今日の臨床サポート

侵襲性アスペルギルス症

著者: 加藤英明 横浜市立大学附属病院感染制御部、医学部血液・免疫・感染症内科

監修: 上原由紀 聖路加国際病院 臨床検査科/感染症科

著者校正/監修レビュー済:2021/11/24
参考ガイドライン:
  1. 米国感染症学会(IDSA)ガイドライン:Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60.
  1. 欧州臨床微生物感染症学会(ESCMID)ガイドライン:Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24:e1-e38.
  1. 日本臨床腫瘍学会:発熱性好中球減少症(FN)診療ガイドライン(改訂第2版)(2017)
  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(2007)
患者向け説明資料

概要・推奨   

  1. アスペルギルスは糸状菌と呼ばれる真菌の一つで、常に気道から吸入されているが免疫正常者ではアスペルギルス症を発症しない。ホストの免疫状態と病原体とのバランスによって発症リスクが変化する患者背景として、好中球減少、造血幹細胞移植など免疫抑制状態が想定される(推奨度1G
  1. A. fumigatusを代表とする糸状菌による侵襲性真菌症は増加している(推奨度1O
  1. 侵襲性アスペルギルス症の診断は困難である。確診例“proven IAproven invasive Aspergillosis”もしくは疑い例possible IApossible invasive Aspergillosis”という表現がなされる(推奨度G)
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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:
加藤英明 : 特に申告事項無し[2021年]
監修:上原由紀 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 新型コロナウイルス感染症(COVID-19)での侵襲性肺アスペルギルス症合併について追記した。
  1. 好中球減少症患者における深在性真菌症の予防にポサコナゾールを追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 侵襲性アスペルギルス症は、造血器悪性腫瘍・造血幹細胞移植・好中球減少症・固形臓器移植術・長期ステロイド内服など強力な免疫抑制状態にある患者に発症する深在性真菌感染症で、死亡率は30~70%と見積もられている。
  1. 免疫正常者かつ慢性呼吸器疾患を合併しないものに発症することはまずない。
  1. 起因菌はAspergillus fumigatus 67%、 A. flavus 13%、 A. niger 9%、 A. terreus 7%とされる。(<図表>,<図表>
  1. 感染臓器は肺および副鼻腔が最も多く、消化管・皮膚などもエントリーになり得る。
  1. 初発感染臓器から脳膿瘍・眼内炎・心内膜炎など播種性病変を合併することがあり、その場合の機能予後・致死率は極めて高い。
 
  1. アスペルギルスは常に気道から吸入されているが、免疫正常者ではアスペルギルス症を発症しない。ホストの免疫状態と病原体とのバランスによって発症リスクが変化する。患者背景として、好中球減少、造血幹細胞移植など免疫抑制状態が想定される(推奨度1、GCOVID-19において続発することがある
  1. まとめ:侵襲性アスペルギルス症を発症する患者背景に関して複数のシステムレビューおよび観察研究がある。
  1. 代表事例:侵襲性アスペルギルス症は呼吸器からの病原微生物吸入により発症し、エントリーとして肺と副鼻腔が最も典型的である。免疫抑制療法の進展に伴い、侵襲性アスペルギルス症の頻度は増多している。好中球減少症(特に10日間以上のもの)・造血幹細胞移植(発症頻度は同種移植で2.3~3.2%[1]、8~15%[2]、自家移植で0.5%)、固形臓器移植(特に肺移植5~15%[2])が代表的である。HIV感染症・慢性呼吸器感染症・慢性肉芽腫性疾患(CDG)も高リスクである[3]。症状は発熱・呼吸困難・咳嗽・血痰・体重減少など非特定的である[1]<図表>)。骨髄移植後の平均発症期間は120日である[2]<図表>)。リスク解析によると骨髄移植後に急性GVHDがあればHazard ratioは7.1、慢性GVHD 5.7、CMV再活性化があると32.9に上昇する。骨髄移植後のステロイド投与は糸状菌感染症による死亡のリスク因子である。プレドニン換算で<2mg/kgのステロイド投与を受けている場合は1年生存率が44%、>2mg/kgで11%とされている[4]。日本での病理解剖での統計で発見される深在性真菌症として、深部臓器にアスペルギルスが発見される頻度はカンジダを抜いて最大である[5]<図表>)。日本でのガイドラインでは、高リスク患者として血液内科領域では、好中球<500/µlが10日間・同種造血幹細胞移植・90日以内の細胞性免疫抑制薬・3週間以上のステロイド(≥0.3mg/kg)投与・GVHD・入院施設の改築工事・CMV感染症を挙げている。呼吸器内科領域では低栄養・一般抗菌薬の長期投与・糖尿病などを挙げている。HIV感染症ではCD4陽性リンパ球数<50/µlが高リスクである[6]。HIV感染者での侵襲性アスペルギルス症の頻度は低下しているが、発症すると死亡率は38%にのぼる[7]。COVID-19剖検例443例において侵襲性肺真菌症合併は11例(2%)にみられ、11例中8例がアスペルギルスであった。死亡例においても合併頻度は稀と考えられる[8]
  1. 結論:これらの免疫抑制状態にある患者では常に発症リスクを想定することが必要である。
  1. 追記:患者状態によって侵襲性アスペルギルス症の発症リスクは変わる。これらの背景のある患者では、常に侵襲性アスペルギルス症を疑うべきである。死亡率が高いため疾患背景から高リスク患者を適切にモニタリングすることが必要である。
 
侵襲性肺アスペルギルス症に関する宿主側の素因と臨床的および組織学的特徴

アスペルギルス症は種々な免疫低下状態に発症し、特に免疫能の低下した状態では急速に進行し、ときとして致死的である。
Segal BH: Aspergillosis. N Engl J Med. 2009;360(18):1870-84. PMID:19403905を参考に作製

出典

img1:  著者提供
 
 
 
移植レシピエントにおける侵襲性アスペルギルス症の疫学的特徴

臓器移植は、侵襲性アスペルギルス症を起こし得る免疫抑制の典型である。造血幹細胞移植の2~26%、固形臓器移植の1~15%に発症するとされている。総じて、移植後1年以内の死亡原因としてアスペルギルス症は9.3~16.9%を占めるとされている。

出典

img1:  Aspergillus infections in transplant recipients.
 
 Clin Microbiol Rev. 2005 Jan;18(1):44-69・・・
 
剖検例における真菌症全体の検出率と個々の病原性微生物感染の変化(1969~2007年、2009年、日本)

日本で1969~2007年に行われた病理解剖で、深在性真菌症が認められたものを菌種別に示した。近年になって、アスペルギルス症の頻度が上昇し、カンジダ症を逆転している。1989年にフルコナゾールが発売されカンジダの頻度が減少したこと、2001年までアスペルギルス症治療薬が少なかったことが原因と推測される。2009年までの追加解析によれば、アスペルギルスは深在臓器で検出された真菌の47.2%を占め、カンジダ(29.1%)より多い。
 
参考文献:
Suzuki Y, Kume H, Togano T, et al. Epidemiology of visceral mycoses in autopsy cases in Japan: the data from 1989 to 2009 in the Annual of Pathological Autopsy Cases in Japan. Med Mycol 2013; 51(5):522-6. PMID:23327545

出典

img1:  Epidemiology of visceral mycoses in autopsy cases in Japan: comparison of the data from 1989, 1993, 1997, 2001, 2005 and 2007 in Annual of Pathological Autopsy Cases in Japan.
 
 Med Mycol J. 2011;52(2):117-27.
 
  1. A. fumigatusを代表とするアスペルギルス属による侵襲性真菌症は増加している(推奨度1)
  1. まとめ:侵襲性アスペルギルス症の病原微生物について報告がある。
  1. 代表事例:侵襲性アスペルギルス症と診断された患者438人に対する観察研究で、移植後1年間での累積発症者数は、同種移植(青)が累積10%、自家移植(緑)が2~4%である(<図表>)。分離された起因菌は、1990年より以前の報告ではA. fumigatusが多数であったが、A. nigerA. flavusA. terreusなどが検出され(<図表>)、造血幹細胞移植ではA. terreusの頻度が増加していると報告されており、A. fumigatusに比較して予後が悪いとされている。A. terreusはアムホテリシンBへの感受性が悪く、死亡率が高い[9]。 またフサリウム、接合菌など他の真菌感染症も認められる*注)。日本の病理解剖での深部臓器真菌検出率を記した論文によると、1993年から2009年の報告ではアスペルギルス属の検出数がカンジダ属より多い(<図表>)。原疾患別では、造血器悪性腫瘍での深部臓器真菌検出は、2007年に18.8%と減少傾向になったが、接合菌症(ムコールなど)は増加している[5]。欧州のオランダではイトラコナゾール(ITCZ)耐性のA. fumigatusが増加しており12.9%認められ、これらはボリコナゾール(VRCZ)へもMICが高い傾向がみられる傾向にあった[10]
  1. 分子疫学的な解析の発達によって、これまでA. fumigatusと同定されてきた菌株のなかに隠蔽種としてA. lentulus等があり、第1選択のボリコナゾールに耐性傾向があることが判明してきた[11]。またA. fumigatus自体のアゾール(ITCZ, VRCZ)耐性も英国では2.2%程度あると報告されている[12]。日本からもボリコナゾール耐性のcyp51A領域にTR34/L98H変異を持つA. fumigatusが報告されている[13]。感受性試験は全例に行うことは推奨されず(真菌の薬剤感受性試験は技術的に難しいという現実もある)、アゾール耐性が強く疑われる場合に行う[14]。ボリコナゾール耐性アスペルギルスによる侵襲性肺アスペルギルス症は高い死亡率と相関する[15]
  1. 結論:A. fumigatusを代表とする糸状菌による侵襲性真菌症はカンジダ属が減少するのに比較して増加している。フルコナゾール等の予防投与が行われるようになった可能性があると推測され[16]、日本での急性骨髄性白血病の治療中には寛解導入療法中の肺炎の15.8%、地固め療法中の肺炎の19.7%が侵襲性アスペルギルス症だったと報告されている[17]
  1. 補足:*注) フサリウム・ムコール症の治療には、アスペルギルス症とは異なりポサコナゾール、アムホテリシンBが用いられる。フサリウムでは呼吸器よりも皮膚からの侵入があり、また血液培養陽性率が高い。アスペルギルス属のなかでも非A. fumigatusが増加していること、またフサリウムなど形態的に鑑別の難しい真菌も報告されている。
 
造血幹細胞移植後患者で糸状菌(主にアスペルギルス)感染症の合併率は上昇している

シアトルのFred Hutchinsonがんセンターで診断された造血幹細胞移植後の侵襲性アスペルギルス症。1992年以降、同種移植で発生率は上昇している。

出典

img1:  Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients.
 
 Clin Infect Dis. 2002 Apr 1;34(7):909-17・・・
 
臨床的に分離されるアスペルギルスの菌名と頻度

確定診断には、肺生検など生体材料からの培養検査が必要である。分離菌は、A. fumigatusが一般的だが、1995年以降、A. fumigatus以外のアスペルギルス属の分離頻度が上昇している。造血幹細胞移植ではA. terreusの頻度が増加していると報告されており、A. fumigatusに比較して予後が悪いとされている。
 
参考文献:Invasive aspergillosis caused by Aspergillus terreus: an emerging opportunistic infection with poor outcome independent of azole therapy.J Antimicrob Chemother 2014; 69: 3148–3155 PMID:25006241

出典

img1:  Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients.
 
 Clin Infect Dis. 2002 Apr 1;34(7):909-17・・・
問診・診察のポイント  
  1. 患者の免疫状態を把握する。造血器悪性腫瘍の既往・造血幹細胞移植や固形臓器移植の時期・ステロイド投与・HIV感染( HIV/AIDS )リスクを確認する。

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文献 

著者: Brahm H Segal
雑誌名: N Engl J Med. 2009 Apr 30;360(18):1870-84. doi: 10.1056/NEJMra0808853.
Abstract/Text
PMID 19403905  N Engl J Med. 2009 Apr 30;360(18):1870-84. doi: 10.1056・・・
著者: Nina Singh, David L Paterson
雑誌名: Clin Microbiol Rev. 2005 Jan;18(1):44-69. doi: 10.1128/CMR.18.1.44-69.2005.
Abstract/Text Aspergillus infections are occurring with an increasing frequency in transplant recipients. Notable changes in the epidemiologic characteristics of this infection have occurred; these include a change in risk factors and later onset of infection. Management of invasive aspergillosis continues to be challenging, and the mortality rate, despite the use of newer antifungal agents, remains unacceptably high. Performing molecular studies to discern new targets for antifungal activity, identifying signaling pathways that may be amenable to immunologic interventions, assessing combination regimens of antifungal agents or combining antifungal agents with modulation of the host defense mechanisms, and devising diagnostic assays that can rapidly and reliably diagnose infections represent areas for future investigations that may lead to further improvement in outcomes.

PMID 15653818  Clin Microbiol Rev. 2005 Jan;18(1):44-69. doi: 10.1128/・・・
著者: Sophie Blumental, Richard Mouy, Nizar Mahlaoui, Marie-Elisabeth Bougnoux, Marianne Debré, Julien Beauté, Olivier Lortholary, Stéphane Blanche, Alain Fischer
雑誌名: Clin Infect Dis. 2011 Dec;53(12):e159-69. doi: 10.1093/cid/cir731.
Abstract/Text BACKGROUND: Invasive fungal infection (IFI) represents a life-threatening condition for patients with chronic granulomatous disease (CGD) and causes one-third of deaths in this population. This study offers a descriptive review of invasive mold infection (mIFI) in children with CGD over an extended period of time.
METHODS: In a cohort of patients with CGD registered in the French National database for Primary Immunodeficiency, we performed a retrospective review of proven mIFI episodes (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group 2008 criteria) occurring from 1984 through 2009.
RESULTS: Twenty-nine proven mIFIs were identified in 24 patients. Thirteen (54%) of 24 children were receiving itraconazole prophylaxis. Seven episodes were caused by Aspergillus fumigatus, 10 by Aspergillus nidulans, 2 by Aspergillus species, and 6 by other opportunistic molds (4 patients only had positive pathological examination findings). First proven mIFI occurred later in the group that received itraconazole than in the group without (median time to mIFI, 10 vs 4 years; P < .01), with a higher proportion of infections due to A. nidulans and other opportunistic molds (P < .05). Course of IFI was complex, with the median duration of therapy and hospitalization reaching 446 and 153 days, respectively. Combined antifungal therapy was commonly used. Four patients received geno-identical hematopoietic stem cell transplantation as salvage therapy. Global cure rate among the cohort reached 75%, but sequelae were frequent. Prognosis has improved over time (43% mortality during 1985-1990 vs 6% thereafter; P = .06). Mortality tended to be lower in the group that recieved itraconazole prophylaxis but at the cost of a longer duration of therapy among cured patients.
CONCLUSIONS: Management of mIFI remains challenging in patients with CGD, but significant improvements have been made over the past decade.

PMID 22080130  Clin Infect Dis. 2011 Dec;53(12):e159-69. doi: 10.1093/・・・
著者: Takahiro Fukuda, Michael Boeckh, Rachel A Carter, Brenda M Sandmaier, Michael B Maris, David G Maloney, Paul J Martin, Rainer F Storb, Kieren A Marr
雑誌名: Blood. 2003 Aug 1;102(3):827-33. doi: 10.1182/blood-2003-02-0456. Epub 2003 Apr 10.
Abstract/Text The incidence of invasive mold infections has increased during the 1990s among patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) after myeloablative conditioning. In this study, we determined risk factors for invasive mold infection and mold infection-related death among 163 patients undergoing allogeneic HCT with nonmyeloablative conditioning. The cumulative incidence rates of proven or probable invasive fungal infections, invasive mold infections, invasive aspergillosis, and invasive candidiasis during the first year after allogeneic HCT with nonmyeloablative conditioning were 19%, 15%, 14%, and 5%, respectively, which were similar to those after conventional myeloablative HCT. Invasive mold infections occurred late after nonmyeloablative conditioning (median, day 107), with primary risk factors including severe acute graft-versus-host disease (GVHD), chronic extensive GVHD, and cytomegalovirus (CMV) disease. The 1-year survival after diagnosis of mold infections was 32%. High-dose corticosteroid therapy at diagnosis of mold infection was associated with an increased risk for mold infection-related death. Overall, nonrelapse mortality was estimated at 22% (36 patients) after nonmyeloablative conditioning, of which 39% (14 patients) were mold infection-related (9% of the overall mortality). More effective strategies are needed to prevent invasive mold infections, which currently account for a notable proportion of nonrelapse mortality after nonmyeloablative allogeneic HCT.

PMID 12689933  Blood. 2003 Aug 1;102(3):827-33. doi: 10.1182/blood-200・・・
著者: Hikaru Kume, Toshikazu Yamazaki, Tomiteru Togano, Michiko Abe, Hiroyuki Tanuma, Seiji Kawana, Masahiko Okudaira
雑誌名: Med Mycol J. 2011;52(2):117-27.
Abstract/Text The data on visceral mycoses reported in the " Annual of Pathological Autopsy Cases in Japan " were analyzed epidemiologically every four years from 1989 to 2005, and in 2007. The frequency rates of visceral mycoses dropped sharply between 1989 (4.5%) and 1994 (3.2%), but by 2001 had risen again and have remained (4.4-4.6%) generally stable since then. The predominant causative agents were Candida and Aspergillus. Although the rate of candidosis showed a gradual decrease, the rate of aspergillosis showed an increase by degrees. Furthermore, the rate of aspergillosis exceeded that of candidosis in 1994, and the difference in the rates between the two conditions apparently further increased until 2001. After 2005, however no changes in this difference were observed. For complicated infections, the incidence of coinfection with Aspergillus and Candida showed a decreasing, and that with Aspergillus and Zygomycetes showed an increasing tendency. Severe infections with Zygomycetes showed a clear increase from 57.4% in 1989 to 88.9% in 2007. Comparing underlying diseases with mycoses in 1989 and 2007, leukemia (including myelodysplastic syndrome) decreased from 26.1% to 18.8% and bacterial infections (including interstitial pneumonia) increased from 11.1% to 22.1%. By age, the highest frequency rate of mycoses was observed in the range of 60-79 years, and the frequency rate of exogenous fungal infections such as aspergillosis, cryptococcosis, zygomycosis and trichosporonosis showed an increasing trend in the less than one-year old group.

PMID 21788723  Med Mycol J. 2011;52(2):117-27.
著者: Blandine Denis, Marguerite Guiguet, Nathalie de Castro, Frédéric Mechaï, Matthieu Revest, Giovanna Melica, Dominique Costagliola, Olivier Lortholary, French Hospital Database on HIV National Agency for Research on AIDS and Viral Hepatitis, France CO4
雑誌名: Clin Infect Dis. 2015 Oct 15;61(8):1273-80. doi: 10.1093/cid/civ492. Epub 2015 Jun 29.
Abstract/Text BACKGROUND: Before the advent of combination antiretroviral therapy (cART), roughly 50% of cases of invasive aspergillosis (IA) associated with human immunodeficiency virus (HIV) infection involved individuals without classical predisposing host factors, and the median survival time was <4 months after diagnosis. We examined if the situation evolved over time using the revised European Organisation for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC) definition and analyzed survival trends after diagnosis over 20 years.
METHODS: A data review committee evaluated 342 medical records that mentioned IA in the French Hospital Database on HIV. Validated cases were classified as fulfilling the EORTC criteria or otherwise as "HIV-related IA." Three periods were analyzed: pre-cART (before 1996), cART era prevoriconazole (1996-2001), and 2002-2011.
RESULTS: Among 242 validated cases of IA, 124 (51%) fulfilled the EORTC criteria (EORTC-IA) and 118 (49%) were classified as "HIV-related," with similarly low CD4 cell counts in both groups. The proportion of EORTC-IA cases remained stable across the 3 periods (50%, 48%, and 54%, respectively). The 3-month survival rate improved after the advent of cART (38% vs 69%), with no difference between EORTC-IA and HIV-related IA (hazard ratio [HR], 1.2 95% confidence interval [CI] {0.7-1.8}). Voriconazole exposure decreased mortality in 2002-2011 (HR, 0.1 95% CI [0.01-0.8]).
CONCLUSIONS: In the cART era, EORTC criteria, developed for use in hematology/oncology, still applied to only half the cases diagnosed among HIV-infected patients. A rapid diagnosis of IA is paramount to improve survival. For patients who do not fulfill the EORTC definition, we suggest that the addition of "HIV infected with a CD4 count <100 cells/µL" to the EORTC host criteria be validated.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID 26123932  Clin Infect Dis. 2015 Oct 15;61(8):1273-80. doi: 10.109・・・
著者: Brittany E Kula, Cornelius J Clancy, M Hong Nguyen, Ilan S Schwartz
雑誌名: Lancet Microbe. 2021 Aug;2(8):e405-e414. doi: 10.1016/S2666-5247(21)00091-4. Epub 2021 Jun 23.
Abstract/Text Invasive mould disease (IMD) might affect up to a third of critically ill patients with COVID-19. COVID-19-associated pulmonary aspergillosis (CAPA) is typically diagnosed on the basis of a combination of non-specific clinical, radiographical, and mycological findings, but whether most cases represent invasive disease is unresolved. We systematically reviewed autopsy series of three or more decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase), and medRxiv for studies in English or French published from Jan 1, 2019, to Sept 26, 2020. We identified 1070 references, of which 50 studies met the criteria. These studies described autopsies from 677 decedents, with individual-level data for 443 decedents. The median age was 70·0 years (IQR 57·0-79·0). Of decedents with individual-level data, 133 (30%) had diabetes, 97 (22%) had pre-existing lung disease, and 27 (6%) had immunocompromising conditions. Of 548 decedents with such data, 320 (58%) received invasive mechanical ventilation; among 140 decedents for whom this was known, ventilation was for a median of 9·0 days (IQR 5·0-20·0). Treatment included immunomodulation in 60 decedents and antifungals in 50 decedents. Autopsy-proven IMD occurred in 11 (2%) of 677 decedents, including eight CAPA, two unspecified IMD, and one disseminated mucormycosis. Among 320 decedents who received mechanical ventilation, six (2%) had IMD. We conclude that IMD, including CAPA, is an uncommon autopsy finding in COVID-19.

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
PMID 34189490  Lancet Microbe. 2021 Aug;2(8):e405-e414. doi: 10.1016/S・・・
著者: Kieren A Marr, Rachel A Carter, Fulvio Crippa, Anna Wald, Lawrence Corey
雑誌名: Clin Infect Dis. 2002 Apr 1;34(7):909-17. doi: 10.1086/339202. Epub 2002 Feb 26.
Abstract/Text Reports have focused on the emergence of moulds as pathogens in recipients of hematopoietic stem cell transplants. To review the incidence of and risks for mould infections, we examined the records of 5589 patients who underwent hematopoietic stem cell transplantation at the Fred Hutchinson Cancer Research Center (Seattle) from 1985 through 1999. After 1992, the incidence of invasive aspergillosis increased in allograft recipients and remained high through the 1990s. Infections with non-fumigatus Aspergillus species, Fusarium species, and Zygomycetes increased during the late 1990s, especially in patients who received multiple transplants. Although infection caused by Scedosporium species was common in patients who had neutropenia, infection caused by Zygomycetes typically occurred later after transplantation, when patients had graft-versus-host disease. The overall 1-year survival rate was equally poor (similar20%) for all patients with mould infections. The results of the present study demonstrate the changing epidemiology of mould infections, emphasizing the increasing importance of amphotericin B--resistant organisms and the differences in risks and outcome of infection with different filamentous fungi.

PMID 11880955  Clin Infect Dis. 2002 Apr 1;34(7):909-17. doi: 10.1086/・・・
著者: Eveline Snelders, Henrich A L van der Lee, Judith Kuijpers, Anthonius J M M Rijs, János Varga, Robert A Samson, Emilia Mellado, A Rogier T Donders, Willem J G Melchers, Paul E Verweij
雑誌名: PLoS Med. 2008 Nov 11;5(11):e219. doi: 10.1371/journal.pmed.0050219.
Abstract/Text BACKGROUND: Resistance to triazoles was recently reported in Aspergillus fumigatus isolates cultured from patients with invasive aspergillosis. The prevalence of azole resistance in A. fumigatus is unknown. We investigated the prevalence and spread of azole resistance using our culture collection that contained A. fumigatus isolates collected between 1994 and 2007.
METHODS AND FINDINGS: We investigated the prevalence of itraconazole (ITZ) resistance in 1,912 clinical A. fumigatus isolates collected from 1,219 patients in our University Medical Centre over a 14-y period. The spread of resistance was investigated by analyzing 147 A. fumigatus isolates from 101 patients, from 28 other medical centres in The Netherlands and 317 isolates from six other countries. The isolates were characterized using phenotypic and molecular methods. The electronic patient files were used to determine the underlying conditions of the patients and the presence of invasive aspergillosis. ITZ-resistant isolates were found in 32 of 1,219 patients. All cases were observed after 1999 with an annual prevalence of 1.7% to 6%. The ITZ-resistant isolates also showed elevated minimum inhibitory concentrations of voriconazole, ravuconazole, and posaconazole. A substitution of leucine 98 for histidine in the cyp51A gene, together with two copies of a 34-bp sequence in tandem in the gene promoter (TR/L98H), was found to be the dominant resistance mechanism. Microsatellite analysis indicated that the ITZ-resistant isolates were genetically distinct but clustered. The ITZ-sensitive isolates were not more likely to be responsible for invasive aspergillosis than the ITZ-resistant isolates. ITZ resistance was found in isolates from 13 patients (12.8%) from nine other medical centres in The Netherlands, of which 69% harboured the TR/L98H substitution, and in six isolates originating from four other countries.
CONCLUSIONS: Azole resistance has emerged in A. fumigatus and might be more prevalent than currently acknowledged. The presence of a dominant resistance mechanism in clinical isolates suggests that isolates with this mechanism are spreading in our environment.

PMID 18998768  PLoS Med. 2008 Nov 11;5(11):e219. doi: 10.1371/journal.・・・
著者: Seung-Beom Hong, Dae-Ho Kim, In-Cheol Park, Young-Joon Choi, Hyeon-Dong Shin, Robert Samson
雑誌名: J Microbiol. 2010 Oct;48(5):607-15. doi: 10.1007/s12275-010-0084-z. Epub 2010 Nov 3.
Abstract/Text The species concept of Aspergillus fumigatus sensu stricto has recently been defined by polyphasic taxonomy. Based on the new concept of species delimitations, 146 worldwide strains of Aspergillus fumigatus sensu lato were re-identified. Of those 146 strains, 140 (95.8%) could be identified as A. fumigatus sensu stricto, 3 (2.1%) as A. lentulus, and the remaining 3 strains as A. viridinutans complex, Neosartorya udagawae, and N. cf. nishimurae. Of 98 clinical strains, only 1 from dolphin nostril was identified as A. lentulus and not A. fumigatus sensu stricto. Random amplification of polymorphic DNA-polymerase chain reaction (RAPD-PCR) with primers PELF and URP1F produced nearly the same band patterns among 136 strains of A. fumigatus sensu stricto while discriminated the species from its related species. We also discussed about identification of several atypical A. fumigatus strains from clinical environments.

PMID 21046338  J Microbiol. 2010 Oct;48(5):607-15. doi: 10.1007/s12275・・・
著者: Alireza Abdolrasouli, Michael A Petrou, Hyun Park, Johanna L Rhodes, Timothy M Rawson, Luke S P Moore, Hugo Donaldson, Alison H Holmes, Matthew C Fisher, Darius Armstrong-James
雑誌名: Front Microbiol. 2018;9:2234. doi: 10.3389/fmicb.2018.02234. Epub 2018 Sep 20.
Abstract/Text Background/Objectives:Aspergillus fumigatus is the leading cause of invasive aspergillosis. Treatment is hindered by the emergence of resistance to triazole antimycotic agents. Here, we present the prevalence of triazole resistance among clinical isolates at a major centralized medical mycology laboratory in London, United Kingdom, in the period 1998-2017. Methods: A large number (n = 1469) of clinical A. fumigatus isolates from unselected clinical specimens were identified and their susceptibility against three triazoles, amphotericin B and three echinocandin agents was carried out. All isolates were identified phenotypically and antifungal susceptibility testing was carried out by using a standard broth microdilution method. Results: Retrospective surveillance (1998-2011) shows 5/1151 (0.43%) isolates were resistant to at least one of the clinically used triazole antifungal agents. Prospective surveillance (2015-2017) shows 7/356 (2.2%) isolates were resistant to at least one triazole antifungals demonstrating an increase in incidence of triazole-resistant A. fumigatus in our laboratory. Among five isolates collected from 2015 to 2017 and available for molecular testing, three harbored TR34/L98H alteration in the cyp51A gene that are associated with the acquisition of resistance in the non-patient environment. Conclusion: These data show that historically low prevalence of azole resistance may be increasing, warranting further surveillance of susceptible patients.

PMID 30294314  Front Microbiol. 2018;9:2234. doi: 10.3389/fmicb.2018.0・・・
著者: Yasuhiro Tsuchido, Michio Tanaka, Satoshi Nakano, Masaki Yamamoto, Yasufumi Matsumura, Miki Nagao
雑誌名: Med Mycol. 2019 Jan 25;. doi: 10.1093/mmy/myz003. Epub 2019 Jan 25.
Abstract/Text The prevalence of azole-resistant Aspergillus fumigatus (ARAF) in Japan is unclear. We aimed to investigate the epidemiology of clinically isolated Aspergillus species and the frequency of azole resistance in Aspergillus species, particularly Aspergillus fumigatus, in the Kyoto and Shiga regions of Japan. Strains of clinically isolated Aspergillus species were prospectively collected from nine acute care hospitals. Species identification was performed by DNA sequence analysis, and all strains were subjected to antifungal susceptibility testing. Sequencing of the Aspergillus cyp51A gene and promoter region and genotyping by short tandem repeats were performed for ARAF isolates. A total of 149 strains were collected, and 130 strains were included for the subsequent analysis after the exclusion of duplicate isolates. The most commonly isolated species was Aspergillus fumigatus, accounting for 43.1% (56 isolates) overall, and seven (12.7%) of 55 strains of A. fumigatus were azole-resistant. Azole-resistance of other Aspergillus species were also found that two (22.2%) of nine strains of A. tubingensis and two (28.6%) of seven strains of A. flavus were azole-resistant. DNA sequence analysis of the ARAF strains revealed that two carried the cyp51A TR34/L98H mutation, one carried G448S, one carried M220I, and three had no relevant mutations (wild type). Genotyping and phylogenetic analyses showed that the TR34/L98H strains were clustered with the strains from the Netherlands and France. These data suggest the emergence of ARAF with TR34/L98H in Japan, and continuous surveillance will be important to identify trends in resistance.

PMID 30690480  Med Mycol. 2019 Jan 25;. doi: 10.1093/mmy/myz003. Epub ・・・
著者: A J Ullmann, J M Aguado, S Arikan-Akdagli, D W Denning, A H Groll, K Lagrou, C Lass-Flörl, R E Lewis, P Munoz, P E Verweij, A Warris, F Ader, M Akova, M C Arendrup, R A Barnes, C Beigelman-Aubry, S Blot, E Bouza, R J M Brüggemann, D Buchheidt, J Cadranel, E Castagnola, A Chakrabarti, M Cuenca-Estrella, G Dimopoulos, J Fortun, J-P Gangneux, J Garbino, W J Heinz, R Herbrecht, C P Heussel, C C Kibbler, N Klimko, B J Kullberg, C Lange, T Lehrnbecher, J Löffler, O Lortholary, J Maertens, O Marchetti, J F Meis, L Pagano, P Ribaud, M Richardson, E Roilides, M Ruhnke, M Sanguinetti, D C Sheppard, J Sinkó, A Skiada, M J G T Vehreschild, C Viscoli, O A Cornely
雑誌名: Clin Microbiol Infect. 2018 May;24 Suppl 1:e1-e38. doi: 10.1016/j.cmi.2018.01.002. Epub 2018 Mar 12.
Abstract/Text The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
PMID 29544767  Clin Microbiol Infect. 2018 May;24 Suppl 1:e1-e38. doi:・・・
著者: Pieter P Lestrade, Robbert G Bentvelsen, Alexander F A D Schauwvlieghe, Steven Schalekamp, Walter J F M van der Velden, Ed J Kuiper, Judith van Paassen, Ben van der Hoven, Henrich A van der Lee, Willem J G Melchers, Anton F de Haan, Hans L van der Hoeven, Bart J A Rijnders, Martha T van der Beek, Paul E Verweij
雑誌名: Clin Infect Dis. 2019 Apr 24;68(9):1463-1471. doi: 10.1093/cid/ciy859.
Abstract/Text BACKGROUND: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking.
METHODS: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated.
RESULTS: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days.
CONCLUSIONS: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PMID 30307492  Clin Infect Dis. 2019 Apr 24;68(9):1463-1471. doi: 10.1・・・
著者: Shun-Ichi Kimura, Hiroyuki Fujita, Hideaki Kato, Nobuhiro Hiramoto, Naoko Hosono, Tsutomu Takahashi, Kazuyuki Shigeno, Naoko Hatsumi, Hitoshi Minamiguchi, Junichi Miyatake, Hiroshi Handa, Nobu Akiyama, Yoshinobu Kanda, Minoru Yoshida, Hitoshi Kiyoi, Yasushi Miyazaki, Tomoki Naoe, Japan Adult Leukemia Study Group (JALSG)
雑誌名: Support Care Cancer. 2017 Nov;25(11):3515-3521. doi: 10.1007/s00520-017-3775-8. Epub 2017 Jun 6.
Abstract/Text PURPOSE: We performed a nationwide questionnaire-based survey to evaluate the current clinical practices of infectious complications during chemotherapy for acute leukemia in Japan.
METHODS: We e-mailed a questionnaire to member institutions of the Japan Adult Leukemia Study Group in September, 2013. The questionnaire consisted of 50 multiple-choice questions covering therapeutic environment, antimicrobial prophylaxis, screening test during neutropenia, empirical therapy for febrile neutropenia, and the use of granulocyte-colony stimulating factor. The results were compared to those of previous surveys conducted in 2001 and 2007, and also to the recommendations described in the guidelines.
RESULTS: Usable responses were received from 141 out of 222 (63.5%) institutions. Chemotherapy for acute myeloid leukemia was performed in protective environment in 90% of the institutions, which increased compared to previous survey (76%). Fluoroquinolones and fluconazole were the most commonly used antimicrobial agents for antibacterial and antifungal prophylaxis, followed by sulfamethoxazole-trimethoprim and itraconazole, respectively. In empirical therapy for febrile neutropenia, monotherapy with β-lactum antibiotics was the first-line therapy in most of the institutions. While empirical antifungal therapy was adopted for persistent fever in more than half of the institutions, preemptive/presumptive therapy was also used in approximately 40% of the institutions. Most of the clinicians were reluctant to use granulocyte-colony stimulating factor routinely in chemotherapy for acute myeloid leukemia.
CONCLUSIONS: This study clarified the current clinical practices of infectious complications during chemotherapy for acute leukemia and would provide important information for the development of a suitable guideline in Japan.

PMID 28584934  Support Care Cancer. 2017 Nov;25(11):3515-3521. doi: 10・・・
著者: Hideaki Kato, Hiroyuki Fujita, Nobu Akiyama, Shun-Ichi Kimura, Nobuhiro Hiramoto, Naoko Hosono, Tsutomu Takahashi, Kazuyuki Shigeno, Hitoshi Minamiguchi, Junichi Miyatake, Hiroshi Handa, Yoshinobu Kanda, Minoru Yoshida, Shuichi Miyawaki, Shigeki Ohtake, Tomoki Naoe, Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Japan Adult Leukemia Study Group
雑誌名: Support Care Cancer. 2018 Dec;26(12):4187-4198. doi: 10.1007/s00520-018-4292-0. Epub 2018 Jun 2.
Abstract/Text PURPOSE: The Japan Adult Leukemia Study Group (JALSG) AML201 protocols are regimens for remission induction and consolidation chemotherapy of acute myeloid leukemia (AML) and have been widely accepted in Japan since 2001. Management of infectious complications during chemotherapy has a key role in the supportive care of AML patients.
METHODS: By using case report forms collected in December 2001 and December 2005, we retrospectively analyzed the infectious complications in adult patients treated by using the JALSG AML201 protocols against AML (excluding promyelocytic leukemia).
RESULTS: Of 980 patients, 80.2% experienced febrile neutropenia (FN), 8.3% bacteremia/fungemia, and 10.3% pulmonary infection at least once during remission-induction chemotherapy. Gram-positive bacteremia accounted for 65.1% of bacteremia/fungemia in 2001-2005, compared with 38.2% in 1987-1991 and 45.9% in 1992-1995. Of 750 patients, 81.9% experienced FN, 21.9% bacteremia/fungemia, and 9.1% pulmonary infection at least once during consolidation chemotherapy. During consolidation chemotherapy, bacteremia/fungemia and pulmonary infection were significantly more frequent in the high-dose cytarabine (HDAC) arm than in the conventional multiagent arm (25.9 vs. 17.9% and 12.7 vs. 7.7%, respectively). Invasive pulmonary aspergillosis accounted for 15.8% of pulmonary infections during remission induction and 19.7% during consolidation chemotherapy.
CONCLUSIONS: Our data suggest that patterns of infectious complications have changed between 1987 and 2005, possibly because of chemoprophylaxis with oral fluoroquinolones and improved diagnosis of invasive pulmonary aspergillosis by serum antigen analysis.

PMID 29860713  Support Care Cancer. 2018 Dec;26(12):4187-4198. doi: 10・・・
著者: Alison G Freifeld, Eric J Bow, Kent A Sepkowitz, Michael J Boeckh, James I Ito, Craig A Mullen, Issam I Raad, Kenneth V Rolston, Jo-Anne H Young, John R Wingard, Infectious Diseases Society of Americaa
雑誌名: Clin Infect Dis. 2011 Feb 15;52(4):427-31. doi: 10.1093/cid/ciq147. Epub 2011 Jan 4.
Abstract/Text This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

PMID 21205990  Clin Infect Dis. 2011 Feb 15;52(4):427-31. doi: 10.1093・・・
著者: Thomas J Walsh, Peter Pappas, Drew J Winston, Hillard M Lazarus, Finn Petersen, John Raffalli, Saul Yanovich, Patrick Stiff, Richard Greenberg, Gerald Donowitz, Mindy Schuster, Annette Reboli, John Wingard, Carola Arndt, John Reinhardt, Susan Hadley, Robert Finberg, Michél Laverdière, John Perfect, Gary Garber, Giuseppe Fioritoni, Eli Anaissie, Jeanette Lee, National Institute of Allergy and Infectious Diseases Mycoses Study Group
雑誌名: N Engl J Med. 2002 Jan 24;346(4):225-34. doi: 10.1056/NEJM200201243460403.
Abstract/Text BACKGROUND: Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative.
METHODS: In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy.
RESULTS: A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03).
CONCLUSIONS: Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

PMID 11807146  N Engl J Med. 2002 Jan 24;346(4):225-34. doi: 10.1056/N・・・
著者: Edith Vermeulen, Johan Maertens, Annelies De Bel, Eric Nulens, Jerina Boelens, Ignace Surmont, Anna Mertens, An Boel, Katrien Lagrou
雑誌名: Antimicrob Agents Chemother. 2015 Aug;59(8):4569-76. doi: 10.1128/AAC.00233-15. Epub 2015 May 18.
Abstract/Text Aspergillus disease affects a broad patient population, from patients with asthma to immunocompromised patients. Azole resistance has been increasingly reported in both clinical and environmental Aspergillus strains. The prevalence and clinical impact of azole resistance in different patient populations are currently unclear. This 1-year prospective multicenter cohort study aimed to provide detailed epidemiological data on Aspergillus resistance among patients with Aspergillus disease in Belgium. Isolates were prospectively collected in 18 hospitals (April 2011 to April 2012) for susceptibility testing. Clinical and treatment data were collected with a questionnaire. The outcome was evaluated to 1 year after a patient's inclusion. A total of 220 Aspergillus isolates from 182 patients were included. The underlying conditions included invasive aspergillosis (n = 122 patients), allergic bronchopulmonary aspergillosis (APBA) (n = 39 patients), chronic pulmonary aspergillosis (n = 10 patients), Aspergillus bronchitis (n = 7 patients), and aspergilloma (n = 5 patients). The overall azole resistance prevalence was 5.5% (95% confidence interval [CI] 2.8 to 10.2%) and was 7.0% (4/57; 95% CI, 2.3 to 17.2%) in patients with APBA, bronchitis, aspergilloma, or chronic aspergillosis and 4.6% in patients with invasive aspergillosis (5/108; 95% CI, 1.7 to 10.7%). The 6-week survival in invasive aspergillosis was 52.5%, while susceptibility testing revealed azole resistance in only 2/58 of the deceased patients. The clinical impact of Aspergillus fumigatus resistance was limited in our patient population with Aspergillus diseases.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.
PMID 25987612  Antimicrob Agents Chemother. 2015 Aug;59(8):4569-76. do・・・
著者: Oliver A Cornely, Johan Maertens, Drew J Winston, John Perfect, Andrew J Ullmann, Thomas J Walsh, David Helfgott, Jerzy Holowiecki, Dick Stockelberg, Yeow-Tee Goh, Mario Petrini, Cathy Hardalo, Ramachandran Suresh, David Angulo-Gonzalez
雑誌名: N Engl J Med. 2007 Jan 25;356(4):348-59. doi: 10.1056/NEJMoa061094.
Abstract/Text BACKGROUND: Patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome are at high risk for difficult-to-treat and often fatal invasive fungal infections.
METHODS: In this randomized, multicenter study involving evaluators who were unaware of treatment assignments, we compared the efficacy and safety of posaconazole with those of fluconazole or itraconazole as prophylaxis for patients with prolonged neutropenia. Patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks, whichever came first. We compared the incidence of proven or probable invasive fungal infections during treatment (the primary end point) between the posaconazole and fluconazole or itraconazole groups; death from any cause and time to death were secondary end points.
RESULTS: A total of 304 patients were randomly assigned to receive posaconazole, and 298 patients were randomly assigned to receive fluconazole (240) or itraconazole (58). Proven or probable invasive fungal infections were reported in 7 patients (2%) in the posaconazole group and 25 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group, -6%; 95% confidence interval, -9.7 to -2.5%; P<0.001), fulfilling statistical criteria for superiority. Significantly fewer patients in the posaconazole group had invasive aspergillosis (2 [1%] vs. 20 [7%], P<0.001). Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (P=0.04). Serious adverse events possibly or probably related to treatment were reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole or itraconazole group (P=0.01). The most common treatment-related adverse events in both groups were gastrointestinal tract disturbances.
CONCLUSIONS: In patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome, posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole and improved overall survival. There were more serious adverse events possibly or probably related to treatment in the posaconazole group. (ClinicalTrials.gov number, NCT00044486 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17251531  N Engl J Med. 2007 Jan 25;356(4):348-59. doi: 10.1056/N・・・
著者: Johan A Maertens, Galia Rahav, Dong-Gun Lee, Alfredo Ponce-de-León, Isabel Cristina Ramírez Sánchez, Nikolay Klimko, Anne Sonet, Shariq Haider, Juan Diego Vélez, Issam Raad, Liang-Piu Koh, Meinolf Karthaus, Jianying Zhou, Ronen Ben-Ami, Mary R Motyl, Seongah Han, Anjana Grandhi, Hetty Waskin, study investigators
雑誌名: Lancet. 2021 Feb 6;397(10273):499-509. doi: 10.1016/S0140-6736(21)00219-1.
Abstract/Text BACKGROUND: Voriconazole has been recommended as primary treatment for patients with invasive aspergillosis. Intravenous and tablet formulations of posaconazole that have improved systemic absorption could be an effective alternative to voriconazole. We aimed to assess non-inferiority of posaconazole to voriconazole for the primary treatment of invasive aspergillosis.
METHODS: We did a randomised, prospective, double-blind, double-dummy, controlled trial comparing posaconazole (intravenous or oral posaconazole 300 mg twice on day 1, followed by 300 mg once a day for days 2-84) with voriconazole (6 mg/kg intravenous or 300 mg oral twice on day 1 followed by 4 mg/kg intravenously or 200 mg orally twice a day for days 2-84) for 12 weeks or less in the primary treatment of invasive aspergillosis. Participants were from 91 study sites in 26 countries, were aged 13 years or older, weighed at least 40 kg, and met criteria for proven, probable, or possible fungal disease. Participants were randomly assigned (1:1) via a computer-generated randomisation schedule with stratification by risk status. The primary endpoint was cumulative all-cause mortality up until day 42 in the intention-to-treat (ITT) population (defined as randomly assigned participants who received ≥1 dose of study drug), with a 10% non-inferiority margin. The ITT population was also evaluated for safety. This study is registered with ClinicalTrials.gov, NCT01782131, and EudraCT, 2011-003938-14.
FINDINGS: Between Oct 25, 2013, and Sept 10, 2019, of 653 individuals assessed for eligibility, 575 ITT participants were randomly assigned and received one or more doses of study drug (n=288 [50%] posaconazole, n=287 [50%] voriconazole). Mortality up until day 42 was 15% (44 of 288) in the posaconazole group and 21% (59 of 287) in the voriconazole group (treatment difference -5·3% [95% CI -11·6 to 1·0]; p<0·0001). Mortality up until day 42 in the full-analysis-set subpopulation (ITT participants with proven or probable invasive aspergillosis) supported this conclusion: 31 (19%) of 163 participants in the posaconazole group and 32 (19%) of 171 participants in the voriconazole group (treatment difference 0·3% [95% CI -8·2 to 8·8]). The most frequently reported treatment-related adverse events (incidence >3%) were increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT), nausea, hypokalaemia, and vomiting in the posaconazole group and increased ALT, AST, or alkaline phosphatase, hallucination, increased γ-glutamyltransferase peptidase, nausea, and blurred vision in the voriconazole group. The overall incidence of treatment-related adverse event rates in the ITT population was 30% for posaconazole and 40% for voriconazole (treatment difference -10·2% [95% CI -17·9 to -2·4]).
INTERPRETATION: Posaconazole was non-inferior to voriconazole for all-cause mortality up until day 42 in participants with invasive aspergillosis. Posaconazole was well tolerated, and participants had fewer treatment-related adverse events than in the voriconazole group. This study supports the use of posaconazole as a first-line treatment for the condition.
FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 33549194  Lancet. 2021 Feb 6;397(10273):499-509. doi: 10.1016/S01・・・
著者: Kieren A Marr, Haran T Schlamm, Raoul Herbrecht, Scott T Rottinghaus, Eric J Bow, Oliver A Cornely, Werner J Heinz, Shyla Jagannatha, Liang Piu Koh, Dimitrios P Kontoyiannis, Dong-Gun Lee, Marcio Nucci, Peter G Pappas, Monica A Slavin, Flavio Queiroz-Telles, Dominik Selleslag, Thomas J Walsh, John R Wingard, Johan A Maertens
雑誌名: Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M13-2508.
Abstract/Text BACKGROUND: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy.
OBJECTIVE: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA.
DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479).
SETTING: 93 international sites.
PATIENTS: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed.
MEASUREMENTS: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures.
RESULTS: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P  = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different.
LIMITATIONS: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability.
CONCLUSION: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority.
PRIMARY FUNDING SOURCE: Pfizer.

PMID 25599346  Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M・・・
著者: Johan A Maertens, Rocus Klont, Christine Masson, Koen Theunissen, Wouter Meersseman, Katrien Lagrou, Christine Heinen, Brigitte Crépin, Johan Van Eldere, Marc Tabouret, J Peter Donnelly, Paul E Verweij
雑誌名: Clin Infect Dis. 2007 May 15;44(10):1329-36. doi: 10.1086/514349. Epub 2007 Apr 4.
Abstract/Text BACKGROUND: Many health care centers worldwide use the Platelia Aspergillus enzyme immunoassay (PA-EIA; Bio-Rad Laboratories) for diagnosis of invasive aspergillosis (IA). A cutoff optical density (OD) index of 1.5 was originally recommended by the manufacturer, but in practice, most institutions use lower cutoff values. Moreover, a cutoff OD index of 0.5 was recently approved in the United States. In the present study, we set out to optimize the cutoff level by performing a retrospective analysis of PA-EIA values for samples that had been obtained prospectively from adult patients at risk for IA at 2 European health care centers.
METHODS: In total, 239 treatment episodes were included of which there were 19 episodes of proven IA and 19 episodes of probable IA. Per-episode and per-test analyses and receiver operating characteristic curves were used to determine the optimal cutoff value.
RESULTS: In the per-episode analysis, lowering the cutoff OD index for positivity from 1.5 to 0.5 increased the overall sensitivity by 21% (from 76.3% to 97.4%) but decreased the overall specificity by 7% (from 97.5% to 90.5%). Requiring 2 consecutive samples with an OD index > or = 0.5 resulted in the highest test accuracy, with an improved positive predictive value. At a cutoff OD index of 0.5, the antigen test result was positive during the week before conventional diagnosis in 65% of cases and during the week of diagnosis in 79.5% of cases.
CONCLUSIONS: A cutoff OD index of 0.5--identical to the approved cutoff in the United States--improves the overall performance of the PA-EIA for adult hematology patients.

PMID 17443470  Clin Infect Dis. 2007 May 15;44(10):1329-36. doi: 10.10・・・
著者: Jorien D'Haese, Koen Theunissen, Edith Vermeulen, Hélène Schoemans, Greet De Vlieger, Liesbet Lammertijn, Philippe Meersseman, Wouter Meersseman, Katrien Lagrou, Johan Maertens
雑誌名: J Clin Microbiol. 2012 Apr;50(4):1258-63. doi: 10.1128/JCM.06423-11. Epub 2012 Feb 1.
Abstract/Text Invasive pulmonary aspergillosis (IPA) is frequent and often fatal in immunosuppressed patients. Timely diagnosis of IPA improves survival but is difficult to make. We examined the analytical and clinical validity of galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid in diagnosing IPA in a mixed population by retrospectively reviewing records of 251 consecutive at-risk patients for whom BAL fluid GM testing was ordered. The performance of the enzyme immunoassay was evaluated by using a range of index cutoffs to define positivity. Three samples were associated with proven IPA, 56 were associated with probable IPA, 63 were associated with possible invasive fungal disease (IFD), and 129 were associated with no IFD. Using a BAL fluid GM index of ≥0.8 (optimal optical density [OD] index cutoff identified by a receiver operating characteristic curve), the sensitivity in diagnosing proven and probable IPA was 86.4%, and the specificity was 90.7%. At this cutoff, positive and negative predictive values were 81% and 93.6%, respectively. However, an OD index value of ≥3.0 corresponded to a 100% specificity, thus ruling the disease in, irrespective of the pretest probability. Conversely, an OD index cutoff of <0.5 corresponded to a high sensitivity, virtually always ruling the disease out. For all values in between, the posttest probability of IPA depends largely on the prevalence of disease in the at-risk population and the likelihood ratio of the OD index value. Detection of GM in BAL fluid samples of patients at risk of IPA has an excellent diagnostic accuracy provided results are interpreted in parallel with clinico-radiological findings and pretest probabilities.

PMID 22301025  J Clin Microbiol. 2012 Apr;50(4):1258-63. doi: 10.1128/・・・
著者: Drosos E Karageorgopoulos, Evridiki K Vouloumanou, Fotinie Ntziora, Argyris Michalopoulos, Petros I Rafailidis, Matthew E Falagas
雑誌名: Clin Infect Dis. 2011 Mar 15;52(6):750-70. doi: 10.1093/cid/ciq206.
Abstract/Text We aimed to assess the accuracy of measuring serum or plasma (1→3)-β-D-glucan (BDG) for the diagnosis of invasive fungal infections (IFIs) by means of a meta-analysis of relevant studies. We searched in bibliographic databases for relevant cohort or case-control studies. We primarily compared BDG between patients with proven or probable IFIs (excluding Pneumocystis jirovecii infections), according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group or similar criteria, and patients without IFIs (excluding healthy individuals as controls). A total of 2979 patients (594 with proven or probable IFIs), included in 16 studies, were analyzed. The pooled sensitivity of BDG was 76.8% (95% confidence interval [CI], 67.1%-84.3%), and the specificity was 85.3% (95% CI, 79.6%-89.7%). The area under the summary receiver operating characteristic curve was 0.89. Marked statistical heterogeneity was noted. BDG has good diagnostic accuracy for distinguishing proven or probable IFIs from no IFIs. It can be useful in clinical practice, if implemented in the proper setting and interpreted after consideration of its limitations.

PMID 21367728  Clin Infect Dis. 2011 Mar 15;52(6):750-70. doi: 10.1093・・・
著者: Ben De Pauw, Thomas J Walsh, J Peter Donnelly, David A Stevens, John E Edwards, Thierry Calandra, Peter G Pappas, Johan Maertens, Olivier Lortholary, Carol A Kauffman, David W Denning, Thomas F Patterson, Georg Maschmeyer, Jacques Bille, William E Dismukes, Raoul Herbrecht, William W Hope, Christopher C Kibbler, Bart Jan Kullberg, Kieren A Marr, Patricia Muñoz, Frank C Odds, John R Perfect, Angela Restrepo, Markus Ruhnke, Brahm H Segal, Jack D Sobel, Tania C Sorrell, Claudio Viscoli, John R Wingard, Theoklis Zaoutis, John E Bennett, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group, National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group
雑誌名: Clin Infect Dis. 2008 Jun 15;46(12):1813-21. doi: 10.1086/588660.
Abstract/Text BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies.
METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved.
RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only.
CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.

PMID 18462102  Clin Infect Dis. 2008 Jun 15;46(12):1813-21. doi: 10.10・・・
著者: R Greene
雑誌名: Med Mycol. 2005 May;43 Suppl 1:S147-54.
Abstract/Text Imaging findings in the pulmonary aspergilloses can answer important clinical questions. Steroid-responsive chronic asthma due to allergic bronchopulmonary aspergillosis can be differentiated from simple asthma by computed tomography (CT) evidence of extensive and severe central bronchiectasis, mucoid impaction, or small airways lesions. The simple aspergilloma can be differentiated from the complex aspergilloma by the absence of: constitutional symptoms, para-cystic lung opacities, cyst expansion, or progressive pleural thickening. The CT halo sign is a transient finding that can provide a probable diagnosis of early invasive pulmonary aspergillosis in patients who are at extraordinarily high risk of the infection. Patients with a halo sign at baseline are more likely to have a satisfactory treatment response than those without this indicator.

PMID 16110807  Med Mycol. 2005 May;43 Suppl 1:S147-54.
著者: J A Horvath, S Dummer
雑誌名: Am J Med. 1996 Feb;100(2):171-8.
Abstract/Text PURPOSE: To define the role of lower-respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised hosts.
METHODS: Immunocompromised patients with a positive, nonbiopsy, lower-respiratory-tract culture for Aspergillus species were classified as having definite, probable, indeterminate, or no IPA. Culture data, positive predictive values (PPVs), correlation with clinical and radiographic findings, and the relationship between the number of specimens submitted and the likelihood of recovering Aspergillus were assessed.
RESULTS: Definite or probable IPA was diagnosed in 72% of episodes from patients with hematologic malignancy, granulocytopenia, or bone-marrow transplant; in 58% of those with solid-organ transplant or using corticosteroids; and in 14% of those with human immunodeficiency virus infection. The PPV of cultures ranged from 14% in the latter group to 72% in the first group (bone-marrow-transplantation subgroup, 82%). Fungal cultures were more often positive than were routine cultures (P < 0.001). Clinical and radiographic findings suggestive of IPA were present more frequently in infected than uninfected patients (59% versus 24%, P < 0.025); and 73% versus 6%, (P < 0.0001, respectively). Infected patients with > or = 1 positive node had more cultures submitted than a control group of patients with no positive cultures (5.8 +/- 4.7 versus 2.1 +/- 2.2 cultures, P < 0.001).
CONCLUSION: Recovery of Aspergillus species from high-risk patients is associated with invasive infection. Clinical and radiographic correlations help to separate true- from false-positive cultures. At least 3 sputum specimens should be submitted for fungal culture whenever fungal infection is suspected.

PMID 8629651  Am J Med. 1996 Feb;100(2):171-8.
著者: Johan Maertens, Koen Theunissen, Eric Verbeken, Katrien Lagrou, Jan Verhaegen, Marc Boogaerts, Johan Van Eldere
雑誌名: Br J Haematol. 2004 Sep;126(6):852-60. doi: 10.1111/j.1365-2141.2004.05140.x.
Abstract/Text The recent advent of an improved commercial serum enzyme-linked immunosorbent assay (ELISA) for the detection of circulating galactomannan (GM), a major constituent of Aspergillus cell walls, has contributed to the diagnosis of invasive aspergillosis (IA) in many haematology and transplant centres. However, the optimal threshold for positivity remains a matter of debate. We prospectively evaluated the impact of lowering the cut-off in 124 neutropenic episodes with a high pretest probability for IA. Two new cut-off points, lower than previously accepted, are proposed: (a) a 'static' cut-off at 0.8 and (b) a 'dynamic' cut-off at 0.5. A single assay with an optical density (OD) index > or = 0.8 warrants the initiation of anti-Aspergillus therapy. A further lowering of the 'static' threshold seems not clinically feasible given the drop in positive predictive value (PPV). However, the demonstration of at least two sequential sera with an OD > or = 0.5 ('dynamic' threshold) increased the specificity and the PPV to 98.6% and the efficiency to 98%. Applying both cut-offs to a subgroup of 21 'possible' fungal infections further identified and upgraded six cases of IA. However, the clinical benefit of lower cut-offs (particularly for earlier diagnosis) depends upon the kinetics of antigenaemia and the intensity of serum sampling.

PMID 15352990  Br J Haematol. 2004 Sep;126(6):852-60. doi: 10.1111/j.1・・・
著者: Mariska M Leeflang, Yvette J Debets-Ossenkopp, Caroline E Visser, Rob J P M Scholten, Lotty Hooft, Henk A Bijlmer, Johannes B Reitsma, Patrick Mm Bossuyt, Christina M Vandenbroucke-Grauls
雑誌名: Cochrane Database Syst Rev. 2008 Oct 8;(4):CD007394. doi: 10.1002/14651858.CD007394. Epub 2008 Oct 8.
Abstract/Text BACKGROUND: Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mycosis in immunocompromized patients. A test for IA needs to be not too invasive and not too big a burden for the already weakened patient. The serum galactomannan ELISA seems to have potential for both requirements.
OBJECTIVES: To obtain summary estimates of the diagnostic accuracy of galactomannan detection in serum for the diagnosis of IA.
SEARCH STRATEGY: We searched MEDLINE, EMBASE and Web of Science with both Medical Headings and text words for both aspergillosis and the sandwich ELISA. We checked reference lists of included studies and review articles for additional studies.
SELECTION CRITERIA: Cross-sectional studies, case-control designs and consecutive series of patients assessing the diagnostic accuracy of galactomannan detection for the diagnosis of IA in patients with neutropenia or patients whose neutrophils are functionally compromised were included. The reference standard was composed of the criteria given by the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG).
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed quality and extracted data
MAIN RESULTS: Thirty studies were included in the meta-analyses, with a median prevalence of IA (proven or probable) of 7.7%. Seven of these (901 patients) reported results for an Optical Density Index (ODI) of 0.5 as cut-off value. The overall sensitivity in these studies was 78% (61% to 89%) and overall specificity was 81% (72% to 88%). Twelve studies (1744 patients) reported the results for cut-off value of 1.0 ODI, overall sensitivity was 75% (59% to 86%) and mean specificity 91% (84% to 95%). Seventeen studies (2600 patients) reported the results for cut-off value 1.5 ODI, sensitivity was 64% (50% to 77%) and mean specificity 95% (91% to 97%).
AUTHORS' CONCLUSIONS: At a cut-off value 0.5 ODI in a population of 100 patients with a disease prevalence of 8% (overall median prevalence), 2 patients who have IA, will be missed (sensitivity 78%, 22% false negatives), and 17 patients will be treated or further referred unnecessarily (specificity of 81%, 19% false negatives). If we use the test at cut-off value 1.5 in the same population, that will mean that 3 IA patients will be missed (sensitivity 64%, 36% false negatives) and 5 patients will be treated or referred unnecessarily (specificity of 95%, 5% false negatives). These numbers should however be interpreted with caution, because the results were very heterogeneous.

PMID 18843747  Cochrane Database Syst Rev. 2008 Oct 8;(4):CD007394. do・・・
著者: Christopher D Pfeiffer, Jason P Fine, Nasia Safdar
雑誌名: Clin Infect Dis. 2006 May 15;42(10):1417-27. doi: 10.1086/503427. Epub 2006 Apr 14.
Abstract/Text BACKGROUND: A double-sandwich enzyme-linked immunosorbent galactomannan assay has been approved for surveillance for invasive aspergillosis in immunocompromised patients. We undertook a meta-analysis to assess the accuracy of a galactomannan assay for diagnosing invasive aspergillosis.
METHODS: Studies of the galactomannan assay that used the European Organization for Research and Treatment of Cancer or similar criteria as a reference standard and provided data to calculate sensitivity and specificity were included. Pooled sensitivity and specificity and summary measures of accuracy, Q* (the upper left-most point on the summary receiver-operating characteristic curve), mean D (a log odds ratio), and Youden index were calculated. Subgroup analyses were performed to explore heterogeneity.
RESULTS: Twenty-seven studies from 1966 to 28 February 2005 were included. Overall, the galactomannan assay had a sensitivity of 0.71 (95% confidence interval [CI], 0.68-0.74) and specificity of 0.89 (95% CI, 0.88-0.90) for proven cases of invasive aspergillosis. The Youden index, mean D, and Q* were 0.54 (95% CI, 0.41-0.65), 2.74 (95% CI, 21.12-3.36), and 0.80 (95% CI, 0.74-0.86), respectively, indicating moderate accuracy. Subgroup analyses showed that the performance of the test differed by patient population and type of reference standard used. Significant heterogeneity was present.
CONCLUSIONS: The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients. The test is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients. Further studies with attention to the impact of antifungal therapy, rigorous assessment of false-positive test results, and assessment of the utility of the test under nonsurveillance conditions are needed.

PMID 16619154  Clin Infect Dis. 2006 May 15;42(10):1417-27. doi: 10.10・・・
著者: O Marchetti, F Lamoth, M Mikulska, C Viscoli, P Verweij, S Bretagne, European Conference on Infections in Leukemia (ECIL) Laboratory Working Groups
雑誌名: Bone Marrow Transplant. 2012 Jun;47(6):846-54. doi: 10.1038/bmt.2011.178. Epub 2011 Sep 19.
Abstract/Text As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); β-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.

PMID 21927034  Bone Marrow Transplant. 2012 Jun;47(6):846-54. doi: 10.・・・
著者: Małgorzata Mikulska, Elisa Furfaro, Valerio Del Bono, Francesca Gualandi, Anna Maria Raiola, Maria Pia Molinari, Paola Gritti, Maurizio Sanguinetti, Brunella Posteraro, Andrea Bacigalupo, Claudio Viscoli
雑誌名: Diagn Microbiol Infect Dis. 2012 Apr;72(4):367-9. doi: 10.1016/j.diagmicrobio.2011.12.009. Epub 2012 Jan 26.
Abstract/Text Galactomannan (GM) is used to diagnose aspergillosis. We present a case of a hematopoietic stem cell transplantation recipient with fusariosis who received early antifungal treatment based on GM positivity. Additionally, 3 Fusarium isolates tested positive for GM. Fusarium is another mold containing GM. GM might be useful for diagnosing fusariosis in high-risk patients.

Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 22280997  Diagn Microbiol Infect Dis. 2012 Apr;72(4):367-9. doi: ・・・
著者: Nam Su Ku, Sang Hoon Han, Jun Yong Choi, Sun Bean Kim, Hye-Won Kim, Su Jin Jeong, Chang Oh Kim, Young Goo Song, June Myung Kim
雑誌名: Scand J Infect Dis. 2012 Aug;44(8):600-4. doi: 10.3109/00365548.2012.657672. Epub 2012 Mar 4.
Abstract/Text BACKGROUND: The serum galactomannan assay (GMA) has been widely used for the diagnosis of invasive aspergillosis (IA). GMA is mainly used in patients with haematological malignancies or in those who have undergone haematopoietic stem cell transplantation (HSCT). However, there are few data from non-haematological patients. We evaluated whether GMA is useful for the diagnosis of IA in non-haematological patients.
METHODS: Patients who were subjected to serum GMA testing from January 2007 to December 2009 were evaluated retrospectively. Patients with haematological diseases or who underwent HSCT were excluded from our analysis. According to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group revised in 2008, the patients were categorized as proven, probable, possible, or non-IA. Proven and probable cases were defined as IA in this study.
RESULTS: Out of 778 patients, 13 (1.6%) had proven (n =9) or probable (n =4) IA. The sensitivity of the GMA was 23.1% (95% confidence interval (CI) 6.1-54.0%) and the specificity was 76.1% (95% CI 72.9-79.0%). The positive predictive value was 1.6% (95% CI 0.4-5.0%) and the negative predictive value was 98.3% (95% CI 96.8-99.1%). The likelihood ratios of a positive and negative test were 0.96 (95% CI 0.35-2.62) and 1.01 (95% CI 0.75-1.36), respectively.
CONCLUSIONS: In this study, the sensitivity of the GMA for the diagnosis of IA was very low in non-haematological patients. Although the GMA test is considered useful for the diagnosis of IA in haematological patients, it had low diagnostic value for IA in non-haematological patients.

PMID 22385270  Scand J Infect Dis. 2012 Aug;44(8):600-4. doi: 10.3109/・・・
著者: Masahito Kawazu, Yoshinobu Kanda, Yasuhito Nannya, Katsunori Aoki, Mineo Kurokawa, Shigeru Chiba, Toru Motokura, Hisamaru Hirai, Seishi Ogawa
雑誌名: J Clin Microbiol. 2004 Jun;42(6):2733-41. doi: 10.1128/JCM.42.6.2733-2741.2004.
Abstract/Text The establishment of an optimal noninvasive method for diagnosing invasive aspergillosis (IA) is needed to improve the management of this life-threatening infection in patients with hematological disorders, and a number of noninvasive tests for IA that target different fungal components, including galactomannan, (1-->3)-beta-d-glucan (BDG), and Aspergillus DNA, have been developed. In this study, we prospectively evaluated the diagnostic potential of three noninvasive tests for IA that were used in a weekly screening strategy: the double-sandwich enzyme-linked immunosorbent assay (ELISA) for galactomannan (Platelia Aspergillus), a real-time PCR assay for Aspergillus DNA (GeniQ-Asper), and an assay for BDG (beta-glucan Wako). We analyzed 149 consecutive treatment episodes in 96 patients with hematological disorders who were at high risk for IA and diagnosed 9 proven IA cases, 2 probable IA cases, and 13 possible invasive fugal infections. In a receiver-operating characteristic (ROC) analysis, the area under the ROC curve was greatest for ELISA, using two consecutive positive results (0.97; P = 0.036 for ELISA versus PCR, P = 0.055 for ELISA versus BDG). Based on the ROC curve, the cutoff for the ELISA could be reduced to an optical density index (O.D.I.) of 0.6. With the use of this cutoff for ELISA and cutoffs for PCR and BDG that give a comparable level of specificity, the sensitivity/specificity/positive predictive value/negative predictive value of the ELISA and the PCR and BDG tests were 1.00/0.93/0.55/1.00, 0.55/0.93/0.40/0.96, and 0.55/0.93/0.40/0.96, respectively. In conclusion, among these weekly screening tests for IA, the double-sandwich ELISA test was the most sensitive at predicting the diagnosis of IA in high-risk patients with hematological disorders, using a reduced cutoff of 0.6 O.D.I.

PMID 15184460  J Clin Microbiol. 2004 Jun;42(6):2733-41. doi: 10.1128/・・・
著者: Kieren A Marr, Rachel A Carter, Michael Boeckh, Paul Martin, Lawrence Corey
雑誌名: Blood. 2002 Dec 15;100(13):4358-66. doi: 10.1182/blood-2002-05-1496. Epub 2002 Aug 22.
Abstract/Text The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation ( 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s.

PMID 12393425  Blood. 2002 Dec 15;100(13):4358-66. doi: 10.1182/blood-・・・
著者: Andrew H Limper, Kenneth S Knox, George A Sarosi, Neil M Ampel, John E Bennett, Antonino Catanzaro, Scott F Davies, William E Dismukes, Chadi A Hage, Kieren A Marr, Christopher H Mody, John R Perfect, David A Stevens, American Thoracic Society Fungal Working Group
雑誌名: Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128. doi: 10.1164/rccm.2008-740ST.
Abstract/Text With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.

PMID 21193785  Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128. do・・・
著者: Thomas J Walsh, Elias J Anaissie, David W Denning, Raoul Herbrecht, Dimitrios P Kontoyiannis, Kieren A Marr, Vicki A Morrison, Brahm H Segal, William J Steinbach, David A Stevens, Jo-Anne van Burik, John R Wingard, Thomas F Patterson, Infectious Diseases Society of America
雑誌名: Clin Infect Dis. 2008 Feb 1;46(3):327-60. doi: 10.1086/525258.
Abstract/Text
PMID 18177225  Clin Infect Dis. 2008 Feb 1;46(3):327-60. doi: 10.1086/・・・
著者: Raoul Herbrecht, David W Denning, Thomas F Patterson, John E Bennett, Reginald E Greene, Jörg-W Oestmann, Winfried V Kern, Kieren A Marr, Patricia Ribaud, Olivier Lortholary, Richard Sylvester, Robert H Rubin, John R Wingard, Paul Stark, Christine Durand, Denis Caillot, Eckhard Thiel, Pranatharthi H Chandrasekar, Michael R Hodges, Haran T Schlamm, Peter F Troke, Ben de Pauw, Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group
雑誌名: N Engl J Med. 2002 Aug 8;347(6):408-15. doi: 10.1056/NEJMoa020191.
Abstract/Text BACKGROUND: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis.
METHODS: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome.
RESULTS: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients).
CONCLUSIONS: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B.

Copyright 2002 Massachusetts Medical Society
PMID 12167683  N Engl J Med. 2002 Aug 8;347(6):408-15. doi: 10.1056/NE・・・
著者: Jose A Vazquez
雑誌名: Clin Infect Dis. 2008 Jun 15;46(12):1889-901. doi: 10.1086/588475.
Abstract/Text In general, mortality rates associated with systemic fungal infections have not improved much in more than a decade, although the number of antifungal agents available for the treatment of serious fungal infections has increased in the past few years. A possible approach to decreasing mortality rates associated with fungal infections may be to treat patients with combinations of different classes of antifungals. Recently, in vitro and animal studies evaluating different combinations of antifungal agents have demonstrated important synergistic and/or additive activity against many genera of fungi. However, prudence is required, because some antifungal combinations have demonstrated antagonistic activity. Well-controlled clinical trials are still necessary to define the most efficacious antifungal combination. In addition, these clinical trials should evaluate the adverse event profile of the combination regimens, as well as their pharmacoeconomic impact.

PMID 18466092  Clin Infect Dis. 2008 Jun 15;46(12):1889-901. doi: 10.1・・・
著者: Peter F Troke, Hans P Hockey, William W Hope
雑誌名: Antimicrob Agents Chemother. 2011 Oct;55(10):4782-8. doi: 10.1128/AAC.01083-10. Epub 2011 Jul 18.
Abstract/Text Voriconazole is approved for treating invasive fungal infections. We examined voriconazole exposure-response relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (C(avg)) and clinical response and between the free C(avg)/MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P < 0.001), therapy (primary/salvage, P < 0.001), primary diagnosis (P < 0.001), race (P = 0.004), baseline bilirubin (P < 0.001), baseline alkaline phosphatase (P = 0.014), and pathogen (yeast/mold, P < 0.001). The C(avg) for 72% of the patients was 0.5 to 5.0 μg/ml, with the maximum response rate (74%) at 3.0 to 4.0 μg/ml. The C(avg) showed a nonlinear relationship to response (P < 0.003), with a lower probability at the extremes. For patients with C(avg) < 0.5 μg/ml, the response rate was 57%. The lowest response rate (56%) was seen with a C(avg) ≥ 5.0 μg/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P < 0.001) but not with voriconazole toxicity. Higher free C(avg)/MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes of C(avg). Patients with higher free C(avg)/MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.

PMID 21768513  Antimicrob Agents Chemother. 2011 Oct;55(10):4782-8. do・・・

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