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4.2.2 Translation to Non-Invasive Biomarkers
While these initial findings were encouraging, they raised two issues for therapeutic
development:
1. These studies were conducted in mild-moderate asthmatics not taking ICS, but the
major unmet medical need in asthma is in more severe patients who are inadequately
controlled despite ICS treatment.
2. Although precise molecular phenotyping is possible using airway samples, collecting
airway samples requires bronchoscopy or sputum induction, which is technically
challenging, time and labor intensive, not widely available outside specialty pulmonary
practices, and thus logistically impractical in large-scale multi-center clinical trials or in
primary care settings, where most asthma patients are managed.
To address these issues, we conducted a new observational study ('BOBCAT') in 67 mod-
erate-severe asthma patients who remained poorly controlled despite high-dose ICS treat-
ment, in which we collected matched sets of induced sputum, endobronchial biopsies, and
peripheral blood. The objectives of BOBCAT were:
1. to characterize the extent and variability of eosinophilic airway inflammation in
moderate-severe asthma;
2. to identify non-invasive biomarkers of eosinophilic airway inflammation for use
in interventional trials of investigational therapeutic candidates targeting type 2
inflammation.
Consistent with previous reports [1,2] and [45] , we observed a range of eosinophilic air-
way inflammation in the BOBCAT cohort, with some but not all patients exhibiting dra-
matically elevated eosinophils in sputum and/or bronchial mucosal tissue [46] . Having
confirmed a range of airway eosinophilia in moderate-severe asthma that remained symp-
tomatic despite high-dose ICS treatment, we sought to identify non-invasive biomarkers of
the eosinophilic airway phenotype.
Th2 cytokine proteins such as IL13 are present at very low levels in peripheral blood, below
the limit of detection of all but the most sensitive assays. A recent report using such an assay
showed that circulating levels of IL13 protein were around 1pg/ml and were not apprecia-
bly different between asthma patients and healthy controls [47] . This concentration of IL13 is
10 3 -10 4 -fold lower than the amount of recombinant cytokine necessary to activate signaling in
target cells in vitro [48] . Given that IL13 receptors are highly expressed in stromal cells in the
airways, it is likely that, in patients with asthma, IL13 is produced in the airways at the site of
inflammation where the majority binds to and/or is consumed by stromal cells in the imme-
diate vicinity. Thus the level of IL13 protein in peripheral blood is unlikely to be a robust sys-
temic biomarker of its own activity in the airways. We hypothesized that IL13 might induce
the expression of genes in bronchial mucosa that could be translated to non-invasive biomark-
ers of the 'Th2-high' molecular phenotype in the airways. We will next consider three differ-
ent examples of biomarkers identified through this process: serum periostin, FeNO, and blood
eosinophil counts.
We searched among the genes correlated with the Th2 signature in epithelial brushings
and endobronchial biopsies for those encoding extracellular proteins to determine whether
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