By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A randomized controlled clinical trial from India found a significant reduction in relapses of chronic pulmonary aspergillosis in patients treated with itraconazole for 12 months compared to those treated for six months. There were more adverse events in the patients treated for 12 months.
SOURCE: Sehgal IS, Dhooria S, Muthu V, et al. Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: An open-label, randomised controlled trial in India. Lancet Infect Dis 2022;22:1052-1061.
Chronic pulmonary aspergillosis (CPA) is a progressive disease that affects more than 1 million individuals worldwide and has a five-year mortality of approximately 50%. CPA differs from invasive pulmonary aspergillosis in that the former occurs in patients with chronic lung disease who are not neutropenic, while the latter is seen most often in neutropenic individuals. Symptoms are nonspecific and difficult to differentiate from other chronic pulmonary conditions, such as tuberculosis and chronic obstructive pulmonary disease (COPD), especially in resource-limited settings. Furthermore, the optimal duration of treatment for CPA is uncertain. Guidelines from the Infectious Diseases Society of America (IDSA) state that patients with CPA and either pulmonary or general symptoms or progressive loss of lung function or radiographic progression should be treated with a minimum of six months of antifungal therapy (strong recommendation; low-quality evidence).1 Sehgal and colleagues sought to determine whether six months or 12 months of oral itraconazole would lead to fewer relapses of CPA at two years.
The study was a randomized, open-label, controlled clinical trial conducted at a single center in India. Patients were included who were diagnosed with CPA based on all the following features: respiratory or systemic symptoms (i.e., persistent cough, recurrent hemoptysis, malaise, fever, dyspnea, and weight loss) for at least three months; progressive or persistent radiologic findings on chest computed tomography (CT) (i.e., one or more cavities, consolidation, fungus ball, or pleural thickening); immunological evidence (i.e., Aspergillus IgG or precipitins) or microbiological evidence (i.e., growth of Aspergillus in culture or positive galactomannan); and exclusion of other pulmonary disorders (e.g., active tuberculosis [MTb], nocardiosis, non-tuberculosis mycobacteria, histoplasmosis, or others). Patients were excluded who failed to provide informed consent, took 10 mg of prednisone or equivalent steroid for at least three weeks in the preceding three months, had a diagnosis of acquired immunodeficiency syndrome (AIDS), received any antifungal therapy for more than three weeks in the preceding six months, had signs of any other form of pulmonary aspergillosis (e.g., invasive pulmonary aspergillosis), or were pregnant.
Patients were randomized to receive either 400 mg/day divided in two doses of oral itraconazole for either six months or 12 months. Therapeutic drug monitoring was done after two weeks of initiation of therapy and during follow-up, with a serum trough target of at least 0.5 mg/L. A multidisciplinary team of physicians assessed treatment response based on clinical and radiological features. The overall response was graded as favorable if there was an improved or stable clinical response with radiological improvement or stable disease, and unfavorable if there was clinical or radiological worsening or death due to any cause during the treatment period. Patients with an unfavorable response at any time then were switched to either oral voriconazole or intravenous amphotericin B. The primary outcome was the proportion of patients who experienced a relapse of CPA two years after treatment initiation.
There were 164 patients included in the study, with 81 randomized to the six-month itraconazole group and 83 to the 12-month group. The mean age of the participants was 44.3 years. There were 31 relapses (38%) in the six-month group and eight relapses (10%) in the 12-month group (absolute risk reduction, 0.29 [95% confidence interval (CI), 0.16-0.4]; P < 0.0001). The number of relapses per 100 patient-years also was significantly greater in the six-month group (21.6) vs. the 12-month group (4.9; estimate difference, 16.7, [95% CI, 9.5-23.9]; P < 0.0001). The mean time to relapse was significantly greater in the 12-month group compared to the six-month group (23 months [95% CI, 22.4-23.8] vs. 18 months [95% CI, 16.9-20.0], respectively; P< 0.0001). There were 10 deaths that occurred before treatment completion, eight of which were due to CPA.
Itraconazole was well tolerated and there was no statistically significant difference in the frequency of adverse events between the groups. The most common averse event was nausea (14/28 patients, 50%). The 12-month group had a significantly decreased relative risk of relapse in all subgroups analyzed. Furthermore, there was a reduced risk of relapse in the 12-month group compared to the six-month group in patients who were more symptomatic, patients with two or more pulmonary cavities, and patients with chronic cavitating pulmonary aspergillosis.
COMMENTARY
The work by Sehgal and colleagues is the first randomized controlled trial comparing the duration of oral antifungal therapy for CPA. This is an important study because of the major impact on quality of life and resulting poor outcomes associated with CPA. Preventing relapses and, therefore, continued lung damage is a major objective in the management of CPA. Thus, the finding that 12 months of itraconazole leads to fewer relapses without increasing the frequency of adverse events means that current treatment recommendations should be reconsidered.
Despite the robust study design, there are a few limitations worth mentioning. There are newer oral antifungal medications (e.g., posaconazole and isavuconazole) with activity against Aspergillus spp. that can be taken once a day and have more reliable bioavailability than itraconazole. It remains uncertain whether these agents would be effective against CPA for a six-month course. Because there was no placebo group, the study was not blinded, which could have biased the differences between the groups. However, the investigators tried to control for this by documenting objective criteria, such as radiological improvement. Finally, although patients with active MTb were excluded, a sizeable number had post-pulmonary tuberculosis lung disease as their predisposing factor for CPA. This may have predisposed them to different outcomes compared to patients with other structural lung diseases.
CPA is a challenging infection that requires a prolonged course of itraconazole, followed by careful monitoring for relapse. While the study by Sehgal likely will be a seminal one in the management of CPA, further elucidation of the underlying immunopathology of the disease is needed to identify and develop novel safe and effective therapies.
REFERENCE
- Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-e60.
