A 70-year-old male Japanese with a history of rheumatoid arthritis (RA) was referred to the outpatient department of pulmonology because of non-resolving infiltration on chest imaging. He was diagnosed with RA 9 years ago, which was stable with iguratimod 100 mg per day, prednisolone (PSL) 0.5 mg per day, and methotrexate 7 mg per week. With respect to the timing of the diagnosis, pulmonary diseases associated with RA, such as bronchitis or interstitial pneumonia, were not detected on chest radiography or computed tomography (CT). Two months ago, he visited a primary care doctor with a chief complaint of cough for 3 months. He was diagnosed with community-acquired pneumonia based on the new nodules in the upper and lower lobes of the right lung, and amoxicillin-clavulanic acid combination was administered for 14 days (Fig. 1A and B). However, the abnormal infiltration on chest CT worsened 1 month after treatment. Another lung disease, such as organizing pneumonia or tuberculosis, was suspected based on the clinical course and chest CT findings and was referred to our department.
At the patient's initial visit to our department, his height was 1.60 m, weight 54 kg, temperature 36.3 , blood pressure 156/76 mm Hg, pulse 92/min, respiratory rate 16/min with an O2 saturation of 95 % on room air, and his consciousness was lucid. Neither wheeze nor crackle was audible on chest auscultation. Laboratory tests showed a white blood cell count of 9000/mm3 with eosinophilia (3825/mm3), C-reactive protein level of 0.34 mg/dL, and negative anti-GLP core IgA antibody test (Table 1). Chest radiographs showed abnormal infiltration in the upper and lower fields of the right lung (Fig. 2A). Chest CT showed a nodular shadow in the apex of the right lung, central bronchiectasis, and centrilobular nodules in the lower lobe of the right lung (Fig. 2B and C). In addition, chest CT showed bronchiectasis with mucus plugs, called high attenuation mucus (HAM), which have a density equal to or greater than that of the paraspinal muscles in the mediastinal window setting (Fig. 2D).
Differential diagnoses included ABPA, airway disease associated with RA, organizing pneumonia, eosinophilic pneumonia, and mycobacterial infection. Three consecutive sputum smears were negative for mycobacteria; bronchoscopy was performed, which revealed the presence of thick sputum filling the lumen of bronchi in the lower lobe of the right lung with findings suggestive of mucoid impaction. Bronchial washing and direct biopsy by forceps of mucus obtained from the bronchial mucosa were performed. Cytology of the bronchoscopy specimen revealed acid-fast bacteria using Ziehl-Neelsen staining and a Y-shaped, Grocott stain-positive fungus, possibly Aspergillus. Histological examination of the mucous membrane around the mucoid impaction revealed eosinophilic inflammation of the bronchial mucosa, consistent with ABPA. Serum total IgE level was 233 IU/mL; however, the results of Aspergillus fumigatus-specific IgE and IgG tests were positive (Table 1). Fungal cultures were negative, while mycobacterial cultures returned positive for M. avium. Based on clinical symptoms combination, bronchoscopic luminal findings, and laboratory and imaging studies, the patient was diagnosed with ABPA and MAC lung infection. While this patient's case did not meet the International Society for Human and Animal Mycology diagnostic criteria for ABPA; however, it met the Japanese criteria. We believed that the negative anti-GLP core IgA antibody test (Table 1) result was a false negative given that the patient was using steroids and his MAC lung disease was mild.
Pulmonary function tests were performed: vital capacity 2.56L (79.3 % of predicted) and forced expiratory volume in 1 second (FEV1) 80.3 % suggestive of a restrictive ventilation disorder. Airway reversibility test using a short-acting beta-2 agonist showed marginal bronchodilator response (FEV1.0) did not improve more than 12 % (10.2 %), which amounted to 200 mL. The level of nitric oxide in the exhaled air was 48 ppb. From these findings, the presence of decreased respiratory function and an asthmatic status was considered.
We administered ethambutol (750 mg/day), clarithromycin (800 mg/day), and rifampicin (450 mg/day) for MAC lung disease treatment because of the progressive worsening of the nodular lesions on chest CT and the risk of exacerbation of MAC lung disease owing to high-dose corticosteroid therapy for ABPA. In addition, we started a systemic corticosteroid (PSL 50 mg/day) for ABPA treatment. Initially, we considered a 25 mg/day PSL dose (0.5 mg/kg); however, we decided to administer 50 mg/day because rifampicin decreases the serum concentration of PSL. Although eosinophil count was restored on the seventh day after treatment initiation, respiratory symptoms such as cough persisted. Thus, we started inhalational vilanterol/fluticasone furoate (VI/FF), one puff per day (VI 25 mug and FF 100 mug/day). The respiratory symptoms gradually improved after the initiation of inhalational VI/FF. After one month, the nodular lesions, consolidation, and mucoid impaction showed significant improvement on chest radiographs (Fig. 2E) and CT (Fig. 2F, G, and H). However, the patient developed a fever one month after initiating treatment. Drug fever was immediately suspected, and his antimycobacterial drugs were discontinued with subsequent resolution of the fever within 7 days. Nevertheless, he developed fever again after re-administering ethambutol (500 mg), and we consequently discontinued administering clarithromycin and ethambutol. Thereafter, the patient was treated with PSL alone because his symptoms and CT findings were stable. The PSL dose was gradually tapered and discontinued for three months. However, three months after discontinuing treatment, the patient visited the outpatient department presenting with cough and dyspnea. Laboratory test results revealed eosinophilia (eosinophil count 1383/muL). Chest CT showed an increased nodular shadow in the upper lobe and newly appeared bilateral, centrilobular nodules in the lingular segments (Fig. 3A-C). The administration of clarithromycin (800 mg), rifampicin (450 mg), and PSL (20 mg) was initiated. After one month, his symptoms and eosinophilia improved, and after four months, the new lesions on chest CT improved (Fig. 3D-F). Antimycobacterial drugs will be continued for at least 12 months, and PSL will be given for about 3-4 months according to the symptoms.