Urinary club cell 16 may be biomarker for childhood asthma

Key takeaways:

• Club cell 16 levels are inversely associated with risks for childhood asthma.
• Urinary levels are inversely associated with recurrent wheeze after lower respiratory tract infections among infants.

BOSTON — Lower levels of urinary club cell 16 were associated with childhood asthma, with potentially stronger associations between these lower levels and atopic childhood asthma, according to a presentation at the CHEST Annual Meeting.

However, there were no statistically significant associations between asthma phenotypes and urinary club cell 16 (CC16), Kathleen Hiltz, MD, clinical fellow, department of medicine, division of allergy, pulmonology and critical care medicine, Vanderbilt University Medical Center, said during her presentation.

The need for a biomarker

“When we all think about allergic asthma, probably for most of us, we have a pretty clear sense of what that is. A clinical image comes to mind. It goes hand in hand with biomarkers and a few different flavors,” Hiltz said.

“It’s the classic triad of asthma, allergies and eczema,” she continued. “Serologically, it’s eosinophilia. It’s elevated IgE levels. It’s increased fractional excretion of nitric oxide. It’s all these markers of type 2 inflammation.”

However, nonallergic asthma is defined by the absence of these biomarkers, Hiltz said.

“We do not today have any real biomarkers for nonallergic asthma to identify clinically in a clinic setting, to identify for clinical trials, or to potentially direct targeted therapeutics the way that the allergic asthma phenotype has,” she said. “A biomarker in the space would be potentially very useful.”

Noting the inverse association between serum levels of CC16 in children and risks for developing asthma, the researchers said they previously had found an inverse association between urinary CC16 (uCC16) levels and recurrent wheeze after lower respiratory tract infections among infants via a validated assay.

“This is a protein that’s secreted in pretty robust quantities by bronchial epithelial cells. It likely has anti-inflammatory, antioxidant, immunomodulatory roles,” Hiltz said. “It can be measured in bronchial washings, in sputum, in serum, and it’s renally excreted.”

Urinary CC16 also would not require a blood draw from pediatric patients, Hiltz added.

The study aimed to determine if urinary CC16 had any association with childhood asthma, if there are any different associations between allergic and nonallergic phenotypes of asthma, and if it could serve as a biomarker for any of these indications.

Study design, results

The cross-sectional study used data from the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure or INSPIRE cohort of healthy term infants. It included 29 children with atopic asthma, 32 with nonatopic asthma and 89 non-asthmatic controls.

“This is a longitudinal cohort of healthy term infants who were enrolled between 2012 and 2013 and actually specifically enrolled to super-saturate for viral season,” Hiltz said. “They were enrolled with births from June through December of those years so that these kids would be at a younger age during their first RSV season.”

The researchers determined atopy among these children via allergen skin testing and specific IgE levels at age 3 years. They also collected urine samples and tested them for uCC16 at age 6 years.

“We saw a nonsignificant trend that the asthmatic kids had a trend to a lower CC16 level than the non-asthmatic children,” Hiltz said.

Adjusted median uCC16 levels included 76 ng (interquartile range [IQR], 30-156) for the atopic asthma group, 83 ng (IQR, 44-242) for the nonatopic group and 101 ng (IQR, 46-230) for the control group.

“We conducted a multivariate analysis to control for a number of factors that might play into the risk of developing asthma that included presence of siblings, maternal breastfeeding, socioeconomic factors and secondhand smoke exposure,” Hiltz said.

With each one-unit log uCC16 difference with a nonasthma reference, adjusted odds ratios for asthma at age 6 years in a multinomial logic regression included 0.71 (95% CI, 0.47-1.07) for atopic asthma and 0.87 (95% CI, 0.6-1.28) for nonatopic asthma.

“Again, there’s a trend toward a protective effect of urinary CC16 against developing allergic asthma,” Hiltz said, “but it’s not statistically significant. And that trend is not seen in the nonallergic asthmatics.”

Conclusions, next steps

Although urinary biomarkers are practical in pediatric patients, the researchers said, additional studies are necessary to ascertain associations between uCC16 and asthma diagnosis, severity and phenotypes among children.

“There’s not enough power to determine difference between really any of the above groups, particularly the asthma phenotypes,” Hiltz said. “We’d like to expand this study with some of the remaining data we have in this cohort.”

Additionally, the researchers said that they are expanding this study to classify asthma phenotypes with atopy assessments at age 6 years since the atopic markers used at age 3 years in this study could yield misclassified asthma phenotypes.

“Presumably some kids between that 3- and 6-year time point, especially in middle Tennessee, which is a land full of pollen, presumably more of those kids if anything developed seasonal allergies or an allergic phenotype in that window,” Hiltz said. “So, we’re probably underestimating our allergic asthma group.”