections are rarely reported in association with DAH, but they should be considered in the diagnostic workup because of the obvious therapeutic implications. In immunocompromised patients, the main infectious diseases that cause DAH are cytomegalovirus, adenovirus, invasive aspergillosis, Mycoplasma, Legionella, and Strongyloides. In immunocompetent patients, the infectious diseases that most frequently cause DAH are influenza A (H1N1), dengue, leptospirosis, malaria, and Staphylococcus aureus infection. Based on a search of the PubMed and Scopus databases, we review the infectious diseases that may cause DAH in immunocompetent patients.

PMID 23128913  Lung. 2013 Feb;191(1):9-18. doi: 10.1007/s00408-012-943・・・

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