渡辺 哲

The lungs are known to be a major focus of infection by various fungi as they are an important port of entry for the same. Among them, Aspergillus and Cryptotococcus are the most well-known, but many other fungi can cause pulmonary infection. The causative agents of these "rare" pulmonary mycoses include zygomycetes such as Rhizopus spp. along with Cunnnighamella bertholletiae, Schizophyllum commune, and Coccidioides immitis. Although no official data on their epidemiology is present, the prevalence of these diseases is considered to be on the rise. Each disease has its own characteristic pathophysiology, and requires specific diagnostic and therapeutic measures.

肺真菌症としてはアスペルギルス症、クリプトコックス症がよく知られているが、深在性真菌症の多くは経気道感染であることから、実際には肺は極めて多種の真菌による感染の標的となる。本稿ではまれな肺真菌症として接合菌症、スエヒロタケ感染症(ABPM)、輸入真菌症の代表としてのコクシジオイデス症を取り上げたが、それ以外にも数多くの疾患が知られている。明確な統計が存在しないものの、それらの頻度の増加や多様化はここ数年専門家の間で共通に認識されている。それぞれ病態や診断法、治療法に特色があるため、十分な理解が望まれる。(著者抄録)

Gliotoxin is an important virulence factor of Aspergillus fumigatus. Although GliA putatively belongs to the major facilitator superfamily in the gliotoxin biosynthesis cluster, its roles remain unclear. To determine the function of GliA, we disrupted gliA in A. fumigatus. gliA disruption increased the susceptibility of A. fumigatus to gliotoxin. The gliT and gliA double-disrupted mutant had even higher susceptibility to gliotoxin than each individual disruptant. The extracellular release of gliotoxin was greatly decreased in the gliA disruptant. Mice infected with the gliA disruptant of A. fumigatus showed higher survival rates than those infected with the parent strain. These results strongly indicate that GliA, in addition to GliT, plays a significant role in the tolerance to gliotoxin and protection from extracellular gliotoxin in A. fumigatus by exporting the toxin. This also allows the fungus to evade the harmful effect of its own gliotoxin production. Moreover, GliA contributes to the virulence of A. fumigatus through gliotoxin secretion.

国内で感染する深在性真菌症と異なり、海外では健常人でも感染し得る強力な真菌が存在する。一般の旅行者でも感染の頻度が高い疾患としてコクシジオイデス症、ヒストプラスマ症、ガッティ型クリプトコックス症が挙げられ、各疾患により流行地が異なる。いずれも症状は非特異的であるため確定診断にいたるためにはまず主治医が詳細な渡航歴を聴取したうえでこれらの疾患を疑うことが重要である。また原因菌は極めて感染力が強く危険であるため、一般医療機関におけるような通常の微生物検査室では培養を行わず専門機関に相談・依頼するべきである。なお、人種により原因菌に対する感受性が異なるものも知られており、一概に海外のガイドラインを盲信すべきではない。(著者抄録)

Azole resistance among clinical isolates of Aspergillus fumigatus is becoming a serious problem in Europe, but the status in Japan is not yet known in detail. The aim of this study was to determine the present status of azole resistance in A. fumigatus in Japan. We employed 171 clinical isolates of A. fumigatus sensu stricto collected from 1987 to 2008 at the Medical Mycology Research Center, Chiba University, Japan for azole resistance determination. Identification of all isolates were re-examined both from the aspect of morphology and molecular phylogeny. The antifungal susceptibility of these isolates was tested based on the CLSI M38-A2 broth microdilution method. In our collection, only 1 (0.6%) and 2 isolates (1.2%) showed elevated MIC to voriconazole and itraconazole, respectively. Our study disclosed that the frequency of azole resistance in A. fumigatus still remains low in this collection. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Biofilm production by microorganisms is critical for their pathogenicity. Serum promotes biofilm production by Aspergillus fumigatus; however, its effects on other Aspergillus spp. have not been reported. We analyzed biofilm formation by five Aspergillus spp., i.e., A. fumigatus, A. flavus, A. nidulans, A. niger, and A. terreus, and examined the effects of serum/serum proteins such as fetal bovine serum (FBS), fetuin A, and bovine serum albumin (BSA) on hyphal growth, hyphal branching, and extracellular matrix (ECM) formation. The antifungal susceptibility of A. fumigatus isolates that formed biofilms was also examined. All serum/serum proteins promoted the growth of all these fungal species; growth promotion was most evident with FBS, followed by fetuin A and BSA. This effect was most evident in case of A. fumigatus and least evident in case of A. terreus. Electron microscopy showed thick ECM layers surrounding fungal cell walls after culture with FBS, particularly in A. fumigatus. An increase in hyphal branching caused by fetuin A was the highest in case of A. fumigatus and A. nidulans. Biofilm-forming A. fumigatus showed resistance to most antifungal agents, although a synergism of micafungin and amphotericin B was suggested. Our results indicate that serum promotes biofilm formation, including thick ECM, by many Aspergillus spp., particularly A. fumigatus, and that this may be closely related to its virulence.

輸入真菌症の症例数は増加しており、今後もその状況は続くと予想される。我が国においてはコクシジオイデス症、ヒストプラスマ症の患者数が多く、これらの疾患は今後一般医療機関でも遭遇する可能性が高まってくると考えられる。また、近年マルネッフェイ型ペニシリウム症の報告数が増加していることに注意が必要である。いずれの疾患も診断の足がかりとなるのは詳細な渡航歴の聴取である。加えて医療安全の観点から、主治医と検査室との密接な連携が必須であることを強調したい。(著者抄録)

Background: Schizophyllum commune is one of the causative agents of basidiomycosis including disorders such as allergic bronchopulmonary mycosis, allergic fungal sinusitis, and mucoid impaction of bronchi, the incidence of those of which has been increasing. These mycoses are difficult to diagnose because only a limited number of diagnostic tools are currently available. The biggest problem is that no specific antigens of S. commune have been identified to enable serodiagnosis of the disease. Objective: In this study, we attempted to identify a major antigen of S. commune to establish a reliable serodiagnostic method. Methods: We used mass spectrometry to identify an antigen that reacted with the serum of a patient with allergic bronchopulmonary mycosis caused by S. commune. The protein was expressed in Escherichia coli, highly purified, and the patient sera IgG and IgE titres against the protein were determined by enzyme-linked immunosorbent assay. Results: The protein identified as a major antigen of S. commune was named Sch c 1 it was a homolog of glucoamylase. The IgG and IgE titres against Sch c 1 in patient sera were significantly higher than those in healthy volunteer sera (P &lt 0.01). Conclusions and Clinical Relevance: Sch c 1 is recognized by the host immune system of patients as an antigen/allergen. The purified glucoamylase Sch c 1 is a promising candidate antigen for the serodiagnosis of S. commune-induced mycosis. © 2013 John Wiley &amp Sons Ltd.

輸入真菌症は真菌症のなかでも感染力・病原性とも抜群に高く,特殊な疾患という認識が必要である.原因菌の多くはコロニーを見ただけでは一般の真菌と鑑別が困難なことから培養による感染事故が多く,培養に頼らない診断手順をまず考える必要がある.疾患に関する知識に加えて,流行地への旅行歴の綿密な確認と診療科-検査部の緻密な連絡が大切である.(著者抄録)

Background: Treatment with systemic corticosteroids is often used for acute liver failure (ALF), but this has increased the number of profoundly immunocompromised patients and cases of opportunistic infection. Methods: Between January 2007 and December 2012, all patients (n = 51) referred to the Chiba University Hospital for treatment of ALF were studied. Patients with prothrombin activity of 40 % or less of the standardized values were defined as having ALF. Patient age, sex, cause of ALF, alanine aminotransferase and total bilirubin levels, prothrombin activity and total amount of corticosteroid were analyzed to determine the factors associated with the occurrence of opportunistic infection. Results: Opportunistic infections occurred in 21.6 % (n = 11) of ALF patients. Thirty-five patients underwent systemic corticosteroid therapy, and 31.4 % of those patients showed opportunistic infections. Cytomegalovirus (n = 9, 81.8 %) and Pneumocystis jiroveci (n = 6, 54.5 %) were the microorganisms frequently suspected as the causes of opportunistic infection. In 7 (63.6 %) of the 11 cases of opportunistic infection, 2 or more species of microorganism were detected. Seven patients (63.6 %) with opportunistic infection were cured by treatment. Cox regression analysis for the patients who underwent systemic corticosteroid therapy steroid treatment revealed that age over 52 years (compared to younger patients: odds ratio = 9.62, 95 % confidence interval = 1.22-76.9) was only the predictive factor for the occurrence of opportunistic infection. Conclusion: Opportunistic infections are not rare in ALF patients, and the appropriate diagnosis and treatment of these infections are critical during ALF treatment. © 2014 Asian Pacific Association for the Study of the Liver.

Mucormycosis is an increasingly important cause of morbidity and mortality for patients with hematological malignancies. The diagnosis of mucormycosis usually requires mycological evidence through tissue biopsy or autopsy because the signs and symptoms are nonspecific and there are currently no biomarkers to identify the disease. We herein present two autopsied cases of acute myeloid leukemia with prolonged neutropenia who developed invasive mucormycosis accompanied by pulmonary artery embolism. Our cases were featured by unexplained fever and rapidly progressive dyspnea. Computed tomography scan detected nodular lesions or nonspecific consolidations in the lungs. Cultures, cytological study, and serum fungal markers consistently gave negative results. Autopsy revealed embolism of the pulmonary artery which consisted of fibrin clots by filamentous fungi. Genomic DNA was extracted from the paraffin-embedded clots and was applied to polymerase chain reaction amplification, leading to the diagnosis of infection by Rhizopus microsporus. We should carefully search for life-threatening pulmonary embolism when patients with hematological malignancies develop pulmonary mucormycosis.

輸入真菌症は真菌症のなかでも感染力・病原性とも抜群に高く、特殊な疾患という認識が必要である。原因菌の多くは形態学的には識別が困難で、検査中の感染事故を防ぐためにも正しい理解が必要である。(著者抄録)

76歳,男性.初診日1ヵ月前に屋外で転倒し左母指を受傷した.左母指の基部に辺縁が周堤状に隆起し,中央に潰瘍を伴う結節を認めた.潰瘍部を生検したところ,真皮間質にPAS染色陽性の淡紅色の円形構造物を多数認め,真菌培養によりCryptococcus neoformansを同定し,皮膚クリプトコッカス症と診断した.イトラコナゾール内服にて消長を繰り返しつつ徐々に軽快した.外傷を契機に発症したため,一見原発性を疑うが,胸部X線にて左下肺に陰影を認めたこと,単発性でなく外傷部以外にも紅斑局面を生じ,そこからも同じ菌が検出されたこと,病理組織像にて炎症細胞浸潤に乏しく,肉芽腫形成のないゼラチン状と称される所見であることなどより続発性と考えた.(著者抄録)

トロピカルディジーズの中では真菌感染症は比較的目立たない存在である。ヒト-ヒト感染がないこと、劇的で急速な経過をとる症例が少ないことなどがその理由と考えられる。しかし、わが国における症例は確実に増加を続け、コクシジオイデス症は72例、ヒストプラズマ症は75例に達していること、本症の多くが一歩間違うと致死的な疾患であること、さらに検査中の感染事故が多いことなどを考慮すると、もはや、どの医療機関でも無視しえない疾患となった。健常人でも容易に感染すること、全身播種をともないやすいこと、そして他疾患と紛らわしく、誤認の原因となりやすいことなどを考え、十分な知識をもち、準備を整えておくことが求められている。(著者抄録)

アスペルギルス症は患者の免疫状態や基礎疾患により病型が異なる。感染様式は経気道的であり、通常は肺に限局した病変を形成するがときに他臓器への播種を起こすこともある。主な病型として高度な免疫低下宿主に発症する侵襲性肺アスペルギルス症、主として肺に基礎疾患を有する患者に発症する慢性肺炎アスペルギルス症がある。診断は困難である例が多いため、確定診断に至る前に経験的治療あるいは推定治療がしばしば選択される。原則として抗真菌薬による治療が行われるが、病変が限局している場合は外科的切除も考慮される。(著者抄録)