Levels of neutrophil elastase, a pro-inflammatory enzyme normally released by immune cells known as neutrophils, plus a greater diversity and amount of microbes could drive disease severity in cystic fibrosis (CF), a study in two siblings suggests.
The study, Two Siblings Homozygous for F508del-CFTR Have Varied Disease Phenotypes and Protein Biomarkers, was published in the International Journal of Molecular Sciences.
Accurate, non-invasive, and clinically important biomarkers are critical to support diagnosis, monitor disease progression, and optimize treatment decisions.
Researchers detailed the case of two sisters, born one year apart and both living at home, described as patient A and patient B. Each had two copies of the CFTR gene with a delF508 mutation, the most common CF-causing mutation.
Despite a similar CFTR genetic profile and home environment, the two girls, 15 years old when this study started, showed different disease features.
To understand these differences and identify potentially relevant biomarkers, researchers at University of Tennessee Health Science Center and LeBonheur Children’s Hospital, in Memphis, analyzed several inflammatory proteins in the siblings’ sputum to determine a possible association between their levels and disease severity.
Sputum samples were collected during routine hospital visits and pulmonary exacerbations. Patient A had seven hospital visits between November 2015 and June 2017; patient B made five visits between August 2016 and June 2017. Their medical records and data from the CF Foundation Patient Registry were also explored.
Analyzed inflammatory markers included neutrophil elastase (NE) and interleukin-8 (IL-8), a molecule that helps recruit neutrophils to sites of inflammation.
A possible association between these inflammation markers and predicted forced expiratory volume in one second (FEV1), an indicator of lung health that measures the amount of air forcibly exhaled in the first second after a breath, was assessed.
Sputum samples were also screened for a panel of other inflammatory markers, including molecules associated with neutrophils and with certain T helper (Th) cells. Collectively, these cells promote immune responses by helping activate other immune cells to secrete antibodies and destroy ingested microbes. They also activate cytotoxic T-cells, so named because they kill infected cells.
Patient A was also being treated with Orkambi (ivacaftor/lumacaftor, by Vertex), but showed a more severe disease, with two pulmonary flares shortly after visits one and three, and a predicted FEV1 between 34% and 45%. Her sister, who was not taking Orkambi, had one mild pulmonary flare during the study and a predicted FEV1 ranging from 48% to 90%.
When examined, patient A had crackles (caused by excessive fluid) in both lungs on inspiration, while patient B had crackles at the base of her right lung on visit four.
Compared with her sister, patient A generally showed higher levels of IL-8 and NE. Levels of both IL-8 and NE increased drastically during the flare in patient B, and before exacerbations in patient A.
Researchers found a relationship between NE levels and predicted FEV1 in patient A. No such association was evident between IL-8 levels and FEV1 in either patient.
Overall, these findings seemed to support neutrophil elastase as the most informative biomarker of disease severity, the researchers wrote.
Measures associated higher levels of other inflammation markers in patient A with the response of certain helper T-cells: Th17 (such as interleukin-6, or IL-6), Th1 (including interferon gamma), and Th2 (IL-13).
According to the researchers, patient A’s higher levels indicate that different branches of the immune response were activated, which may explain her more severe lung disease and lower predicted FEV1.
This activation may result from her exposure to different types and amounts of microorganisms, the scientists said.
In fact, the siblings’ sputum showed differences in microorganisms. Sputum from patient A “routinely” tested positive for methicillin-resistant Staphylococcus aureus (MRSA; for over 10 years), Aspergillus fumigatus, and occasionally for Stenotrophomonas maltophilia.
Her sister showed the presence of Pseudomonas aeruginosa, MRSA, stenotrophomonas, Candida albicans, Escherichia coli, and Klebsiella pneumoniae.
These differences in microbial infections, the researchers wrote, could play a key role in determining the differences in disease severity observed in the two sisters.
“After our study, the subjects continued mostly the same therapy/treatment until they started triple combination CFTR modulators with [Trikafta, also by Vertex] in late 2019. They experienced an improvement in lung function and reduced PEs [pulmonary exacerbations]. Both have now transitioned their care to an adult CF program,” the team wrote.
“It will be interesting to see the long-term effect of Trikafta on their disease trajectories and how inflammatory mediators (e.g., NE and IL-8) respond to this novel therapy,” the investigators added.
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