Immune dysfunction found in CF children, even absent infections
Elevated levels of immune cells seen in lungs of preschoolers in study
Evidence of immune dysfunction — elevated levels of immune cells and immune-related molecules — were found in the lungs of preschool children with cystic fibrosis (CF), even among kids without CF-related lung infections, a new study showed.
Treatment with Kalydeco (ivacaftor), but not Orkambi (ivacaftor/lumacaftor), partially restored the immune balance in the lungs of these young patients, the researchers reported, noting that the approved oral therapy Kalydeco “ameliorates pulmonary [lung] inflammation in early life.”
“We provide a rationale for targeted anti-inflammatory intervention in early-life CF,” the team wrote.
Titled “Inflammation in preschool cystic fibrosis is of mixed phenotype, extends beyond the lung and is differentially modified by CFTR modulators,” their study was published in the journal Thorax.
Investigating immune dysfunction in children with, without CF
In CF, the thick mucus that builds up in the lungs and blocks patients’ airflow also promotes infection and inflammation. Treatments like CFTR modulators “address the underlying defect in CF and have resulted in dramatic improvements [to] clear mucus,” the researchers wrote. However, they noted, “their impact on inflammation is less clear.”
The team further noted that “for children unable to access CFTR modulator therapy … anti-inflammatory therapies that ameliorate lung disease severity are desperately needed.”
According to the researchers, “understanding the early-life origins and characteristics of inflammation [are] essential for the development of new therapies to ensure best long-term outcomes for people with CF.”
To that end, a team from the Murdoch Children’s Research Institute in Australia examined the immune signatures of 70 preschool children with CF. Among them, 16 were on CFTR modulator therapy. A group of 32 age-matched children without a history of lung disease served as controls.
In the bronchoalveolar lavage fluid (BALF) of untreated CF children, obtained by rinsing the lungs with a saline solution, the team detected 40 immune-related molecules that were significantly elevated compared with those seen in the controls. Likewise, the counts of certain immune cells were also significantly higher in CF children than in the controls. Specifically, such differences were seen with neutrophils (31.31 vs. 1.8%), eosinophils (0.55 vs. 0.06%), and monocytes (1.91 vs. 0.45%).
When compared, higher neutrophil counts in BALF were associated with elevated levels of 35 immune-related molecules, while eosinophilic were linked with 19.
Kalydeco, Orkambi tested as possible treatments for lung inflammation
To explore the effect of CFTR modulator therapy on lung inflammation, the team conducted a clustering analysis — a way to group similar things together based on their characteristics — of immune-related molecules and immune cells detected in BALF. Here, samples from patients treated with Kalydeco clustered more closely to non-CF samples, while those given Orkambi matched untreated CF samples.
In blood samples collected to assess systemic, or bodywide, inflammation, the levels of 13 immune signaling proteins were significantly higher than those seen in the controls. Of these, 11 were also elevated in BALF, suggesting that blood “could act as a surrogate for lung inflammation in early-life CF,” the team wrote.
In particular, three such signaling proteins were highly elevated in both the lungs and blood of CF children: interleukin-4, known as IL-4, IL-13, and FGF-2.
In clinical microbiology testing of BALF, fewer CF children tested negative for the four key microbes that contribute to CF lung disease than non-CF children (57.14% vs. 69.57%). These microbes were Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Aspergillus.
Aspergillus alone was detected in 2.85% of CF children, while 12.85% had evidence of co-colonization of the common microbes. In controls, there were no signs of Aspergillus or co-colonization. By contrast, S. aureus alone was detected in more controls than CF children (17.39% vs. 15.71%), as was H. influenzae (13.04% vs. 11.43%).
These results inform future research into the management of inflammation in CF and provide evidence for translating anti-inflammatory therapy into [pediatric] CF clinical care.
When comparing the median BAL levels of immune-related molecules or cells, there was no significant difference between children with CF not on modulators, who had at least one of these microbes in their BAL, and those who did not. This suggested a “limited effect of these pathogens [disease-causing agents] on the inflammatory profile in early-life CF,” the researchers wrote.
Among all participants without any signs of the four key microbes, CF children alone showed a markedly elevated inflammatory response, as indicated by higher levels of immune molecules and immune cells.
Lastly, looking at the youngest CF children, ages 6 months to 2 years, no differences were observed in the levels of immune molecules in those with or without lung microbes. Still, CF infants without microbes in the lungs had evidence of lung inflammation, as indicated by increases in several immune signaling proteins.
“These results inform future research into the management of inflammation in CF and provide evidence for translating anti-inflammatory therapy into [pediatric] CF clinical care,” the researchers wrote.
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