A 56-year-old, healthy man who was a current smoker required emergency admission at Asakura Medical Hospital with chief complaints of a fever, cough, sputum, and dyspnea for 10 days. He had no history of medications or circumstances indicative of inhaled hyphal exposure before the onset of respiratory symptoms. His respiratory rate was 30 beats per min, and his oxygen saturation was 92% (87% at room air) with 4 L/min of nasal oxygen therapy. His blood test showed values almost within the normal range: neutrophil count (4,940x103 cells/mL), fasting glucose (10.8 mg/L), and hemoglobin A1c (6.2% of the value recommended by the National Glycohemoglobin Standardization Program). The 1-3-beta-D glucan level in blood was 488 pg/mL (cut-off value, 20 pg/mL). The serum galactomannan antigen level for Aspergillus, assessed by an enzyme-linked immunosorbent assay, was 3.8 according to the cut-off index. A complement fixation test (BML, Tokyo, Japan) indicated a less than four-fold increased level of anti-Aspergillus antibodies (negative results). Serum human immunodeficiency virus (HIV)-1 and HIV-2 antibodies and HIVp24 antigen were not detected by a chemiluminescent enzyme immunoassay (BML). Chest computed tomography (CT) revealed multiple regions of bronchial wall thickening with peribronchial infiltrations before treatment (Fig. 1). No evidence of rhinosinusitis was found on facial CT. Fiberoptic bronchoscopy showed multiple areas of ulceration and swelling, with geographical, moss-like white coats on the tracheobronchial mucosa (Fig. 2A).
Treatment with a combination of empirical intravenous anti-fungal agents [250 mg twice daily (total 500 mg/body/day) of voriconazole and 150 mg twice daily (total 300 mg/boy/day) of micafungin] was initiated after confirming the presence of fungal hyphae in bronchial lavage samples (eighth day of hospitalization). Evidence of bacterial and mycobacterial infections in the sputum, bronchial lavage, and blood and tests for urinary antigens of Legionella and pneumococcus were negative; nevertheless, intravenous administration of 500 mg thrice daily (total 1,500 mg/body/day) of doripenem and 200 mg twice daily (total 400 mg/body/day) of minocycline was added to the treatment regimen for suspected mixed typical and/or atypical pneumonia with fungal infections from day 1 to 10 after hospitalization. Pneumocystis jirovecii DNA was not detected in the bronchial lavage samples by a polymerase chain reaction assay.
Transbronchial lung biopsies (TBLBs) of the right B1, B3, B5, and B8 lung segments were performed. Each TBLB specimen stained with hematoxylin and eosin showed similar findings of the presence of extensive fungal hyphae, although the presence of hyphal invasion into the lung parenchyma and surrounding blood vessels could not be verified (Fig. 2B). Grocott staining revealed multiple septate hyphae, branched at acute angles, and the hyphae were grouped in typical Aspergillus conidial heads (Fig. 2C). Chest CT 14 days after treatment initiation revealed cylindrical bronchiectatic changes with peribronchial infiltration (Fig. 3). The patient died on the 29th day of hospitalization due to multiple organ failure with disseminated intravascular coagulation despite being transferred from the intensive-care unit to the high-care unit of Kurume University Hospital (16th day of hospitalization). Aspergillus fumigatus was repeatedly isolated from the bronchial washings and sputum, and the minimum inhibitory concentration (MIC) for micafungin and voriconazole, calculated based on the isolated strains by the modified broth dilution method (BML), were found to be <=0.015 and 0.25 mug/mL, respectively.
Chest CT findings before treatment. lower lobe. revealed bronchial wall thickening with para-bronchi infiltration in almost all large bronchi. CT: computed tomography.