SPLUNC1 may be marker of flares, treatment response in children

Protein's levels in sputum fell during exacerbations, then rose after antibiotic use

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A protein secreted into the airways, called SPLUNC1, may be a sensitive biomarker of both mild pulmonary exacerbations and treatment response in children with cystic fibrosis (CF), a study suggested.

Data showed that SPLUNC1 levels in patients’ sputum were low during an exacerbation, then significantly rose after oral and, although less often needed, intravenous antibiotic treatment.

Children with higher SPLUNC1 sputum levels following treatment also went without another exacerbation for longer periods than did those with lower levels.

“The present study suggests that SPLUNC1 has potential as a sensitive biomarker for mild pulmonary exacerbations and for assessing treatment response,” researchers wrote in the study, “SPLUNC1 as a biomarker of pulmonary exacerbations in children with cystic fibrosis,” published in the Journal of Cystic Fibrosis.

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Pulmonary exacerbations or flares — acute bouts of worsening lung symptoms, often due to infections — are a common complication of CF, an inherited condition marked by the buildup of thick mucus in various organs, including the lungs.

Disease treatments for these events typically involve antibiotics, administered either orally for milder flares or directly into the bloodstream (intravenously) for more severe episodes.

With increased cough being the most common symptom of a pulmonary exacerbation, treatment decisions are challenging, particularly among children with CF. Due to a lack of sensitive biomarkers, how these flares are diagnosed and treated can vary significantly.

As such, “there is an unmet need for biomarkers sensitive to diagnose mild PEx [pulmonary exacerbation] events, that can also be used to follow up on treatment efficacy,” according to researchers at The Hospital for Sick Children in Toronto, Canada.

SPLUNC-1 is a protein secreted into the liquid on airway surfaces that plays an essential role in keeping the airways moist. A recent study indicated that SPLUNC1 levels in sputum were lower in CF adults than in healthy adults, and they decreased further during a pulmonary exacerbation. This suggests that SPLUNC1 could be used as a biomarker for such flares.

Its potential use for diagnosing exacerbations in children with milder lung disease, however, has not been assessed.

To address this gap, the team measured SPLUNC1 in sputum samples from children with CF treated for a pulmonary exacerbation with oral antibiotics, those treated with intravenous (IV) antibiotics, and children who were TRACK study participants. TRACK involved school-age children with preserved lung function and recorded their pulmonary exacerbations over two years.

Changes in SPLUNC1 sputum levels consistent across 3 groups of children

In the group of 11 children (seven girls) treated with IV antibiotics, median SPLUNC1 sputum levels significantly rose from 529.3 nanograms/mL (ng/mL) before treatment to 2,705 ng/mL after treatment. Likewise, among the seven children (four girls) treated with oral antibiotics for a flare, median SPLUNC1 levels increased from 189.5 to 362.5 ng/mL after treatment.

Among 17 of the 48 TRACK participants, median SPLUNC1 levels fell from 3,101 ng/mL — recorded at a clinic visit with stable lung function — to 1,515 ng/mL at a later visit requiring oral antibiotics for a pulmonary exacerbation. Conversely, SPLUNC1 levels rose from a median of 1,390 ng/mL at an exacerbation visit to 3,482 ng/mL at a stable follow-up visit.

“Our results show a consistent pattern of SPLUNC1 response for both intravenous and oral antibiotic therapy for PEx across three groups of pediatric CF patients,” the researchers wrote.

No associations were found between SPLUNC1 levels and those of two CF inflammatory markers: interleukin-8 (IL-8) and neutrophil elastase.

Based on findings in the first two groups, no correlation was seen between SPLUNC1 levels and lung function assessments. A lower SPLUNC1 level at exacerbation visits with TRACK participants, however, did associate with lung clearance index, a lung function test that measures how long it takes a tracer gas to be cleared from the lungs.

Higher protein levels after treatment tied to longer time without a flare

TRACK participants with higher sputum SPLUNC1 levels at a stable visit also went for a significantly longer time without a pulmonary exacerbation than those with lower levels. Periods without these flares did not relate to levels of IL-8 and neutrophil elastase.

“Our study establishes SPLUNC1 as a promising biomarker for detecting, monitoring, and predicting pulmonary exacerbations in children with CF,” the researchers wrote. “SPLUNC1 levels exhibit significant changes during PEx, are responsive to antibiotic treatment, and correlate with the LCI [lung clearance index], suggesting its potential to provide valuable clinical information.”

A study limitation was that “most of its participants” were not using a CFTR modulator therapy when their samples were collected, they noted.

“Future research should focus on validating these findings in larger cohorts [groups], exploring the mechanistic aspects of SPLUNC1 in CF exacerbations, and evaluating the potential clinical utility of SPLUNC1 in routine clinical practice,” the researchers recommended.