Patterns of early lung damage revealed in children with cystic fibrosis

Researchers have mapped how lung damage begins early in the life of children with cystic fibrosis, providing new insights that will help reshape future care.

The research team, led by the Murdoch Children’s Research Institute (MCRI) and the Peter MacCallum Cancer Centre, has created the largest lung atlas of the lower airways in young cystic fibrosis patients to date, offering new clues into preventing long-term disease.

MCRI Associate Professor Melanie Kneeland said the findings showed that while immune abnormalities in cystic fibrosis patients were well established by childhood, current treatments were failing to protect the lungs from irreversible damage.

The team analyzed more than 190,000 individual cells from 45 lung samples from 37 children aged between five months and six years who were being treated for cystic fibrosis at The Royal Children’s Hospital (RCH). Using advanced single-cell sequencing and protein analysis, they identified 43 different types of immune and epithelial cells, creating a detailed cellular map of the developing lung.

The research was supported by the Chan Zuckerberg Initiative, reflecting his interest in studying how cells function to better understand why disease occurs and how to cure it.

published in mucosal immunologyThe study found that even in preschool-age children with cystic fibrosis, their key immune cells, particularly macrophages, are not strong enough to help fight infection. These cells displayed abnormal activity in several important biological pathways, including inflammation, cholesterol regulation, and tissue lesioning associated with lung fibrosis.

Importantly, these abnormalities were more pronounced in children who had already begun to develop bronchiectasis, a form of irreversible lung damage that can cause lifelong breathing problems.

Children with cystic fibrosis often suffer frequent lung infections due to thick mucus in their airways. In Australia, about 1,600 children have cystic fibrosis and one baby is born with the condition every four days.

The researchers also examined the effects of commonly used cystic fibrosis drugs focusing on the genetic defect underlying the condition.

Associate Professor Kneeland said that despite major advances in treating cystic fibrosis, the findings showed that targeted anti-inflammatory treatments may be necessary alongside existing drugs to prevent permanent lung damage.

“We found that immune dysfunction in the lungs begins in the preschool years and persists despite current successful treatments,” he said.

“Although these treatments have been considered highly effective treatments, our findings in children suggest that their impact on lung disease may not be as great as once predicted”

“This suggests that early intervention strategies that combine these drugs with targeted anti-inflammatory therapies may help prevent lung damage. These findings provide a powerful new resource, highlighting an important window for intervention.”

Studies show there is still a long way to go to ensure that people with cystic fibrosis can remain unaffected by the disease. It also highlights the importance of studying lung disease in preschool children, who are often overlooked in research focused on adults.”

Shivanthan Shantikumar, Associate Professor, Pediatric Respiratory Specialist at MCRI, RCH

Lewis, 12, who has cystic fibrosis, took part in the first MCRI trials to change the way we look at early-life lung disease in cystic fibrosis.

Mum Justine said cystic fibrosis research has been transformative and has encouraged other families to enroll in clinical trials. To help find new treatments, MCRI researchers have also developed human lung stem cell models in the laboratory to screen thousands of existing drugs to see if any might be effective against cystic fibrosis.

“We’ve taken part in research before and would do so again if it helps other children,” Justin said. “The only reason Lewis has access to life-changing drugs is because a team of researchers somewhere has proven that they work.

“We were encouraged by his doctors not to keep Lewis in the bubble, so with the help of various treatments, he can still play sports and thrive in outdoor activities.”

Researchers from the University of Melbourne, The Royal Children’s Hospital, Walter and Eliza Hall Institute of Medical Research, The Garvan Institute of Medical Research and the University of New South Wales also contributed to the research.