Paulami Chatterjee, PhD: Lowering Airway Iron to Treat ABPA in Pediatric Cystic Fibrosis

A new investigation from the Division of Pulmonary, Allergy and Critical Care Medicine at Stanford School of Medicine suggested that lowering airway iron could be a potential treatment for allergic bronchopulmonary aspergillosis (ABPA) in children with cystic fibrosis.

The data were presented during a late-breaker session at the American Thoracic Society 2020 International Conference in San Francisco.

Allergic bronchopulmonary aspergillosis can be found in approximately 10-25% of children with cystic fibrosis, and is caused by aspergillus fumigatus (Af).

This particularspecies of fungus secretes proteases that incite a Th-2 mediated allergic response that can result in progressive lung function decline. However, no current therapies are available to modify disease progression, and some therapies such as corticosteroids have long-term negative sequelae.

Investigators cited an urgent need for new treatment strategies and hypothesized that reducing airway iron would result in a decrease in the production of Af proteases and lessen Th-2 mediated immune inflammation associated with ABPA.

“The cystic fibrosis airway is unique; there are higher level of iron found in the cystic fibrosis airway than healthy controls, and previous studies have reported that the iron metabolism mechanism in cystic fibrosis airway is really altered in this patient population than healthy controls,” said study author Paulami Chatterjee, PhD, of Stanford University said in an interview with HCPLive.

The investigative team cultured both Wild type Af (10AF) and iron intolerant mutants (ΔsreA/cccA and ΔprtT) with iron, xenosiderophore (DFO), and iron chelator (DFX) before measuring Af by RT-PCR.

Meanwhile, the effect of an iron-avid pseudomonas filamentous bacteriophage (Pf4) on Af protease expression was assessed through co-culturing Af and Pf4 in increasing iron concentrations.

Regarding in-vivo iron, Chatterjee and colleagues modulated graft iron with a nanoparticle solution containing iron or DFX. Meanwhile, protease activity was measured in sputum samples of CF pediatric patients and association of Af infection.

“Our study found that both DFX and Pf4, they can reduce iron levels and reduce protease production in the in-vitro model, ” Chatterjee said.

Currently the team are evaluating the effect of iron chelation strategies using DFX and Pf4 on an established CF-ABPA mice model.

However, the investigative team also conducted a pilot study that applied incorporated this data when evaluated sputum samples from pediatric patients.

The study evaluated the association between of aspergillus and bacteriophage infection status and correlated that association with the clinical outcomes of cystic fibrosis.

Chatterjee noted that despite the small sample size, the primary outlook was “very encouraging”, and she and her colleagues found that patients who had both aspergillus and bacteriophage in their sputum showed less exacerbation and less protease concentration in their sputum.

Meanwhile, patients with only aspergillus showed the highest level of exacerbation as well as the highest concentration of sputum protease concentration.

“We are very hopeful with this data, this is very promising and this actually supports our hypothesis,” Chatterjee said. “This shows the possible clinical translatability of our work. We are planning on doing a bigger study which can replicate the findings we have and give us more information on host-pathogen interaction and polymicrobial interaction which is happening in the ABPA and cystic fibrosis scenario.”

Watch the full interview above to hear more from Dr. Chatterjee, and click here for more news from ATS2022.