Inflammatory Markers to Inform Treatment of Asthma With Biologicals: FeNO Versus Blood Eosinophils.

The introduction of biological therapies for the treatment of asthma has stimulated need for validated inflammatory markers to identify patients most likely to derive clinical benefit (Figure 1). Those most in use today are the fraction of exhaled nitric oxide (FeNO), blood eosinophil (B-Eos) count, and total IgE. Both FeNO and B-Eos are candidates to predict response to biologicals targeting type-2 inflammation, whereas total IgE is used to dose omalizumab (anti-IgE) therapy. The European Medicines Agency claims that patients with asthma considered for treatment with the dual interleukin IL-4/IL-13 blocker dupilumab should have evidence of type-2 inflammation manifest by elevated FeNO and/or B-Eos count. FeNO and blood eosinophils represent related and not distinct inflammatory pathways and correlate modestly at best.1Alving K. Malinovschi A. Basic aspects of exhaled nitric oxide.Eur Respir Monograph. 2010; 49: 1-31Crossref Google Scholar Accordingly, the 2 markers independently associate with asthma morbidity.2Malinovschi A. Fonseca J.A. Jacinto T. Alving K. Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects.J Allergy Clin Immunol. 2013; 132: 821-827.e5Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar However, independent associations between FeNO or B-Eos count and responsiveness to biological therapies have been much less studied. In this issue of The Journal of Allergy and Clinical Immunology: In Practice, Pavord et al3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar report that the pretreatment FeNO predict clinical response to treatment with dupilumab independently of B-Eos count. The search for biomarkers predicting a clinical response to anti–IL-4/IL-13 biologicals started years ago, in a phase 2 trial in patients with moderate asthma who received the anti–IL-13 antibody lebrikizumab or placebo for 24 weeks.4Corren J. Lemanske R.F. Hanania N.A. Korenblat P.E. Parsey M.V. Arron J.R. et al.Lebrikizumab treatment in adults with asthma.N Engl J Med. 2011; 365: 1088-1098Crossref PubMed Scopus (1380) Google Scholar Patients were stratified into type-2 high and low (based on total IgE and B-Eos count) or high/low serum periostin; the primary outcome for the trial was increased FEV1. Participants in the biomarker-high groups had better responses. However, in a post hoc analysis, the stratification of patients according to baseline FeNO, below and above the median (21 parts per billion, ppb), showed that the predictive value of FeNO was at least as good, if not better, than serum periostin. Although periostin had less intrasubject variability during run-in compared with FeNO, in contrast to FeNO, periostin was only slightly reduced by lebrikizumab,5Hanania N.A. Noonan M. Corren J. Korenblat P. Zheng Y. Fischer S.K. et al.Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies.Thorax. 2015; 70: 748-756Crossref PubMed Scopus (326) Google Scholar and FeNO better predicted sputum eosinophilia.6Wagener A.H. de Nijs S.B. Lutter R. Sousa A.R. Weersink E.J. Bel E.H. et al.External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma.Thorax. 2015; 70: 115-120Crossref PubMed Scopus (360) Google Scholar Subsequent phase 3 studies of lebrikizumab (LAVOLTA I and II) in asthma were disappointing, possibly because both periostin and/or B-Eos performed relatively poorly as predictive markers. FeNO was inconsistently reported in the LAVOLTA studies; thus, it was difficult to precisely resolve its performance. Hence, the report of Pavord et al3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar is notable in addressing this gap in understanding. Pavord et al3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar conducted a post hoc analysis of a large phase 3, double-blind, randomized, controlled trial in patients 12 years or older with moderate to severe asthma who received 200 or 300 mg of dupilumab every 2 weeks up to 52 weeks (LIBERTY ASTHMA QUEST).7Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (1149) Google Scholar The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the prebronchodilator FEV1. In the original analysis, dupilumab significantly reduced exacerbation rates and improved lung function at both doses in patients with a B-Eos count of greater than or equal to 300 μL or FeNO of greater than or equal to 25 ppb but not in patients with B-Eos count of less than 150 μL or FeNO less than 25 ppb.7Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (1149) Google Scholar However, that study raised an important question: which of the 2 markers, FeNO or B-Eos count, or both, is best measured by clinicians considering dupilumab treatment? Pavord et al3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar have tried to answer this question by examining independent associations between baseline FeNO and the effects of dupilumab, and adjusted the analysis for clinical characteristics and baseline B-Eos count. In the previous LIBERTY ASTHMA QUEST study, elevated FeNO independently predicted severe exacerbations apart from baseline B-Eos and total IgE in participants who received placebo.8Busse W.W. Wenzel S.E. Casale T.B. FitzGerald J.M. Rice M.S. Daizadeh N. et al.Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis.Lancet Respir Med. 2021; 9: 1165-1173Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar In the present study,3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar baseline FeNO was analyzed as a continuous and not binary (elevated yes/no) variable. The rate of severe exacerbations had a near-linear increase as pretreatment FeNO increased in the combined placebo groups and fell in the combined dupilumab groups. Furthermore, participants with higher baseline FeNO had a continuous increase in prebronchodilator FEV1 with dupilumab. Although providing helpful new information that supports use of FeNO testing in clinical practice to guide response to anti–IL-4/IL-13 biologicals, there are important limitations in the study of Pavord et al.3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar The study sample was enriched in late adolescent and adult subjects with established airflow limitation and bronchodilator responsiveness pretreatment. This is not the case for most children and many young adults with severe asthma, who often have normal lung function yet a significant burden of type-2 inflammation.9Teague W.G. Phillips B.R. Fahy J.V. Wenzel S.E. Fitzpatrick A.M. Moore W.C. et al.Baseline features of the Severe Asthma Research Program (SARP III) cohort: differences with age.J Allergy Clin Immunol Pract. 2018; 6: 545-554Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar B-Eos, FeNO, and changes in lung function vary in asthma with seasonal allergen exposures and respiratory virus infections. Furthermore, the magnitude of FeNO is informed by dietary nitrates, the pH,10Gaston B. Kelly R. Urban P. Liu L. Henderson E.M. Doctor A. et al.Buffering airwayacid decreases exhaled nitric oxide in asthma.J Allergy Clin Immunol. 2006; 118: 817-822Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar and storage reservoir of nitrites in the lung fluid, and may be stimulated by type-1 as it is by type-2 inflammatory signatures, for example, during rhinovirus infections.1Alving K. Malinovschi A. Basic aspects of exhaled nitric oxide.Eur Respir Monograph. 2010; 49: 1-31Crossref Google Scholar NO in exhaled breath originates primarily in epithelial cells; whether eosinophils per se contribute to its presence in the breath is uncertain. In the Severe Asthma Research Program (III) cohort, FeNO levels were better estimates of symptom control status than in discerning asthma severity.9Teague W.G. Phillips B.R. Fahy J.V. Wenzel S.E. Fitzpatrick A.M. Moore W.C. et al.Baseline features of the Severe Asthma Research Program (SARP III) cohort: differences with age.J Allergy Clin Immunol Pract. 2018; 6: 545-554Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar So how should clinicians apply the results of Pavord et al3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar in decisions to initiate and monitor the response to biologicals targeting type-2 inflammation in daily practice? Foremost, we propose that measures of the magnitude of type-2 inflammation in individual patients are important considering the heterogeneity of asthma endotypes, including many with neutrophilic and pauci-granulocytic inflammatory signatures.11Hastie A.T. Moore W.C. Meyers D.A. Vestal P.L. Li H. Peters S.P. et al.Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes.J Allergy Clin Immunol. 2010; 125: 1028-1036Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar Considering the evidence, measures of FeNO and B-Eos are helpful in different ways to classify patients.2Malinovschi A. Fonseca J.A. Jacinto T. Alving K. Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects.J Allergy Clin Immunol. 2013; 132: 821-827.e5Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Clinicians faced with choosing a biomarker to assess probability of treatment response, based on Pavord et al,3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar might select FeNO when considering dupilumab, whereas B-Eos may be preferable when considering anti–IL-5/IL-5R treatment. It is important to note from Pavord et al that FeNO levels at a lower threshold (15 ppb) than the standard of 25 ppb predicted improvement in both clinical outcomes, indicating that clinical cutoffs should be refined. With regard to monitoring response to treatment, B-Eos typically increase with dupilumab; thus, its pharmacodynamic effect is best measured with FeNO. Vice versa, the anti-inflammatory effect of anti–IL-5/IL-5R is best measured with B-Eos. In summary, given the day-to-day variability of type-2 markers in individual patients, we propose that similar to lung function, clinicians might consider deviations from baseline values established during a period of stable symptom control to be more helpful than comparison to population reference standards. Nonetheless, the era whereby biomarkers are used to guide treatment strategies is rapidly approaching if not here. Thus, it is incumbent for clinicians to understand the subtleties and limitations of their use, a goal clearly advanced by the significant analysis reported in The Journal of Allergy and Clinical Immunology: In Practice by Pavord et al.3Pavord I. Deniz Y. Corren J. Casale T. Fitzgerald J.M. Izuhara K. et al.Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 1213-1220Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Baseline FeNO Independently Predicts the Dupilumab Response in Patients With Moderate-to-Severe AsthmaThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 4PreviewFeNO may have a role as both a prognostic and predictive biomarker in combination with eosinophils for assessing responsiveness to some biological therapies. Full-Text PDF Open Access