Is TWEAK a New Biomarker in Asthma?

Soo Yeon Kim, MD

A component in the pathogenesis of inflammatory conditions such as rheumatoid arthritis plays a role in airway inflammation, and a new study suggests it could serve as a biomarker for non-eosinophilic asthma (NEA) in children.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a type II-transmembrane protein expressed in a variety of cells, can be cleaved to form a soluble cytokine with functions that include pro-inflammation. It acts through a highly inducible receptor, fibroblast growth factor-inducible 14 (Fn14), and has been found to be elevated in inflammatory disease.

Soo Yeon Kim, MD, Department of Pediatrics, Institute of Allergy, Severance Hospital and Yonsei University College of Medicine, Seoul, Korea and colleagues note that while there have been a few studies investigating the effect of TWEAK/Fn14 signaling in human bronchial epithelial cells and these suggest a role in airway inflammation, there have been no reports of its expression in patients with respiratory disease.

"Although asthma was traditionally believed to result from inflammation driven by T-helper type 2 (Th2) responses, recent studies have focused on the highly heterogeneous features of the disease, including multiple phenotypes and endotypes," Kim and colleagues wrote. "However, airway inflammation has been rarely measured in clinics, and the inflammatory process remains inconsistently identified."

In this first investigation into a possible relationship between TWEAK and asthma, Kim and colleagues targeted NEA, which is characterized by neutrophilic airway inflammation and frequently associated with severe, steroid resistant symptoms. They pointed out there is also less known about underlying phenotypes and molecular mechanisms than there is with eosinophilic asthma.

Kim and colleagues identified 95 children with non-eosinophilic asthma from eosinophil and neutrophil counts in sputum, and 78 healthy controls, aged 5-18 years. The children were further differentiated for having high or low sputum TWEAK levels. The diagnosis of persistent asthma by referring physicians was confirmed by either a bronchodilator response of at least 12% increase in the forced expiratory volume in 1 second (FEV1) or bronchial hyperresponsiveness corresponding to decrease of FEV1 of at least 20% with inhalation of less than 16 mg/ml methacholine.

The investigators reported that children with asthma had higher sputum TWEAK levels than healthy controls, and that this was particularly evident in those with severe and uncontrolled asthma. The TWEAK levels were significantly correlated with pulmonary function test parameters reflecting airway obstruction and were particularly prominent in subjects with NEA inflammation. In contrast, there was no statistically significant differences in TWEAK levels across asthma severity levels in those with eosinophilic asthma.

"Accordingly, TWEAK may have a greater association with NEA inflammation, potentially explaining the underlying molecular process of non-eosinophilic asthma," researchers wrote.

In an accompanying editorial, Ulrich Wahn, MD, Professor Emeritus of Pediatrics and Allergy, Department of Pediatric Pulmonology and Immunology, University Hospital Charité, Berlin, Germany welcomed the possibility of a new biomarker for NEA, but cautioned that more analysis is needed.

"While this is the first study to investigate the possible relationship between airway TWEAK and childhood asthma, following molecular and clinical studies are required to clarify the potential role of TWEAK in non-eosinophilic asthma," Wahn wrote.

The study, "Sputum TWEAK expression correlates with severity and degree of control in non-eosinophilic childhood asthma," was published online in Pediatric Allergy and Immunology this February.