Biomarkers predict type 2-high, uncontrolled asthma
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Key takeaways:
- 30.4% of patients with uncontrolled asthma had higher levels of FeNO, blood eosinophils and serum-free IgE.
- 69.6% of patients with well-controlled asthma had lower levels of these three biomarkers.
Blood eosinophil counts, serum IgE and fractional exhaled nitric oxide may be used to classify patients with T2-high or uncontrolled asthma, according to a study published in Annals of Allergy, Asthma & Immunology.
These biomarkers also may be used to indicate which patients may benefit from T2 biologics, Seong-Dae Woo, MD, PhD, division of pulmonology, department of internal medicine, Chungnam National University School of Medicine, and colleagues wrote.
The study classified 133 patients age 18 years and older with asthma based on whether their blood eosinophil counts (BECs) were 300 cells/µL or higher, their serum-free IgE was 120 ng/mL or higher and their FeNO was 25 parts per billion (ppb) or higher.
Patients with higher levels of all three T2 markers were categorized as group 1 (n = 23; 17.3%), those with higher levels of one or two of these markers were categorized as group 2 (n = 87; 65.4%), and those with lower levels of all three markers were categorized as group 3 (n = 23; 17.3%).
The cohort included 57 (42.9%) patients with higher BECs, 79 (59.4%) with higher serum-free IgE and 61 (45.9%) with higher FeNO values. The researchers reported a moderate positive correlation between BECs and FeNO levels (Spearman correlation coefficient = 0.445; P < .001).
There also was a weak positive correlation between BECs and serum-free levels (Spearman correlation coefficient = 0.173; P = .04), the researchers said, but there was no correlation between serum-free IgE and FeNO levels (Spearman correlation coefficient = 0.073).
Compared with group 3, group 1 had greater proportions of patients who used high doses of inhaled corticosteroids (P = .03); higher serum-free IgE levels, BECs and FeNO levels (P < .001 for all); and higher atopic status (P =.04).
Also, group 1 had lower FEV1 percent predicted values (P = .03) and tended to have lower forced vital capacity (FVC) percent values and FEV1/FVC values than group 3.
Sputum eosinophil counts included 38.8% ± 33.3% for group 1 and 16% ± 31.2% for group 3 (P = .02). Sputum neutrophil counts included 52.7% ± 36.7% for group 1 and 75.8% ± 31.2% for group 3 (P = .01).
Plasma eosinophil-derived neurotoxin levels included 21.2 ± 12.3 ng/mL for group 1 and 9.7 ± 4.9 ng/mL for group 3 (P = .001). Serum periostin levels were 82.7 ± 27.8 ng/mL for group 1 and 70.1 ± 20.7 ng/mL for group 3.
Based on Global Initiative for Asthma Control guidelines, 15 patients (11.3%) had uncontrolled asthma, 48 (36.1%) had partly controlled asthma and 70 (52.6%) had well-controlled asthma.
In group 1, 30.4% had uncontrolled asthma, 43.5% had partly controlled asthma and 26.1% had well-controlled asthma. These percentages were 9.2%, 36.8% and 54%, respectively, in group 2, and 0%, 30.4% and 69.6% in group 3.
The researchers said that rates of partly controlled and uncontrolled asthma were significantly higher in group 1 compared with group 2 (RR = 1.608; 95% CI, 1.152-2.243) and group 3 (RR = 2.429; 95% CI, 1.25-4.717), although they did not see any differences between groups 2 and 3 (RR = 1.511; 95% CI, 0.782-2.919).
Further, the uncontrolled group had higher BEC levels (786.7 µL ± 324.5 µL) than the partly controlled group (320.2 µL ± 37.1 µL; P = .02) and the well-controlled group (279.1 µL ± 25.8 µL; P = .002).
The uncontrolled group also had higher FeNO levels (54.3 ppb ± 9.9 ppb) than the well-controlled group (28.8 ppb ± 3.5 ppb; P = .004). Although they did not note any statistical significance, the researchers said the uncontrolled group also had higher serum-free IgE levels than the well-controlled group (488.2 ng/mL ± 107.2 ng/mL vs. 298.2 ng/mL ± 46.9 ng/mL).
FEV1 percent predicted values included 66.2% ± 21.4% for the uncontrolled group, 92.6% ± 12.9% (P < .001) for the partly controlled group and 95.6% ± 14% (P < .001) for the well-controlled group.
Using areas under the curve, the researchers determined cutoff points for predicting uncontrolled asthma of 22 ppb for FeNO, 161.4 cells/µL for BEC and 85.9 ng/mL for serum-free IgE.
Additionally, patients with high FeNO levels had higher levels of Singlec8+ eosinophils (P = .03) and CD66+ neutrophils (P = .003) than patients with low FeNO levels. Patients with high levels of BECs had higher levels of Siglec8+ eosinophils than patients with low BEC levels as well (P < .001).
These findings validated BEC, serum-free IgE and FeNO as T2 biomarkers, as patients with high levels were characterized by the T2-high immune pathway along with lower FEV1 percent predicted and uncontrolled asthma, the researchers said.
Patients with asthma who have high levels of these biomarkers, the researchers said, may be candidates for additional T2 biologics even if they are on maintenance treatment including inhaled corticosteroids.
Perspective
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Christopher O'Brien, MD, PhD, FCCP
As the development of advanced anti-inflammatory therapeutics for patients with asthma has progressed to include a range of mechanisms, a parallel evolution in the characterization of identifiable endotypes and practical adoption of these concepts in clinical practice has also occurred.
The increasing understanding of T2 high vs. T2 low endotypes has gained particular attention as therapeutics targeted against IgE, IL-5/IL-5r, IL-4/13 and thymic stromal lymphopoietin or TSLP are now commercially available, and multiple potential therapeutics with novel mechanisms and a variety of delivery routes are also under active investigation.
As a result, the optimal application of practical and available biomarkers to identify at-risk patients and facilitate appropriate use of these advanced therapeutics in real-world practice has also gained significant attention.
The study by Woo and colleagues is an interesting and useful real-world addition to the body of evidence supporting mechanism-based personalized medicine strategies. This cross-sectional study was conducted in a large, well-characterized single center cohort in South Korea of severe asthma patients maintained on inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) regimens with the objective of characterizing the distribution and relationships of three clinically available biomarkers of T2 inflammation, evaluating correlations to measures of control, and identifying optimal cutoff values for prediction of asthma patients at risk for uncontrolled or T2 asthma that might warrant advanced therapy.
The authors performed receiver operating characteristic analysis to derive optimal cutoffs for two commonly used measures, FeNO and BEC, as well as for serum-free IgE, an updated measure of IgE distinct from the commonly obtained total serum IgE measure.
Reassuringly, in this real-world population of patients maintained on ICS/LABA-based treatment in a demographic group that is relatively understudied in global clinical programs, the authors derived cutoff values for FeNO (22 ppb) and for BEC (161 cells/µl) for predicting uncontrolled asthma in line with those increasingly cited in guidelines and employed in practice. In addition, novel information on cutoffs for serum-free IgE levels (86 ng/ml) was developed.
Of interest, the authors offer a nice presentation of the relationship between each of the three parameters, corroborating in this population that earlier findings that the overlap across these parameters and sensitivity of each measure in identifying type 2 patients is not always as tight as many assume.
Similarly, in this population, the researchers evaluate the relationship between the three biomarkers and measures of uncontrolled asthma as well as inflammatory cell markers of T2 and non-T2 inflammation, yielding the finding that FeNO and BEC have the highest correlation with inflammatory cell markers in T2 high patients.
As the authors note, the next step in this and other similar exercises will be to perform longitudinal studies that allow assessment of how these measures, used alone or as composite measures to classify patient endotype groups, perform in both predicting risk and outcomes to therapy.
These next steps will be critical to providing informed guidance on the use of an increasingly diverse armamentarium of therapeutics for patients with moderate to severe asthma who are not controlled on ICS/LABA-based maintenance regimens.
Perspective
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Blood eosinophil count (IL-5 pathway), FeNO (IL-13 pathway) and IgE (IL-4 pathway) are not perfectly overlapped, which may reflect different facets of T2 high asthma. Also, since current biologics are used for severe eosinophilic asthma, optimal cutoff values for blood eosinophils, IgE and FeNO should be investigated in severe asthma, which might be higher than the values identified in the current study.
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