Pulmonary mycosis

Japanese: 肺真菌症

Pulmonary mycosis is a deep-seated mycosis caused by fungi. The causative fungi are mainly transmitted via the respiratory tract. The most frequent diseases in Japan are pulmonary aspergillosis and pulmonary cryptococcosis. The incidence of Pneumocystis pneumonia is high in patients infected with human immunodeficiency virus (HIV). In recent years, there are also imported mycoses that require caution when traveling abroad.
(1) Pulmonary aspergillosis
Concept: A general term for respiratory diseases caused by inhaling conidia of the Aspergillus genus. The Aspergillus genus is widely present in nature as airborne bacteria indoors and as food contaminants. Aspergillus fumigatus accounts for the majority of the bacterial species that cause respiratory diseases.
Disease type and clinical symptoms The following disease types occur depending on the host's immune system and existing pulmonary lesions.
1) Invasive pulmonary aspergillosis (IPA):
The risk factor for the disease is a decrease in neutrophil function. It is most common in patients with acute leukemia, hematopoietic stem cell transplantation, anticancer chemotherapy, and chronic sarcomatous disease. It can also develop during the administration of corticosteroids or immunosuppressants. Clinical symptoms include fever, cough, and chest pain that do not respond to broad-spectrum antibiotics, and may be accompanied by hemoptysis and hemoptysis. It may progress to a disseminated infection that spreads to the central nervous system, heart, etc. Chest X-ray findings in the early stages of infection often show single or multiple nodular shadows. Chest CT scans show a halo sign (ground-glass shadow surrounding a circular shadow) in approximately one-third of cases. It may also show a wedge-shaped shadow with its base on the chest wall. Over time, infiltrative shadows appear, and imaging findings make it impossible to distinguish this from other infections, such as bacterial infections. When neutrophil function is restored, neutrophils process necrotic tissue and form a crescent-shaped cavity (air-crescent sign) with a round shadow inside (necrotic lung ball) (Figure 7-2-17).
2) Chronic pulmonary aspergillosis (CPA): This is a chronic infection in which the Aspergillus genus invades the lower respiratory tract of patients with existing pulmonary lesions, colonizes the area in a saprophytic manner, or invades the surrounding lung tissue. Existing lesions are often cavitary lesions such as old pulmonary tuberculosis, nontuberculous mycobacterial disease, chronic obstructive pulmonary disease, interstitial pneumonia, bronchiectasis, and lesions following thoracic surgery. In typical cases, fungus balls that move within the cavity depending on the patient's position are observed. Aspergilloma is a condition in which there is only saprophysis and no invasive infection, whereas chronic necrotizing pulmonary aspergillosis (CNPA) is a condition in which there is thickening of the cavity wall or infiltrative shadows around the cavity, and there is active infection such as cough, sputum, bloody sputum, fever, and weight loss. Pulmonary aspergilloma and CNPA are collectively referred to as CPA, as they are a series of diseases that depend on the host's immune function. CNPA often occurs in the background of a weakened host immune function due to the administration of corticosteroids, diabetes mellitus, malnutrition, etc.
3) Allergic bronchopulmonary aspergillosis:
This disease is caused by type I, III, or IV allergy to inhaled Aspergillus, and is characterized by asthma attacks and mobile or fixed pulmonary infiltrates (for details, see [⇨7-4-2)]).
Diagnosis Pulmonary aspergillosis should be suspected when at-risk patients develop respiratory symptoms such as fever, cough, and bloody sputum that do not respond to broad-spectrum antibiotics.
1) Definitive diagnosis:
Aspergillus is isolated from sputum or bronchial washings, or fungal components are pathologically proven by cytology or histology.
2) Clinical diagnosis:
Clinical diagnosis of IPA is made based on typical chest X-ray findings and detection of Aspergillus (galactomannan) antigen and β-d-glucan in serum.
In approximately 90% of cases of CPA, serum Aspergillus antibodies are positive. Unlike IPA, Aspergillus antigens and β-d-glucan may not be positive.
Treatment and prognosis : Antifungal drugs are administered in IPA whether it is a definitive diagnosis or a clinical diagnosis. IPA is the most serious form of pulmonary aspergillosis and has a high mortality rate. Even if a clinical diagnosis has not been made, if IPA is suspected, antifungal drugs are administered. Antifungal drugs are administered prophylactically in patients undergoing hematopoietic stem cell transplantation or high-risk chemotherapy.
If CPA does not cause symptoms, the patient is monitored over time. If there are signs of active infection, such as fever or respiratory symptoms, antifungal drugs are administered. If there is bloody sputum or hemoptysis, the administration of hemostatic drugs and bronchial artery embolization or surgery should be considered. CPA gradually worsens, with periods of remission and exacerbation occurring.
Antifungal drugs should be selected from amphotericin B liposomal preparations, voriconazole, itraconazole, micafungin, or caspofungin.
(2) Pulmonary cryptococcosis
Concept: A respiratory infection caused by the genus Cryptococcus. In Japan, the causative agent is Cryptococcus neoformans.
Disease type and clinical symptoms Depending on the presence or absence of underlying diseases, it is conventionally classified as follows. C. neoformans has a strong affinity for the meninges, and when meningitis develops, symptoms of meningeal irritation such as headache, nausea, vomiting, and neck stiffness are observed.
1) Primary pulmonary cryptococcosis:
Pulmonary cryptococcosis occurs in healthy individuals without underlying diseases. Clinical symptoms are rarely observed, and the disease is often discovered by chance due to abnormalities in medical examinations.
2) Secondary pulmonary cryptococcosis:
Cryptococcosis develops in patients with underlying diseases. These diseases vary, including malignant tumors, renal disease, diabetes, HIV infection, and administration of corticosteroids. Symptoms include cough, phlegm, fever, chest pain, general malaise, and weight loss.
A definitive diagnosis is made by identifying the bacteria in bronchoalveolar lavage fluid or bronchopulmonary biopsy specimens. The C. neoformans capsule in bronchoalveolar lavage fluid and cerebrospinal fluid can be observed by India ink staining. Biopsy reveals cryptococcal organisms in granulomatous and cyst-like lesions. Pathological findings show that the cryptococcal capsule stains red with mucicarmine or PAS staining, blue with Alcian blue staining, and dark brown with Grocott staining.
The serum cryptococcal antigen test is the most reliable serodiagnosis among fungal infections, and if the test is positive, a clinical diagnosis of pulmonary cryptococcosis can be made in conjunction with images and clinical findings, even if the fungus is not confirmed. In addition to blood, cerebrospinal fluid and bronchoalveolar lavage fluid are useful samples for this test. β-d-glucan does not increase in this disease.
Chest X-ray findings vary, including solitary or multiple nodular shadows and pneumonia-like shadows. Nodular shadows are relatively dense and have sharp borders. Pneumonia-like shadows often contain cavities. In general, nodular shadows appear in immunocompetent hosts, whereas pneumonia-like shadows appear in immunocompromised hosts.
Treatment and prognosis: In primary cases, symptoms often do not appear even without treatment. If cellular immunity is extremely impaired, the disease progresses to disseminated infection and the prognosis is poor.
In principle, treatment is given to cases with a clinical or definitive diagnosis of pulmonary cryptococcosis. In primary and mild secondary cases, fluconazole or itraconazole is administered. In severe secondary cases, the above drugs are used in combination with flucytosine. Voriconazole and amphotericin B are also effective. The treatment period is usually three months for primary cases and six months for secondary cases, but may be longer if the disease develops as an opportunistic infection. It takes a long time for cryptococcal antigen titers to become negative, so this is not an indication of when to end treatment.
(3) Pneumocystis pneumonia (PCP)
Pneumonia caused by Pneumocystis jiroveci. It is an opportunistic infection that frequently occurs in HIV patients, and often develops when the peripheral blood CD4 lymphocyte count is below 200/μL. In non-HIV patients, it develops in those receiving corticosteroids (for details, see [⇨ 4-14-7)].
(4) Pulmonary zygomycosis/pulmonary mucormycosis
This refers to zygomycosis that develops in the lungs. Since the lungs are often infected by Mucorales organisms, it is also called pulmonary mucormycosis (for details, see [⇨ 4-14-4)].
(5) Imported mycosis: Infections caused by fungi that do not inhabit Japan, contracted in endemic areas overseas and occurring in Japan. Representative pulmonary mycoses include coccidioidomycosis, histoplasmosis, and gattii-type cryptococcosis. Travel to endemic areas is important in the medical history (for details, see [⇨ 4-14-6)]). [Tokimatsu Kazunari]
■ References <br /> Edited by the Committee for the Preparation of Guidelines for the Use of Antifungal Drugs for Deep Mycoses for General Medical Professionals, Japan Chemotherapy Society: Guidelines for the Use of Antifungal Drugs, Kyorinsha, Tokyo, 2009.
Compiled by the Committee for the Preparation of Guidelines for Deep Mycoses: Diagnosis and Treatment Guidelines for Deep Mycoses 2007, Kyowa Kikaku, Tokyo, 2007.

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

肺真菌症は真菌を原因とする深在性真菌症のことである．原因となる真菌は主として経気道的に感染する．わが国で頻度の多い疾患は肺アスペルギルス症と肺クリプトコックス症である．ヒト免疫不全ウイルス（HIV）感染患者ではニューモシスチス肺炎の罹患率が高い．近年，海外渡航先で感染する輸入真菌症にも注意すべき疾患がある．
（1）肺アスペルギルス症（pulmonary aspergillosis）
概念
　アスペルギルス属の分生子を吸入して生じた呼吸器疾患の総称である．アスペルギルス属は，室内の空中浮遊菌や食品の汚染菌として自然界に広く存在している．呼吸器疾患の原因菌種ではAspergillus fumigatusが多数を占めている．
病型・臨床症状
　宿主の免疫能や既存の肺病変により以下の病型を呈する．
1）侵襲性肺アスペルギルス症（invasive pulmonary aspergillosis：IPA）：
発症の危険因子は好中球機能の低下である．急性白血病，造血幹細胞移植，抗癌化学療法，慢性肉腫症患者に好発する．副腎皮質ステロイド薬や免疫抑制薬の投与中にも発症する．臨床症状は広域抗菌薬に反応しない発熱，咳，胸痛などで，喀血や血痰を伴うことがある．中枢神経，心臓などに感染が及ぶ播種性感染症に進展することがある．感染症初期の胸部X線所見では，単発あるいは多発の結節陰影を呈することが多い．胸部CTでは約1/3にハローサイン（halo sign：円形陰影周囲のすりガラス陰影）を認める．また，胸壁側を底とする楔形陰影を呈することがある．経過とともに浸潤影を呈し，画像所見では細菌などほかの感染症との区別はできない．好中球機能が回復すると，好中球が壊死した組織を処理し，内部に円形陰影（necrotic lung ball）を伴う三日月状の空洞（air-crescent sign）を形成する（図7-2-17）．
2）慢性肺アスペルギルス症（chronic pulmonary aspergillosis：CPA）： 肺に既存病変が存在する患者の下気道に，アスペルギルス属が侵入し，腐生的に定着，あるいは周囲の肺組織に侵襲していく慢性感染症のことである．既存病変には陳旧性肺結核症，非結核性抗酸菌症，慢性閉塞性肺疾患，間質性肺炎，気管支拡張症，胸部外科手術後などの空洞性病変が多い．典型例では空洞内に体位で移動する真菌球（fungus ball）を認める．腐生のみで侵襲的な感染症がないものを肺アスペルギローマ（pulmonary aspergilloma），空洞壁の肥厚や空洞周囲の浸潤影を伴い，咳・痰・血痰・発熱・体重減少などの感染症としての活動性を有するものを，慢性壊死性肺アスペルギルス症（chronic necrotizing pulmonary aspergillosis：CNPA）とよぶ．これらは宿主の免疫能に応じた一連の疾患であるとして，肺アスペルギローマとCNPAを総じてCPAとよぶ．CNPAは副腎皮質ステロイド薬の投与や糖尿病の合併，低栄養状態など宿主の免疫能の低下を背景に有することが多い．
3）アレルギー性気管支肺アスペルギルス症（allergic bronchopulmonary aspergillosis）：
吸入したアスペルギルス属に対するⅠ型およびⅢ型，Ⅳ型アレルギーにより発症する疾患で，喘息発作や移動性または固定性の肺浸潤影を特徴とする（詳細は【⇨7-4-2）】）．
診断
　発症リスクを有する患者に，広域抗菌薬投与に反応しない発熱や咳，血痰などの呼吸器症状が出現したときには，肺アスペルギルス症を疑う．
1）確定診断：
痰や気管支洗浄液からアスペルギルス属を分離するか，細胞診や組織診で真菌の菌体成分を病理学的に証明する．
2）臨床診断：
IPAでは典型的な胸部X線像や，血清中のアスペルギルス（ガラクトマンナン）抗原，β-d-グルカンの検出から臨床診断を行う．
　CPAでは血清中のアスペルギルス抗体が約90％で陽性となる．IPAと異なり，アスペルギルス抗原やβ-d-グルカンが陽性化しないこともある．
治療・予後
　IPAでは確定診断・臨床診断のいずれも抗真菌薬を投与する．IPAは肺アスペルギルス症の中で最も重篤な病型であり，死亡率も高い．臨床診断に至らずとも，IPAを疑えば，抗真菌薬を投与する．造血幹細胞移植例やハイリスク化学療法例では，抗真菌薬の予防投与が行われている．
　CPAでは症状がなければ経過観察を行う．発熱や呼吸器症状など，感染症としての活動性があれば抗真菌薬を投与する．血痰や喀血があれば，止血薬投与や気管支動脈塞栓術，手術適応を考慮する．CPAは寛解・増悪を繰り返しながら徐々に悪化していく．
　抗真菌薬は，アムホテリシンBリポソーマル製剤やボリコナゾール，イトラコナゾール，ミカファンギン，カスポファンギンのいずれかを選択する．
（2）肺クリプトコックス症（pulmonary cryptococcosis）
概念
　クリプトコックス属によって起きる呼吸器感染症で，わが国ではCryptococcus neoformansが原因である．
病型・臨床症状
　基礎疾患の有無により慣用的に以下に分類する．C. neoformansは髄膜への親和性が強く，髄膜炎を発症すると，頭痛，悪心，嘔吐と項部硬直などの髄膜刺激症状を認める．
1）原発性肺クリプトコックス症：
基礎疾患を有していない健常者に発症した肺クリプトコックス症．臨床症状を認めることは少なく，検診異常で偶然に発見されることが多い．
2）続発性肺クリプトコックス症：
基礎疾患を有する患者に発症したクリプトコックス症．悪性腫瘍，腎疾患，糖尿病，HIV感染症，副腎皮質ステロイド薬投与中など，基礎疾患はさまざまである．症状は，咳，痰，発熱，胸痛，全身倦怠感，体重減少などである．
診断
　確定診断は気管支肺胞洗浄液や気管支肺生検検体からの菌体の確認による．肺胞洗浄液や髄液中のC. neoformansの莢膜は墨汁染色により観察される．生検では肉芽腫性病変や囊胞様病変のなかにクリプトコックス菌体を認める．病理所見ではクリプトコックスの莢膜はムチカルミン染色やPAS染色で赤く，アルシアンブルー染色で青く，Grocott染色では黒褐色に染色される．
　血清中のクリプトコックス抗原検査は，真菌症の中でも最も血清診断の信頼性が高く，陽性の場合は菌体が確認されなくても，画像や臨床所見とあわせて，肺クリプトコックス症と臨床診断される．本検査は血液のほか髄液，気管支肺胞洗浄液が検体として有用である．本症ではβ-d-グルカンは上昇しない．
　胸部X線所見は，孤立あるいは多発結節影，肺炎様陰影など多彩である．結節状陰影は比較的濃く境界鮮明である．肺炎様陰影は空洞を伴うことが多い．一般に，免疫能が保たれた宿主では結節状となり，免疫不全宿主では肺炎様の陰影となる．
治療・予後
　原発性では無治療でも症状の出現がないことも多い．細胞性免疫能がきわめて低下していると播種性感染症へと進展し予後が不良となる．
　肺クリプトコックス症では原則として臨床診断あるいは確定診断された例に治療を行う．原発性および軽症の続発性症例では，フルコナゾール，またはイトラコナゾールを投与する．重症の続発性症例では，上記薬にフルシトシンを併用する．ボリコナゾールやアムホテリシンBも有効である．治療期間は，通常，原発性では3カ月間，続発性では6カ月間であるが，日和見感染症として発症した場合は長期に及ぶことがある．クリプトコックス抗原価が陰性になるには長期間を要するため治療終了の目安にはならない．
（3）ニューモシスチス肺炎（ Pneumocystis pneumonia：PCP）
　 Pneumocystis jiroveciによる肺炎である．HIV患者に高頻度に合併する日和見感染症で，末梢血のCD4リンパ球数が200/μL以下で発症することが多い．非HIV 患者では副腎皮質ステロイド薬投与中の患者において発症する（詳細は【⇨ 4-14-7）】）．
（4）肺接合菌症（ pulmonary zygomycosis）/ 肺ムーコル症（ pulmonary mucormycosis）
　肺に発症した接合菌症のこと．肺にはムーコル目による感染が多いため，肺ムーコル症ともよばれる（詳細は【⇨ 4-14-4）】）．
（5）輸入真菌症
　日本国内に生息しない真菌による感染症で，海外の流行域で感染し日本で発病がみられたものをいう．代表的な肺真菌症では，コクシジオイデス症，ヒストプラズマ症，ガッティ型クリプトコックス症がある．流行地域への渡航が問診上重要である（詳細は【⇨ 4-14-6）】）．［時松一成］
■文献
本化学療法学会「一般医療従事者のための深在性真菌症に対する抗真菌薬使用ガイドライン作成委員会」編：抗真菌薬使用ガイドライン，杏林舎，東京，2009.
深在性真菌症のガイドライン作成委員会編：深在性真菌症の診断・治療ガイドライン2007，協和企画，東京，2007.

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