Aspergillus is a saprophytic fungus which is present normally in our surroundings and causes a large number of pulmonary diseases spreading through inhalational route. The spectrum of disease caused by aspergillus spp. is wide with the manifestations of the disease being governed primarily by the status of the underlying host immunity, which then determines the nature of the host-aspergillus interaction. Patients with an intact immunity have a more stable and indolent form of disease like aspergilloma whereas with a worsening immune status, the risk of invasive disease increases. Chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA) are two of the commonest pulmonary manifestations seen in non-immunocompromised patients whereas invasive pulmonary aspergillosis being more common in the immunocompromised patients.(1-3) Estimates suggest that CPA affects around 3 million people across the globe, which may still be an under estimated number as the disease co exists with other pulmonary co-morbidities which make accurate diagnosis a pitfall. In India the annual incidence of CPA was estimated in 2011 and varied between 27,000-0.17 million cases, with different estimates. Based on the mortality rate for CPA which was estimated to be 15% annually, the 5-year prevalence of CPA was placed at 290,147 cases with 5-year prevalence rate being 24 per 100,000 in the same year.(4, 5) The disease confers significant morbidity and mortality, making it a significant burden for the society as well as the healthcare. Apart from the respiratory symptoms, CPA causes significant constitutional symptoms as well which adds to the misery of the patient. The diagnosis of CPA is based on presence of chronic symptoms, consistent radiology and demonstration of Aspergillus by direct (culture) or indirect (serological) methods.(1-3) Even though CPA is more of a disease spectrum but overall it is characterized by slowly progressive lung cavitation which may or may not show presence of mycetoma /fungal ball in patients with pre-existing structural lung diseases, even though other patterns have also been identified.
The treatment options majorly consist of medical management with at least 6-month long treatment with antifungal drugs - most significantly the azole groups. Itraconazole is the preferred azole for the treatment of CPA.(6-8) However the response with itraconazole is seen in around 60-75% of the subjects.(9) Moreover, about 30%-50% of the subjects have disease relapse that requires prolonged therapy. The lower response could be because of variable pharmacokinetics and drug absorption of oral itraconazole. Also, itraconazole has many drug interactions. Voriconazole is a third-generation azole and is currently the therapy of choice for invasive aspergillosis due to its lower minimal inhibitory concentration (MIC) values compared to itraconazole. In addition, the pharmacokinetics of voriconazole are not variable and oral form has a good bioavailability (up to 95%). In a previous study, the use of voriconazole resulted in radiological control in 97% of the subjects and a significant improvement in patients' symptoms but global success at six-months was only seen in 32% subjects.(10) However, despite being multicenter the study only included 48 subjects. Moreover, there was no control group and the authors did not use therapeutic dose monitoring. In addition, the study also included subjects with subacute invasive aspergillosis (SAIA). Thus, there is lack of information regarding the role of voriconazole in subjects with CPA. We hypothesize that the use of voriconazole will be associated with better treatment outcomes compared with oral itraconazole in treatment naïve subjects with CPA. In this randomized controlled trial, we compare the clinical outcomes of six months therapy with oral itraconazole with oral voriconazole in treatment naïve subjects with chronic pulmonary aspergillosis.
REFERENCES
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