Inflammatory Markers May Help Predict Exacerbations in Children with CF

Levels of inflammatory markers in the lungs may help predict pulmonary exacerbations in children with cystic fibrosis (CF), a new study suggests.

The study, “BAL inflammatory markers can predict pulmonary exacerbations in children with cystic fibrosis,” was published in the journal Chest.

In people with CF, pulmonary exacerbation is a term that refers to a sudden decline in lung function and worsening of symptoms. Since these exacerbations can cause long-term damage to the lungs, their prompt diagnosis and treatment is important, especially during the first years of life.

Diagnosing exacerbations in children is challenging, because children often have few clear symptoms even when they have lung inflammation. In addition, it is difficult to perform some exacerbation-related diagnostic tests — like measurements of lung function — in children.

In this study, researchers assessed whether inflammatory markers in the lungs might be useful for predicting or identifying pulmonary exacerbations in children with CF.

The team used data from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) study, a longitudinal study of children with CF up to age 7. As part of this study, bronchoalveolar lavage (BAL) fluid was collected shortly after the diagnosis of CF, then annually thereafter.

BAL fluid is basically a rinse of the lung, in which some fluid is introduced to the lung and then collected.

Researchers assessed the amount of inflammatory markers — including immune cells and signaling molecules — in BAL fluid. Through statistical analyses, they looked for markers that were significantly associated with the risk of experiencing an exacerbation within six months of the BAL fluid collection.

“We considered a follow-up of six months to reflect a clinically relevant period in which clinicians would find useful to assess and prognosticate the risk of worsening symptoms and likely exacerbations,” the researchers wrote.

In total, 976 BAL fluid samples taken from 308 children were analyzed. There were 145 recorded hospital admissions for pulmonary exacerbations.  Admissions due to infection with the bacteria Pseudomonas aeruginosa were excluded from the analysis. The median time to exacerbation was 31 days.

The team found three inflammatory markers significantly associated with an increased exacerbation risk.

One was the percentage of neutrophils, a type of immune cell that is important for fighting infections and that also is a primary driver of lung-damaging inflammation in CF. For every one-point increase in interquartile range (IQR) of neutrophil percentage, the risk of exacerbation increased by about 56%.

Another was the presence of neutrophil elastase, a protein produced by neutrophils that breaks down cell and tissue structures. If this protein was present, the risk of exacerbation was more than two times higher.

The third significant marker found was the level of interleukin-8 (IL-8), an inflammatory signaling molecule that helps recruit neutrophils to areas of active inflammation. For every one IQR increase in IL-8 levels, exacerbation risk increased by about 80%.

Additional statistical models were constructed to account for other factors, including previous exacerbations, age, and respiratory symptoms at the time of BAL fluid collection. All three markers remained significant predictors of exacerbations after adjusting for these factors. They also remained significant predictors after adjustment for lung imaging done by CT scans, which was available for 61% of the patients analyzed.

Overall, “we found that free neutrophil elastase activity, high neutrophil percentage and high interleukin-8 from bronchoalveolar lavage are strongly significant predictors of the time to next severe CF pulmonary exacerbations in young children,” researchers wrote.

In a model that considered all three markers concurrently, IL-8 and neutrophil elastase levels were no longer significant predictors. This suggested that “the markers are strongly correlated with each other, and that high neutrophil percentage appears to be the strongest independent predictor for time-to-exacerbation,” the researchers wrote.

The team noted that additional studies will be needed to validate these results. They also acknowledged that BAL fluid collection is a relatively invasive procedure that may not be feasible in all settings. As such, researchers emphasized the importance of developing less invasive methods for sampling inflammatory markers in the lungs, such as analyzing exhaled breath condensate.

“Less invasive tests are required for the regular and routine surveillance for pulmonary exacerbations in young children in order to facilitate early detection and treatment,” the team concluded.