A 54-year-old female patient, active smoker (35 pack-years), with a history of pulmonary tuberculosis in adolescence, was admitted to the Department of Lung Diseases and Tuberculosis due to productive cough, weakness, low exercise tolerance, weight loss (about 7 kg). Symptoms exacerbated during last 6 months. She was treated empirically with oral antibiotics in standard doses (amoxicillin, amoxicillin-clavulanate, levofloxacin, and cefuroxime) without clinical improvement. Three and a half years earlier, the patient underwent radiochemotherapy for locally advanced non-small-cell lung cancer of the right upper lobe (adenocarcinoma, the clinical stage of the tumor was T3N2Mo CS IIIA /T:tumor, N:lymph node, M:metastasis/, Figure 1a). Platinum-based chemotherapy with etoposide (three cycles) was combined with radical radiotherapy of the right lung tumor area, hilum, and mediastinal lymph nodes (66 Gy in 33 fractions). This treatment was well-tolerated and no early complications were observed. Since then, the patient has been under strict oncological control. Follow-up CT images of the chest and abdomen were taken regularly every 6 months. A cavitary lesion developed at the site of the tumor of the right lung 2 years after the end of lung cancer treatment (Figure 1b).
Chest CT scans showed an irregular cavity in the upper part of the right lung with thick walls and accompanying mass of the posterior wall, surrounded by solid consolidation, dilated surrounding bronchus, and emphysema (Figure 1c). Imaging diagnostics was extended to PET-CT, which revealed the unclear nature of the hypermetabolic masses in the right lung, more likely inflammation (Figure 1d).
Physical examination revealed numerous wheezing and rales during lung auscultation. During bronchoscopy, purulent bronchitis was confirmed (Figures 2a,b). Laboratory tests showed increased concentration of C-reactive protein (CRP) (90 mg/dl, normal range <5 mg/dl). Lung function tests revealed a moderate impairment on pulmonary transfer coefficient for carbon monoxide (TLCO; 41% predicted value). No obstruction or restriction was observed.
Microbiological tests (smears, aerobic and anaerobic cultures) of the sputum and bronchial wash were negative for bacteria and fungi. Ziehl-Neelsen staining, cartridge-based nucleic acid amplification test (CBNAAT), and culture of sputum and bronchial wash did not show evidence of Mycobacterial infection. Aspergillus fumigatus precipitins were positive in serum. The test was performed using the qualitative Ouchterlony double immunodiffusion method in an agarose gel. The test was developed with its own research methodology and performed in the Department of Biological Health Hazards and Parasitology, Institute of Rural Health, Lublin, Poland. The result was assessed on the basis of the formed precipitation lines, validated with a negative control serum test. Ceftriaxone (2.0 g per day) and levofloxacin (500 mg twice a day) were administered empirically intravenously with a moderate clinical effect. Control bronchoscopy revealed a partial reduction of purulent mucus.
Due to the suspicion of lung cancer recurrence, a transthoracic, CT-guided fine-needle aspiration of the peripheral margin of the right lung cavity was performed. Only macrophages and inflammatory cells such as lymphocytes and neutrophils were observed in aspirated cytological samples. No microbiological tests were performed because of the small amount of the collected sample. Also, forceps biopsy of bronchial tissue collected from the second right bronchus during the bronchoscopy was negative for neoplastic cells. Moreover, no other clinical or radiographic signs of malignancy were observed.
The low value of transfer factor of the lung for carbon monoxide (TLCO) disqualified the patient from surgical resection of the right lung (pneumonectomy).
The patient met diagnostic criteria for CPA and antifungal treatment with itraconazole was initiated (200 mg orally twice a day). The therapy was well-tolerated. Two months later, sputum culture was positive for A. fumigatus. A sabouraud dextrose agar (SDA) medium with chloramphenicol and gentamicin was used as a selective medium for the isolation of fungi. The species was determined on the basis of both macro- (colony morphology in SDA) and microscopic morphology (conidiophores, vesicles, metules, phialides, and conidia). Drug susceptibility was determined by the microdilution method (Thermo Scientific). The minimum inhibitory concentration (MIC) for itraconazole was 0.12 mug/ml. Every 8 weeks, the patient was re-evaluated clinically by physical examination and radiologically on the basis of chest CT (Figures 3a-d) and x-rays (Figures 4a-d). Follow-up bronchoscopy and microbiological tests of bronchial wash were also performed. Four months after initiation of itraconazole treatment, sputum culture was positive for itraconazole sensitive A. flavus (MIC = 0.25 mug/ml). Taking into account the well-graded clinical response, radiological improvement, and good tolerability, therapy was continued for up to 6 months.
Six months later, the patient was re-admitted to the Department of Lung Diseases and Tuberculosis with symptoms of increasing weakness, productive cough, night sweats, chest pain on the right side, and weight loss (3 kg). Chest imaging confirmed CPA progression (Figures 5a, 6a). Microbiological tests for fungi and bacteria were negative. A bronchial biopsy ruled out cancer recurrence. Once again antifungal treatment with itraconazole (200 mg orally twice a day) was initiated. After 3 months, antifungal medication was switched to orally administered voriconazole (200 mg twice daily) due to radiographic progression (Figures 5b, 6b). The tolerance of the therapy was poor. Four weeks after starting the voriconazole treatment, the patient reported pain in the chest and right upper abdominal quadrant, further weight loss (a total of 7 kg), and temporary visual disturbances. On bronchoscopy, massive purulent bronchitis and concentric stenosis of the right upper lobe were detected. In the cytological examination of the bronchial wash, fungal hyphae were detected for the first time during the entire diagnostic process (Figure 2c). Chest CT images showed further progression. The cavity in the upper right lobe was larger, with a level of thickened, heterogeneous fluid and air in the upper part (Figures 5c, 6c). Physical examination and CT images of the abdominal cavity confirmed the hepatomegaly. The laboratory test revealed elevated transaminases (>5x upper limit of normal), high CRP (90 mg/dl), and anemia (red blood cells-3.4 x 106/mul, hemoglobin-10.2g/dl).
The antifungal treatment was modified again. Itraconazole (200 mg orally twice a day) bridging therapy was used in anticipation of the unavailability of liposomal amphotericin B as part of emergency access to therapy.
After 1 month of itraconazole treatment, clinical and radiological improvement was achieved. The patient confirmed her well-being, an increase in appetite and body weight (2 kg), and good tolerance of the antifungal therapy. Control imaging showed partial regression (Figures 5d, 6d). It was decided to continue treatment with itraconazole for at least 12 months under close clinical and radiological monitoring. The antifungal treatment is still ongoing. Follow-up visits are scheduled. A timeline with all relevant data from this clinical case is available in Figure 7.