Chronic Necrotizing Pulmonary Aspergillosis Following Cryptococcal Infection of the Lung

Case Reports 393 Chronic necrotizing pulmonary aspergillosis following cryptococcal infection of the lung

TAKESHI KITAZAKI1, MITSUHIKO OSUMI2, YOSHITSUGU MIYAZAKI1, CHIHARU KIHARA2, AKITOSHI KINOSHITA2, HIROHARU TSUJI3, MASAHIRO ITOH4, HIROSHI SODA1 & SHIGERU KOHNO1,5

From the 1Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, 2Internal Medicine of National Nagasaki Medical Center, Nagasaki, 3Thoracic Surgery of National Nagasaki Medical Center, 4Pathology of National Nagasaki Medical Center, 5Division of Molecular and Clinical Microbiology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan

Abstract A 64-y-old male with steroid-induced diabetes mellitus was admitted to our hospital because of a nodular shadow found by chest radiography. Pathological examination revealed pulmonary cryptococcosis, and he was positive for serum Cryptococcus antigen. After oral treatment with fluconazole, he experienced clinical and radiographic improvement, but during ensuing observation without antifungal treatment his respiratory symptoms gradually worsened. Chest radiography showed progressive infiltration around the cavity, and Aspergillus mold was isolated by transbronchial lung biopsy from the lesion where previous cryptococcal infection was present. In addition, serum antibodies to Aspergillus antigens were demonstrated by immunodiffusion. Thus, pulmonary aspergillosis was found to complicate a case of pulmonary cryptococcal infection.

Introduction any respiratory infectious symptoms. The results of a blood analysis were normal, showing a white blood Aspergillosis is caused by the mold Aspergillus, and cell (WBC) count of 7400/ml with 65.8% neutro- aspergilloma usually occurs in a pulmonary cavity or phils. However, his C-reactive protein (CRP) value ectatic bronchus that develops after the occurrence was elevated to 141.5 mg/l. In addition, his Human of a previous pulmonary disease such as tuberculo- T-cell lymphotropic virus (HTLV)-I antibody was sis, sarcoidosis or cystic fibrosis. negative, and human immunodeficiency virus (HIV) Chronic necrotizing pulmonary aspergillosis antibody was not tested. A chest radiograph showed (CNPA) was originally described as a semi-invasive a solitary nodular shadow with cavity in the left type of infection [1,2], involving indolent but upper lung field. A chest computed tomography progressive infection of the lung and resulting in showed a cavity with a thin wall of 2 cm in diameter local invasion by Aspergillus mold. Denning et al. in S12, but no pleural effusion or lymphadenopathy proposed a classification of chronic forms of asper- (Figure 1A). Serum glucuronoxylomannan, a cryp- gillosis, which involves 3 categories: CNPA, chronic tococcal antigen (Serodirect† ‘Eiken’ Cryptococcus, cavity pulmonary aspergillosis (CCPA), and chronic Eiken Chemical Co., Ltd, Tokyo, Japan), was fibrosing pulmonary aspergillosis (CFPA) [3]. We positive and pathologically proved as cryptococcosis here report on a case of CNPA that occurred in a from a specimen taken by transbronchial lung biopsy cured cryptococcal lesion. (TBLB) (Figure 2A). A cerebrospinal fluid sample showed no abnormal findings. Case report The patient was diagnosed with pulmonary cryp- A 64-y-old male was admitted to our hospital tococcosis and treated with oral itraconazole (ITCZ) because of a nodular shadow found on a routine 200 mg daily for a month, but a chest radiograph chest radiograph. He had a history of rheumatoid showed no improvement, and the ITCZ treatment arthritis treated with corticosteroids for 2 y, and had was switched to oral fluconazole (FLCZ) 400 mg steroid-induced diabetes mellitus. He had never daily. Over the 6-months FLCZ treatment, the smoked, never fed animals, and he did not have nodular shadow was improved to just a scarred

Correspondence: S. Kohno, Molecular and Clinical Microbiology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Medical Sciences, Nagasaki 852-8523, Japan. Fax: /81 95 849 7285. E-mail: [email protected]

(Received 18 November 2004; accepted 24 January 2005) ISSN 0036-5548 print/ISSN 1651-1980 online # 2005 Taylor & Francis DOI: 10.1080/00365540510034491 394 Case Reports

Figure 1A. A cavity with a thin wall 2 cm in diameter in S12 was seen. 1B. Progressive inﬁltrative shadow around the cavitary lesion was observed. 1C. Inﬁltration disappeared and a thin-walled cavitary lesion was left. lesion, and his serum Cryptococcus antigen level infection site (Figure 1B). Recurrent exacerbation of became negative. pulmonary cryptococcosis was suspected and oral However, 2 months after the completion of FLCZ, FLCZ was again started. However, his symptoms headache, coughing, yellowish sputum and fever worsened and the pulmonary lesion progressed, so gradually returned. Blood analysis revealed a WBC treatment with intravenous 0.5 mg/kg/d amphotericin count of 10,700/ml with 78.8% neutrophils and his B and 120 mg/kg/d oral flucytosine was started to CRP value was elevated to 111.5 mg/l. A chest replace FLCZ. Since he was negative for serum radiograph showed the presence of a progressive and cryptococcal antigen, a bronchoscopic examination infiltrative shadow around the former cryptococcal was performed 7 d after start of the antifungal

Figure 2A. A globular spore was observed (HE stain). 2B. A fungal body and mycelia were observed (HE stain). Case Reports 395 treatment. Mycelial formation was histopathologi- Voriconazole (VRCZ) is considered the first line cally observed in the TBLB samples, in which antifungal in Aspergillus infection [8]; however necrotic change, fungal bodies, mycelia and oxalic VRCZ is not available in Japan as of December acid calcium were found, thus suggesting Aspergillus 2004, so the common treatment for aspergillosis is niger infection. Cryptococcus or significant bacteria still systemic amphotericin B. ITCZ is an effective were not cultured from the samples. Accordingly, the alternative, but surgical resection could be a promis- patient was diagnosed with Aspergillus infection. ing treatment. Surgery was suspended due to poor Itchy eczema was seen on his back and lower general status in our case. extremities, and renal dysfunction was noted by an The patient was diagnosed with CNPA following increased creatinine value 10 d after the antifungal cryptococcosis. We assume that Aspergillus spores treatment was started. Since we suspected anti-fungal had colonized a preexistent cavitary lesion caused by related toxicoderma and renal dysfunction, both cryptococcal infection, and that Aspergillus infection flucytosine and amphotericin B treatment were dis- then occurred in the same lesion. Only rarely 2 continued. The patient subsequently received 300 different fungi, Cryptococcus and Aspergillus spe- mg/d oral ITCZ, after which both his clinical symp- cies are shown pathologically and mycologically to toms and signs almost disappeared. ITCZ treatment exist at the same site. In conclusion, it is necessary to was continued for 6 months, and no relapse was seen 1 take aspergillosis into consideration when therapeu- y after discontinuation of antifungal treatment. tic failure occurs in a case of cavitary pulmonary lesions caused by yeast infection. Discussion CNPA locally invades the lung tissue for a long period of time [5], and the criteria for clinical References diagnosis include growth of Aspergillus sp. from a [1] Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller lung biopsy specimen, bronchoscopic washing, per- WT. ‘Semi-invasive’ pulmonary aspergillosis: a new look at cutaneous lung aspirate or sputum. Another essen- the spectrum of Aspergillus infections of the lung. Radiology tial aspect is its clinical response to antifungal 1981;140:313/21. [2] Binder RE, Faling LJ, Pugatch RD, Mahasean C, Snider GL. therapy [5]. Our case met these criteria as well as Chronic necrotizing pulmonary aspergillosis: a discrete clin- the pathological criteria of local invasion. ical entity. Medicine 1982;61:109/24. CNPA is usually seen in patients with underlying [3] Denning DW, Riniotis K, Dobrashian R, Sambatakou H. lung disease [6,7]; however, prior cryptococcal infec- Chronic cavitary and ﬁbrosing pulmonary and pleural asper- tion as an underlying disease has not been described. gillosis: case series, proposed nomenclature change, and This patient showed a worsened condition by chest review. Clin Infect Dis 2003;37:265/80. [4] Staib F, Seibold M, Grosse M. Aspergillus ﬁndings in AIDS radiography, pathological and mycological proof of patients suffering from cryptococcosis. Mycoses 1989;32: Aspergillus sp. infection, had symptoms such as 516/23. cough and yellowish sputum, and showed increased [5] Saraceno JL, Phelps DT, Ferro TJ, Futerfas R, Schwartz DB. blood-inflammatory reactivity, symptoms which are Chronic necrotizing pulmonary aspergillosis: approach to consistent with the proposed criteria for CNPA. management. Chest 1997;112:541/8. As a confirmatory diagnostic test, determination [6] Rosenheim SH, Schwarz J. Cavitary pulmonary cryptococcosis complicated by aspergilloma. Am Rev Respir Dis 1975; of serum IgG antibody against Aspergillus should be 111:549/53. positive for CNPA during and after the course of [7] Kato T, Usami I, Morita H, Goto M, Hosoda M, Nakamura aspergilloma. Our patient showed antibodies and A, Shima S. Chronic necrotizing pulmonary aspergillosis in was negative for cryptococcal antigen when his pneumoconiosis. Chest 2002;121:118/27. second exacerbation was highlighted by chest radio- [8] Herbrecht R, Denning DW, Patterson TF, Bennett JE, graphy. Aspergillus spp. were found in the specimen Greene RE, Oestmann JW, et al. Invasive Fungal Infections Group of the European Organization for Research and obtained by TBLB at the lesion where cryptococcal Treatment of Cancer and the Global Aspergillus Study infection was previously proven, and the pathological Group. Voriconazole versus amphotericin B for primary observation of crystals of oxalic acid calcium speci- therapy of invasive aspergillosis. N Engl J Med 2002;347: fically suggested Aspergillus niger infection. 408/15.