The patient disposition is summarized in Fig. 1. Fifty-six patients were screened and 48 received at least one dose of voriconazole. Of these 48 patients, 41 had confirmed CPA and comprised the mITT population. Twenty-two patients had confirmed CCPA and 19 confirmed CNPA; one patient with TBA was included into the CNPA group for all analyses, due to the clinical similarities between these two forms. A. fumigatus was isolated from bronchopulmonary specimens in all patients. At the time of inclusion, immunoelectrophoresis revealed at least two anti-A. fumigatus precipitin lines in all patients, with a mean of 4.9 lines (median of 4 lines; range 2–11).
The demographic and clinical characteristics are summarized in Table 1. The relatively low median body mass index of 17.3 kg/m2 may reflect the overall poor health status of the study population. Among the 41 patients in the mITT population, 32 (78 %) continued voriconazole treatment up to 6 months and 22 (54 %) received voriconazole beyond 6 months. The mean treatment duration was 8.3 months (range 5 days to 13.6 months). Fifteen patients (37 %) received concomitant corticosteroid therapy (inhaled, n = 12 and/or oral, n = 6). The proportion of necrotizing and cavitary forms in these patients was similar to those patients who did not receive corticosteroids and the mITT population. Inhaled corticosteroids were started prior to the study in all patients except one, and given at the same dosage for the duration of the study. Oral corticosteroids were given for the whole study in three patients because of sarcoidosis (n = 2) and chronic obstructive pulmonary disease (COPD) (n = 1) and in one patient who received hydrocortisone substitution for adrenal insufficiency. Two other patients received one to three short courses of oral corticosteroids for bronchospasm (n = 1) or COPD exacerbations (n = 1).
Thirty-two baseline strains underwent susceptibility testing. Of these, 12/32 (38 %) and 7/31 (23 %) strains exhibited resistance to amphotericin B and itraconazole, respectively, while a single strain was cross-resistant to itraconazole, voriconazole, and posaconazole, with MICs of >32, 16, and 16 mg/L, respectively (Table 2).
Global success at 6 months, the primary endpoint of this study, was reported in 13/41 (32 %) patients (95 % CI, 18.1–48.1 %): 10/19 (53 %) with CNPA and 3/22 (14 %) with CCPA (p = 0.01) (Fig. 2).
The rate of success was similar after 3 months of treatment for CNPA (53 %) but lower for CCPA (9 %). Global success at EOT was reported in 18/41 (44 %) patients: 11/19 (58 %) with CNPA and 7/22 (32 %) with CCPA (p = 0.09) (Fig. 2). The mean duration of treatment for patients with global success at EOT did not differ between patients with CNPA (10 months; range: 6–13.4) and CCPA (11 months; range: 6.6–12.5).
The success rate at 6 months in patients receiving concomitant corticosteroids (20 %) was lower than in patients who were not receiving concomitant corticosteroids (38 %).
Radiological response was evaluated at EOT for 31 patients (Figs. 3 and 4). CPA was considered as controlled (complete or partial response or stabilization) in all cases, with the exception of one patient with CCPA (30/31; 97 %). Of the radiologically evaluable patients, 41 % with CCPA showed a complete or partial response and 53 % stabilization; 79 % with CNPA had a complete or partial response and 21 % stabilized with voriconazole treatment (Fig. 3).
Improvements in global respiratory symptoms were seen at 6 and 12 months (Fig. 5). A significant improvement in quality of life was noted at 6 months and at the end of study (Supplementary Online Material, Table 1).
Evaluation of the mycological response revealed eradication or presumed eradication of A. fumigatus from the bronchopulmonary specimens of all patients at both 6 months and at EOT. Eradications at 6 months were documented in 26 of 32 (81 %) patients who received study treatment for up to 6 months, and at EOT in 18 of 22 (82 %) patients who continued study treatment beyond 6 months. The patient with the pan-azole-resistant strain had CCPA with a presumed eradication at 6 months and EOT, and was considered a failure at both timepoints because of an insufficient radiological response.
At 6 months, 8/29 (28 %) patients had negative serology and 14 (48 %) showed a marked decrease in their specific immunologic response (decrease of ≥2 lines). All patients with CNPA showed improvement compared to 64 % of patients with CCPA. Overall, the mean number of Aspergillus precipitin lines decreased from 4.9 at baseline to 3.3 at 6 months. However, there was no difference in the respective results between patients with and without global success (Supplementary Online Material, Table 2).
Radiological or mycological relapse was observed at the 6-month post-therapeutic visit in 3/18 (17 %) patients (one each with CCPA, CNPA, and TBA) who had previously experienced global success at their respective EOT visits.
Safety was assessed in all patients who received at least one dose of voriconazole (n = 48). Side effects were consistent with the known adverse-event profile of voriconazole : patients reported visual disturbances (21 %); photosensitivity reactions (19 %); blurred vision (12 %); constipation, vomiting, and γ-glutamyl-transferase increase (10 % each); chills, decreased appetite, headache, and insomnia (8 % each); and vertigo, nausea, cholestasis, weight loss, and anorexia (6 % each). Seven patients discontinued voriconazole for toxicity, i.e., grade 3 liver toxicity (n = 2), grade 1 hyponatremia, QT prolongation (80 ms increase), memory disorder, insomnia and memory loss, or worsening of general condition (n = 1 each). No death was attributable to drug toxicity. Five patients died during the study from comorbidities (bacterial pneumonia, pneumothorax, chronic respiratory failure, ovarian cancer, or septic shock); no deaths were attributable to CPA in this study.