Aspergillus is a ubiquitous fungus that causes a spectrum of human lung diseases
depending on the host immunity and the immune response. In those with overt
immunodeficiency, Aspergillus spp. causes invasive pulmonary aspergillosis. In
immunocompetent individuals with structurally damaged lungs Aspergillus spp. causes
chronic pulmonary aspergillosis. On the other hand, allergic bronchopulmonary
aspergillosis (ABPA) complicated the disease course of asthmatics and cystic fibrosis due
to a hyperimmune response mounted by the host against the fungi colonizing the airways.
Chronic pulmonary aspergillosis (CPA) has significant global burden, yet under-reported
aspergillus related chronic lung disease. CPA is a chronic progressive lung disease that
has a five-year mortality of over 50%. CPA has a significant global burden with more than
a million individuals are affected with CPA globally. In India alone, more than 100,000
individuals are affected with CPA annually. CPA occurs primarily in patients with
pre-existing structural lung disease, including post-pulmonary tuberculosis lung disease
(PTBLD), chronic obstructive pulmonary disease (COPD), and others. In our experience,
PTBLD is the most common risk factor for CPA.(3-5) While the treatment of pulmonary TB is
highly effective, almost 25-30% of the cases are left with sequelae of the disease
including cavities, parenchymal fibrosis, and others. Patients with sequelae are not only
at higher risk of recurrence of TB but are also prone to colonization with Aspergillus
fumigatus. It has been estimated that CPA develops in approximately 20-25% of treated
pulmonary tuberculosis with residual cavity. Unfortunately, the recognition of CPA is
poor amongst physicians and even pulmonary physicians. Patients with recurrent cough,
hemoptysis, fever or weight loss and a negative sputum examination for AFB or Xpert
MTB/Rif are labelled as smear negative pulmonary tuberculosis. In fact, almost 50% of the
patients with CPA are misdiagnosed as pulmonary TB and receive empiric anti-TB therapy
because of the similarities in presentation of the two disorders. Untreated CPA is fatal
with a five-year mortality of 30-80%.This has clinical implications as these patients
with CPA would benefit from antifungal agents. While the actual burden of CPA among
treated TB patients is not known, a mathematical model estimated that approximately 0.14
million cases are affected annually. Further, it was shown that if the mortality of CPA
is estimated as 15% annually, the 5-year burden of CPA is about 290,147 cases with a
5-year prevalence rate of 24 per 100,000.
The diagnosis of CPA is based on the constellation of clinical symptoms (low-grade fever,
weight loss, anorexia, malaise, cough with expectoration, recurrent hemoptysis, fatigue,
chest pain, and dyspnea, for at least three months), persistent or progressive
radiological features (one or more cavities with or without fungal ball, fibrosis,
pericavitary infiltrates, consolidation, nodules and pleural thickening) and the presence
of either direct (positive sputum or bronchoalveolar lavage fluid [BALF] culture) or
indirect (elevated serum or BALF galactomannan index or Aspergillus fumigatus-specific
precipitins [or IgG] antibodies in serum) evidence of Aspergillus infection. Of the
available diagnostic modalities, serology is the most reliable component of the CPA
diagnostic pathway. Currently, the estimation of A.fumigatus-specific IgG by enzyme
immunoassay (Phadia, Immulite and others) is considered the most sensitive test in the
diagnosis of CPA. In a recent study, using a cut-off of 27 mgA/L, the sensitivity of
A.fumigatus-specific IgG in the diagnosis of CPA was about 91.3%.The prevalence of CPA in
India in subjects not known. Our group has estimated the burden of CPA following
pulmonary TB using a mathematical modelling.
The treatment of CPA is with oral itraconazole for 6-12 months. Oral itraconazole results
in better clinical outcomes in CPA compared to supportive care. A recent study comparing
6 months with 12 months of oral itraconazole for longer duration treatment found longer
duration reduced CPA relapse and improved clinical outcomes. However, longer duration of
itraconazole could cause emergence of drug resistant Aspergillus fumigatus and therapy
related adverse event. A recent study found nebulized amphotericin B non-inferior to oral
itraconazole for treating CPA as primary therapy. However, the study was small and
included patients with simple aspergilloma and used nebulized amphotericin B for 7
days.To be effective, an inhaled drug should be delivered in sufficient quantity to
achieve therapeutic levels. The minimum inhibitory concentration of amphotericin B for
A.fumigatus is 0.5 mg/L. In one study, nebulization of 30 mg of amphotericin B
deoxycholate achieved a mean concentration of 0.68 mg/L in the bronchoalveolar lavage
fluid. Notably, the serum levels of amphotericin B after nebulization are 20 times less
than after systemic administration and is safer. Further, there is a dose-response
relation with nebulized amphotericin B, the higher the dose used for nebulization, the
higher are the levels achieved in the lung tissue. Nebulized amphotericin B has been used
in lung transplant recipients to prevent invasive aspergillosis. Also, two recent studies
have demonstrated that use of nebulized amphotericin B as maintenance therapy led to a
reduction in ABPA relapse rates and prolonged time to exacerbation. We believe that
inhaled amphotericin B as a maintenance therapy could reduce CPA relapse and prolong time
to relapse. In this study, we plan to evaluate nebulized amphotericin B as a maintenance
therapy in clinically stable CPA patients treated with 12 months of oral antifungal
therapy.
AIMS To compare the clinical outcomes of nebulized amphotericin B deoxycholate versus
nebulized normal saline as maintenance therapy in CPA subjects treated with 12 months of
antifungal therapy
