A study published in Mucosal Immunology has created a detailed cellular map of the lower airways in young children with cystic fibrosis (CF), revealing that immune system abnormalities are present in the preschool years and persist even in children using current CFTR modulator therapies.
The research suggests that combining current treatments with anti-inflammatory medications may be necessary to prevent irreversible lung damage.
Study Design and Methodology
Researchers from the Murdoch Children's Research Institute (MCRI) and the Peter MacCallum Cancer Centre analyzed over 190,000 individual cells from 45 lung samples. The samples came from 37 children with CF and 8 children without CF, with ages ranging from 5 months to 6 years. All were treated at The Royal Children's Hospital in Australia.
Using single-cell sequencing and protein analysis, the team identified 43 distinct immune and epithelial cell types in the samples. The control group consisted of children without CF who were undergoing medical procedures for upper airway conditions—not healthy volunteers.
Key Findings
The study identified that in children with CF, immune cells called macrophages exhibited abnormal activity. These abnormalities affected pathways related to inflammation, cholesterol regulation, and tissue scarring (fibrosis). These immune dysfunctions were more pronounced in children who had developed bronchiectasis, a form of irreversible lung damage.
Twelve children in the study group were using CFTR modulators for varying durations. The data indicated that these children still showed increased lung inflammation compared to children without CF, suggesting that modulators alone may not fully protect the lungs.
Study Limitations
The researchers noted several limitations in the study:
- Small sample size of 45 children total
- Difficulty in obtaining lung samples from preschool children, particularly healthy volunteers
- Varied duration of CFTR modulator use among participants
Context on Cystic Fibrosis
Cystic fibrosis is a genetic disease that causes thick mucus to build up in the lungs and digestive system. Newborn screening in Australia identifies most cases. According to the researchers, approximately 1,600 children in Australia have CF, with one baby born with the condition every four days. Current life expectancy for children born with CF is into their 60s.
CFTR modulators are medications that help improve the function of the CFTR protein but do not cure the underlying disease.
Researcher Statements
Associate Professor Melanie Neeland (MCRI), the lead author, stated that the study "discovered immune dysfunction in the lungs begins in the preschool years and persists despite current breakthrough therapies."
Associate Professor Shivanthan Shanthikumar (MCRI, Royal Children's Hospital) noted that "the study shows there's still a long way to go to ensure people with cystic fibrosis can live unaffected by the disease" and "highlights the importance of studying lung disease in preschool children, who are often overlooked in research that focuses on adults."
Dr. Elena Schneider-Futschik (University of Melbourne), who was not involved in the study, called the research "significant" and stated that it adds evidence that CF lung disease involves early immune dysregulation. She noted the study's limitations but emphasized the value of the single-cell analysis.
Additional Research
The research was supported by the Chan Zuckerberg Initiative. Co-authors included researchers from MCRI, the University of Melbourne, the Royal Children's Hospital, the Walter and Eliza Hall Institute, the Garvan Institute, and the University of New South Wales.
MCRI researchers have also grown human lung stem cell models to screen existing medicines for potential CF treatments.