Airway Inflammation and Inflammatory Biomarkers

Hui Fang Lim, MBBS, MRCP (UK); Parameswaran Nair, MD, PhD, FRCP, FRCPC

Disclosures

Semin Respir Crit Care Med. 2018;39(1):56-63. 

In This Article

T2 Biomarkers

At present, the T2 biomarkers in clinical use are limited to the following: quantitative sputum cytometry, blood eosinophil count, a fraction of exhaled nitric oxide (FeNO) and serum IgE. The correlation between blood eosinophil count, FeNO, periostin, and serum immunoglobulin E (IgE) levels with sputum eosinophil counts is poor. In a systematic review, the area under the curve for each is only 0.78, 0.75, 0.65, and 0.65, respectively; combinations of the biomarkers did not improve their ability to predict sputum eosinophilia.[14] Still, these biomarkers might represent different disease pathways within the T2-high endotype. We propose a simple decision algorithm based on the presence or absence of these biomarkers, which might help physicians select the most appropriate biologic for their patients (Table 1, Figure 1).

Figure 1.

T2 biomarkers predictive of severe eosinophilic asthma—Periostin, fraction of exhaled nitric oxide (FeNO), eosinophil (eos) counts (blood and sputum). Periostin is a matricellular protein, which is induced by the cytokine interleukin (IL) 13 and secreted basolaterally by the epithelial cells into the blood stream. However, anti-IL13 monoclonal antibody (mAb) therapy did not show clinical efficacy and periostin is currently unavailable for clinical use. FeNO is a nonspecific biomarker for IL5 and IL13 activity on inducible nitrous oxide synthase in the epithelial cells. Blood and sputum eos are induced by IL4, IL5, and IL13. Anti-IL5 mAb will reduce both blood and sputum eos but anti-IL4/IL13 treatment will block the migration of eosinophils into the airway lumen and increase blood eos even when asthma and sputum eos are controlled.

Sputum Quantitative Cytometry

Sputum quantitative cytometry is noninvasive, well-validated, and reproducible,[15,16] with established normal reference ranges.[17,18] It allows the assessment of the intensity of cellularity (total cell count expressed as a gram of sputum), and a white cell differential percentage. The presence of eosinophils is generally a predictor of response to corticosteroids,[19] and the absence is a predictor of nonresponse.[20] Though monitoring of airway inflammation does not seem to add value to the management of patients mild-to-moderate asthma,[21] an airway biomarker strategy had been consistently shown to be superior in the SA group. In this group, corticosteroid treatment can be titrated based on sputum cell counts with significant improvements in asthma control and exacerbation reduction.[22–24] Even in the group who are prednisolone-dependent, this is a cost-effective strategy that had been shown to result in fewer exacerbations (mean 0.3/y) and an improvement in forced expiratory volume in the first second (FEV1).[25]

Also, this biomarker can precisely identify patients with severe eosinophilic asthma who will respond to anti-IL5 therapy. Earlier studies on mepolizumab failed to show improvement in clinical outcomes because they included milder asthma patients and "lumped" SA using nonspecific clinical characteristics.[15,16] Using more precise characterization with sputum eosinophilia as a biomarker for the eosinophilic SA endotype, subsequent phase 2 studies managed to demonstrate significant improvements in reduction of exacerbations and asthma control.[26,27] In the most severe prednisolone-dependent asthmatics subgroup, intravenous mepolizumab resulted in the successful steroid withdrawal in all of these patients and improvement in FEV1.[27] This underscores the accuracy of quantitative sputum cytometry as a T2 biomarker; more importantly, that the maximal clinical benefit from biologics is derived from careful patient selection, especially in the "most severe" group of SA patients.

However, despite the clinical effectiveness of quantitative sputum cytometry in disease monitoring, assessing the risk of future exacerbations, predicting treatment response to anti-IL5 biologics, this biomarker is not widely adopted due to cost and infrastructure constraints in many centers. To overcome these technical issues, readily accessible or point-of-care diagnostic methods are needed, for example, detection of eosinophil peroxidase in sputum using a bioactive paper,[28,29] or on nasal or pharyngeal swabs.[30]

Blood Eosinophils

Due to its accessibility and modest correlation with airway eosinophilia, eosinophil cutoff values were used to predict response to anti-IL5 monoclonal antibodies (mAbs). Different blood values were used: >150 cells/μL for mepolizumab,[31,32] >300 cells/μL for benralizumab,[33,34] and >400 cells/μL for reslizumab.[35] However, the selection of these different thresholds are arbitrary, and there are many limitations in using a single blood count to guide management decisions in SA. In these studies, when the frequency of exacerbations is taken as a function of the baseline blood eosinophil level, a higher blood eosinophil cutoff is associated with a larger reduction in the exacerbation rates.[36] Blood eosinophil is not sensitive in picking up the most severe asthmatics because relationship between sputum and blood eosinophilia becomes weaker with increasing disease severity, especially in the prednisolone-dependent asthmatics.[37] In prednisolone-dependent patients, defined using persistent sputum eosinophilia as a biomarker, 100% of the patients experienced a steroid-sparing effect with intravenous 750 mg mepolizumab,[27] versus only 50% of the patients in the phase 3 study by Bel et al that defined SA based on blood threshold of >150 cells/μL and used subcutaneous mepolizumab 100 mg.[32] Hence choosing a single and lower cutoff for blood eosinophil counts, that is, including less severe asthmatics for anti-IL5 therapy will dilute the overall cost-effectiveness.

Also, blood eosinophil counts cannot be used for monitoring treatment response to biologics.[27] Blood eosinophil counts that have been normalized by an anti-IL5 mAb may not reflect uncontrolled sputum eosinophilia that may be associated with poor asthma control. There is evidence that this may be a reflection of inadequate suppression of local eosinophilopoeitic processes driven,[38–40] by locally derived cytokines from sources such as the type-2 innate lymphoid cells (ILCs)[38,39] or local autoimmune mechanisms.[40] A raised blood eosinophil count is also not a good predictor of treatment response to anti-IL4/IL13.[34] Wenzel et al, showed that dupilumab responders had an improvement in FEV1 and fewer exacerbations regardless of the blood eosinophil counts. Also, dupilumab causes an increase in blood eosinophil levels due to a reduction in eosinophil migration from blood into the airway. In summary, while blood eosinophil count may be used mainly to identify patients who may respond to anti-IL5, there is insufficient evidence to demonstrate if they would be helpful to monitor and guide long-term therapy.

Fractional Exhaled Nitric Oxide

FeNO might reflect ongoing epithelial cell activation driven by IL5 and IL13. IL5 and IL13 activate epithelial inducible nitric oxide synthase's (iNOS), to produce NO. This is measured noninvasively in exhaled breath with standardized methods.[41] Despite the lack of robust evidence, the guidelines suggested that FeNO > 50 ppb in adults (> 35 ppb in children) was a reasonable marker of eosinophilic inflammation. A drop in FeNO by 20% or 10 ppb was considered to signify a response to corticosteroid therapy when baseline FeNO was >50 ppb or <50 ppb, respectively. In patients with difficult-to-treat asthma, a single value of FeNO > 45 ppb (FeNO suppression test) had a reasonable accuracy in detecting treatment nonadherence.[42] In pregnant asthmatics, a FeNO-guided algorithm was shown to reduce exacerbations, improve the quality of life, and reduce neonatal hospitalizations,[43] when inhaled corticosteroids (ICS) is up-titrated when FeNO is ≥30 ppb or down-titrated when ≤15 ppb. Similarly, in frequent "exacerbators," that is, children and adults who experience more than one exacerbation per year, systematic reviews showed that FeNO-guided treatment might be useful in reducing these events (odds ratio: approximately 0.6).[44,45]

However, it is not clear how FeNO can guide therapy with biologics.[46,47] Anti-IL5 mAbs do not consistently reduce FeNO and might be related to the poor correlation with sputum eosinophilia despite in the most severe prednisolone-dependent asthmatics.[48] However, therapy directed against IgE,[49] IL13,[50] and IL4/13[34,51] can reduce FeNO, which suggests that it might represent a T2-high endotype with epithelial dysfunction and might be a weak-to-modest predictor of response to these therapies (Table 2).

Serum Immunoglobulin E

IgE plays a central role in the development of allergic asthma and is a good biomarker for atopy status. Allergen exposure stimulates the production of allergen-specific IgE that binds to its high-affinity receptor FcepsilonRI (FcεRI), found predominantly on mast cells and also other cells, such as basophils, platelets, monocytes, and antigen presenting cells.[52] In atopic patients, reexposure to the allergen results in the bound IgE cross-linking with the allergen, triggering the release of mast cell mediators that result in the clinical manifestations of airway bronchoconstriction, erythema, and soft tissue edema.[53] Serum total IgE had been used as a biomarker for the phase 3 anti-IgE omalizumab studies. In phase 3 INNOVATE trial,[54] omalizumab as an add-on therapy to severe persistent allergic asthma, was able to demonstrate a significant reduction in exacerbations rates (0.68 vs. 0.91), severe exacerbation rates (0.24 vs. 0.48), and emergency department visits (0.254 vs. 0.43) when compared with placebo. In the phase 3b EXTRA study Hanania et al,[49] also showed that omalizumab could significantly improve asthma quality of life and reduce the use of rescue medications and asthma symptoms.

Nonetheless, serum total IgE is a poor biomarker for predicting treatment response to omalizumab.[55] Based on data from the EXTRA study, periostin ≥50 ng/mL, blood eosinophil ≥260/μL and FeNO ≥19.5 ppb were shown to predict a risk reduction of exacerbation by only 30, 32, and 53%, respectively, compared with no biomarkers.[46] Local mucosal IgE rather than serum IgE might be a useful biomarker in nonatopic omalizumab responders.[56] Other ways to assess treatment response to anti-IgE therapy include measurement of cell surface measurements of FcεRI.[57] Posing a management conundrum is a group of severe asthmatics with both high eosinophil and high IgE levels, and it is uncertain if anti-IgE versus anti-IL5 treatment is superior. We propose that in this group, the prednisolone-dependent patients will benefit more from anti-IL5 rather anti-IgE therapy since it would suggest that uncontrolled eosinophilic inflammation mediated by T2 cytokines is the dominant force (Table 2).

Periostin

Periostin is a matricellular protein that is partly regulated by IL13 and is secreted by the basal airway epithelial cells and is associated with eosinophilic inflammation and subepithelial fibrosis (Figure 1).[58] It was initially proposed as a biomarker to predict treatment response to anti-IL13 mAb. Corren et al, first showed in a phase 2 study that patients with high periostin levels had significant improvement in FEV1 and 67% risk reduction of exacerbation when treated with lebrikizumab compared with placebo.[47] In the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study, a cutoff of 25 ng/mL to detect tissue and/or luminal eosinophilia has a sensitivity, specificity, positive predictive value, and negative predictive value of 57, 85, 93, and 37%, respectively.[58] However, in a dose ranging study in mild asthmatics, not on ICS, periostin was unable to predict a treatment response.[59] This emphasized the role of periostin as a biomarker mainly in SA, in which there is an excess IL13-mediated Th2-high response.

Interestingly, serum periostin performs less well when compared with blood eosinophilia as a surrogate marker of sputum eosinophilia.[60] This might be related to whether it is the IL5 or IL13-mediated pathway that is driving the sputum eosinophilia.[61] Unfortunately, recent data from two similar phase 3 studies in lebrikizumab did not consistently demonstrate a risk reduction in exacerbations.[50] Hence the role of periostin as a marker for IL13 activity is limited by the lack of clear clinical efficacy of anti-IL13 therapy. It remains unclear if this test would be available for routine clinical use and if it can be used to predict responders to anti-IL4/IL13.

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