Lack of Efficacy of Voriconazole Therapy in 2 Patients with Pulmonary Fungus Balls

Sir—Whereas surgical resection is the definitive treatment for pulmonary fungus balls (i.e., “aspergilloma”), the best treatment for patients who are ineligible for surgery remains unknown [1–3]. Medical treatments are appealing for such patients, but antifungal agents given either systemically, via nebulization, or by direct instillation into the lesion cavity have had no consistent success [1–3]. Voriconazole shows in vitro activity against many clinically significant filamentous fungi that may be involved in the onset of pulmonary fungus balls, including Aspergillus species [4]. Voriconazole showed a remarkable efficacy in persons with invasive aspergillosis in a clinical trial [5], but there are no data yet on its efficacy in patients with aspergilloma. In a recent report, Chow et al. [6] described a patient with pulmonary aspergilloma that was cured with voriconazole. The favorable outcome in this case report led us to use the drug in 2 patients with pulmonary fungus balls. The clinical characteristics and outcomes of these 2 patients are described below. A 47-year-old man who was known to have ankylosing spondylitis for 29 years presented with a 2-week history of hemoptysis. CT scan showed a thick-walled cavity of 50 × 40 mm at the superior segment of the right upper lobe of the lung with a dense material inside and surrounding paracavitary shadowing. Diffuse pulmonary fibrosis and bronchiectasis were also present. Sputum cultures yielded pure growth of Aspergillus fumigatus. Broth microdilution susceptibility testing was performed as described in NCCLS document M38-A [7], with the modifications described elsewhere [8]. The MIC of voriconazole was 0.5 µg/mL. The patient was ineligible for surgery because of poor respiratory status, and voriconazole therapy (200 mg po b.i.d.) was started. An apparent improvement in respiratory symptoms was observed, and Aspergillus species was no longer isolated from sputum cultures. However, a CT scan did not show significant changes in the size of the fungus ball after a 6-month course of voriconazole therapy. Neither clinical nor radiological improvement was observed after a second, 4-month course. A 41-year-old woman presented with a 5-day history of hemoptysis. The patient's medical history was unremarkable. The results of routine laboratory studies, including a test for detection of HIV, were normal. CT scan showed a solitary cavitary lesion of 37 × 28 mm with a typical air-crescent sign in the lower lobe of the right side of the lung. Microscopic examination of a specimen obtained by percutaneous transthoracic needle aspiration of the pulmonary lesion showed several hyphae, and cultures yielded a filamentous fungus that failed to produce fruiting structures on routine mycological media. The isolate was identified genetically as a Paecilomyces species. The isolate was 95% genetically similar to Paecilomyces sinensis, 85%–87% similar to Paecilomyces variotii, and 50%–60% similar to Paecilomyces lilacinus. The MIC for voriconazole was 0.12 µg/mL. The patient was treated with voriconazole (200 mg po b.i.d.). No changes were observed on the CT scan after 6 months of therapy, at which time surgery was performed. The resected lung included a 45-mm cavity, suspected of being a bronchogenic cyst, containing a fungus ball. Grocott staining showed irregularly branched hyaline septate hyphae and conidia. The organisms isolated from the fungal ball were identified as Paecilomyces species. In contrast to the patient described by Chow et al. [6], neither of our patients cleared the pulmonary fungus ball after several months of therapy with voriconazole, despite the in vitro susceptibility of the fungal isolates. We administered voriconazole at the standard dosage of 200 mg po b.i.d. At this dosage, the expected steady-state serum levels with normal 90% absorption are 2.1–4.8 mg/mL [9], concentrations that are well above the voriconazole MIC for the fungal strains isolated from the patients. The failure of voriconazole treatment might have been due to low penetration of the drug beyond the outer layers of the fungus ball, resulting in insufficient intracavitary levels. Although the lesions did not show a reduction in size, for one of our patients, results of sputum cultures became negative during voriconazole therapy, and a slight improvement in symptoms was observed. The surrounding paracavitary shadowing on the CT scan for this patient suggests that chronic necrotizing pulmonary aspergillosis may have coexisted with the aspergilloma. The 2 entities are probably a continuum of the same pathological process [3], and it is believed that patients with chronic necrotizing pulmonary aspergillosis may actually respond to systemic antifungal therapy. Potential conflicts of interest. All authors: no conflicts.