Sputum Type 2 Markers Could Predict Remission in Severe Asthma Treated With Anti-IL-5

BackgroundBiotherapies targeting IL-5 allow a tangible improvement of asthma. However, all patients do not respond the same way to these treatments. Even if high blood eosinophil counts seem to be associated with a reduction in exacerbations with treatment targeting IL-5, we lack biomarkers for the prediction of remission after these very expensive treatments.Research QuestionAre there biomarkers of remission after therapy targeting IL-5 in the sputum of patients with severe eosinophilic asthma?Study Design and MethodsThis observational study included 52 patients with severe asthma initiated with anti-IL-5 therapy and recruited from the asthma clinic of the Centre Hospitalier Universitaire of Liege, Belgium. Remission was defined as patients who combined the following at 1 year after therapy: no chronic treatment with oral corticosteroids; no exacerbation; asthma control questionnaire score < 1.5, asthma control test score > 19, or both; FEV1 of ≥ 80% predicted, improvement of FEV1 of ≥ 10%, or both; and a blood eosinophil count < 300 cells/μL. Eosinophil peroxidase (EPX), IgE, IL-3, IL-4, IL-5, IL-13, IL-25, IL-33, granulocyte-macrophage colony-stimulating factor, thymic stromal lymphopoietin (TSLP), and eotaxin-1 levels were measured in the sputum of these patients before anti-IL-5 treatment.ResultsAmong the 52 patients, 11 were classified as being in remission. These patients were characterized by higher sputum eosinophil, macrophage, and lymphocyte counts, whereas the sputum neutrophil percentage was lower than in the nonremission group. In addition, the sputum eotaxin-1, TSLP, IL-5, EPX, and IgE protein levels were higher at baseline in the remission group compared with the nonremission group. Univariate regression analysis revealed that male vs female sex, sputum neutrophil percentage, eotaxin-1, IL-5, and EPX were potential predictors of remission.InterpretationSputum type 2 markers seemed to be potentially predictive of remission after anti-IL-5 therapy in a cohort of patients with severe eosinophilic asthma. These results need validation on a larger cohort. Biotherapies targeting IL-5 allow a tangible improvement of asthma. However, all patients do not respond the same way to these treatments. Even if high blood eosinophil counts seem to be associated with a reduction in exacerbations with treatment targeting IL-5, we lack biomarkers for the prediction of remission after these very expensive treatments. Are there biomarkers of remission after therapy targeting IL-5 in the sputum of patients with severe eosinophilic asthma? This observational study included 52 patients with severe asthma initiated with anti-IL-5 therapy and recruited from the asthma clinic of the Centre Hospitalier Universitaire of Liege, Belgium. Remission was defined as patients who combined the following at 1 year after therapy: no chronic treatment with oral corticosteroids; no exacerbation; asthma control questionnaire score < 1.5, asthma control test score > 19, or both; FEV1 of ≥ 80% predicted, improvement of FEV1 of ≥ 10%, or both; and a blood eosinophil count < 300 cells/μL. Eosinophil peroxidase (EPX), IgE, IL-3, IL-4, IL-5, IL-13, IL-25, IL-33, granulocyte-macrophage colony-stimulating factor, thymic stromal lymphopoietin (TSLP), and eotaxin-1 levels were measured in the sputum of these patients before anti-IL-5 treatment. Among the 52 patients, 11 were classified as being in remission. These patients were characterized by higher sputum eosinophil, macrophage, and lymphocyte counts, whereas the sputum neutrophil percentage was lower than in the nonremission group. In addition, the sputum eotaxin-1, TSLP, IL-5, EPX, and IgE protein levels were higher at baseline in the remission group compared with the nonremission group. Univariate regression analysis revealed that male vs female sex, sputum neutrophil percentage, eotaxin-1, IL-5, and EPX were potential predictors of remission. Sputum type 2 markers seemed to be potentially predictive of remission after anti-IL-5 therapy in a cohort of patients with severe eosinophilic asthma. These results need validation on a larger cohort. FOR EDITORIAL COMMENT, SEE PAGE 1341Take-home PointsStudy Question: Are there biomarkers of remission after therapy targeting IL-5 in the sputum of patients with severe eosinophilic asthma?Results: This study highlights that baseline type 2 airway inflammation markers can predict remission in severe eosinophilic asthma treated with anti-IL-5 agents.Interpretation: Sputum markers can be used as surrogate markers of remission 1 year after therapy, but these results need to be validated in a larger cohort. FOR EDITORIAL COMMENT, SEE PAGE 1341 Study Question: Are there biomarkers of remission after therapy targeting IL-5 in the sputum of patients with severe eosinophilic asthma? Results: This study highlights that baseline type 2 airway inflammation markers can predict remission in severe eosinophilic asthma treated with anti-IL-5 agents. Interpretation: Sputum markers can be used as surrogate markers of remission 1 year after therapy, but these results need to be validated in a larger cohort. Refractory asthma still represents between 3% and 10% of patients with asthma.1Chung K.F. Wenzel S.E. Brozek J.L. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (2720) Google Scholar,2Hekking P.P.W. Wener R.R. Amelink M. Zwinderman A.H. Bouvy M.L. Bel E.H. The prevalence of severe refractory asthma.J Allergy Clin Immunol. 2015; 135: 896-902Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar These patients represent a high burden in terms of health-care costs. Biotherapies have been developed in recent years to reduce the use of oral corticosteroids (OCS), which are responsible for long-term and costly side effects. Monoclonal antibodies directed against IL-5 or its receptor, IL-5R, are approved to treat severe eosinophilic asthma with tangible improvements in patient conditions.3Carstens D.D. Katial R. Young J. et al.Real-world effectiveness of benralizumab on asthma exacerbations: results from the ZEPHYR 1 study.. 2021; 128: 669-676Google Scholar,4Schleich F. Graff S. Nekoee H. et al.Real-word experience with mepolizumab: does it deliver what it has promised?.Clin Exp Allergy. 2020; 50: 687-695Crossref PubMed Scopus (55) Google Scholar However, it seems that the patients do not respond the same way to biotherapies. In a recent article, Mukherjee et al5Mukherjee M. Forero D.F. Tran S. et al.Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.Eur Respir J. 2020; 562000117Crossref Scopus (66) Google Scholar analyzed the predictors of suboptimal response to anti-IL-5 therapies, which was defined as a failure to decrease OCS by 50%, asthma control questionnaire (ACQ) score of ≤ 1.5, or exacerbations by 50% with persistent sputum of > 3% and blood eosinophil levels of ≥ 400/μL. They found that OCS intake, sinus disease, late-onset asthma, and sputum eosinophil peroxidase IgG were the most predictive of suboptimal response. In another interesting study, Eger et al6Eger K. Kroes J.A. ten Brinke A. Bel E.H. Long-term therapy response to Anti–IL-5 biologics in severe asthma—a real-life evaluation.J Allergy Clin Immunol Pract. 2021; 9: 1194-1200Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar analyzed a cohort of 114 patients with severe eosinophilia 2 years after anti-IL-5 and IL-5R biologic therapy. They observed that 14% were super responders, defined as patients with no OCS, no exacerbations within 3 months, ACQ score of < 1.5, FEV1 of ≥ 80% predicted, fraction of exhaled nitric oxide (Feno) of < 50 parts per billion, and control of comorbidities. The super response was predicted by shorter asthma duration and higher FEV1. Harvey et al7Harvey E.S. Langton D. Katelaris C. et al.Mepolizumab effectiveness and identification of super-responders in severe asthma.Eur Respir J. 2020; 551902420Crossref PubMed Scopus (110) Google Scholar defined super responders to mepolizumab as the upper 25% of ACQ-5 responders. They represented 24% of the 309 patients followed up. Those patients mostly were female, had a lower BMI, a shorter asthma duration, higher blood eosinophil levels and Feno values, as well as a higher ACQ-5 score. Additionally, those patients were more likely to have a diagnosis of nasal polyps and had fewer comorbidities and a lower percentage of patients were taking maintenance OCS at baseline. Another retrospective study analyzed 99 patients in the United Kingdom and observed that baseline characteristics associated with response (≥ 50% exacerbation reduction or ≥ 50% OCS dose reduction) or superresponse (no exacerbation and no OCS use at 1 year) were the presence of nasal polyps, lower ACQ-6 score, lower BMI, and lower dose of OCS.8Kavanagh J.E. d’Ancona G. Elstad M. et al.Real-world effectiveness and the characteristics of a “super-responder” to mepolizumab in severe eosinophilic asthma.Chest. 2020; 158: 491-500Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Finally, mepolizumab also was shown to be more beneficial in patients with severe asthma who had nasal polyps (patients with more severe disease and more intense systemic eosinophilic inflammation) than in the patients without nasal polyps in terms of reduction of exacerbations.9Howarth P. Chupp G. Nelsen L.M. et al.Severe eosinophilic asthma with nasal polyposis: a phenotype for improved sinonasal and asthma outcomes with mepolizumab therapy.J Allergy Clin Immunol. 2020; 145: 1713-1715Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar In addition to the superresponse, a new concept of asthma remission recently emerged as a therapeutic target to achieve after 12 months of treatment and was defined according to results of randomized control trials as obtaining asthma control, no exacerbation, and no treatment with OCS, although no consensus exists on the importance of improvement in lung function and reduction in type 2 inflammation in the current definition of remission.10Menzies-Gow A. Szefler S.J. Busse W.W. The Relationship of asthma biologics to remission for asthma.J Allergy Clin Immunol Pract. 2021; 9: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 11Thomas D. McDonald V.M. Pavord I.D. Asthma remission—what is it and how can it be achieved?.Eur Respir J. 2022; 60: 2102583Google Scholar, 12Menzies-Gow A. Bafadhel M. Busse W.W. et al.An expert consensus framework for asthma remission as a treatment goal.J Allergy Clin Immunol. 2020; 145: 757-765Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Post hoc analysis of a randomized control trial looked at the predictive factors of response to benralizumab or mepolizumab in vast cohorts of patients and observed that a high blood eosinophil level was linked to a better improvement in terms of reduction of exacerbation rate.13Ortega H.G. Yancey S.W. Mayer B. et al.Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies.Lancet Respir Med. 2016; 4: 549-556Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar,14FitzGerald J.M. Bleecker E.R. Menzies-Gow A. et al.Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies.Lancet Respir Med. 2018; 6: 51-64Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar Even if blood eosinophil level helps to predict a general response to anti-IL-5 and anti-IL-5R, biomarkers reflecting local inflammation, such as those measured in induced sputum, have a better potential to predict the intensity of response to biologics because they reflect what really happens in the bronchi. So, do biomarkers of remission after therapy targeting IL-5 exist in the sputum of patients with severe eosinophilic asthma? However, other than the study cited previously focusing on suboptimal responders, to our knowledge no studies have analyzed inflammatory mediators as predictors of response after 1 year of anti-IL-5 treatment directly in the sputum itself in patients with severe eosinophilic asthma. The goal of this study was to analyze the role of mediators of the type 2 cascade in the sputum as predictors of remission. Fifty-two patients with severe asthma initiated with an anti-IL-5 agent (51 patients with mepolizumab and one patient with reslizumab) were recruited from our asthma clinic. This observational study was performed at the Centre Hospitalier Universitaire of Liege, Belgium, between 2014 and 2021. Inclusion criteria included a diagnosis of asthma defined by the Global Initiative for Asthma (http://ginasthma.org/), and severe asthma was defined according to European Respiratory Society and American Thoracic Society criteria.1Chung K.F. Wenzel S.E. Brozek J.L. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (2720) Google Scholar The treatment was stable for all patients at the time of the sampling, and the time between baseline and the next evaluation in average was 1 year. Remission was defined as patients who, in addition to achieving the instauration of the biotherapy, received no OCS therapy; showed no exacerbations; showed an ACQ score of < 1.5, asthma control test (ACT) of > 19, or both; FEV1 of ≥ 80% predicted, an improvement in FEV1 of ≥ 10%, or both; and a blood eosinophil count of < 300 cells/μL. Subanalyses also were performed to assess the predictive values of sputum mediators in terms of response for some specific parameters alone, such as: improvement in ACT score of > 19 after treatment, decrease in ACQ score of < 1.5 after treatment, a decrease in sputum eosinophil level of < 3% or by 50%, stopping OCS after treatment, no more exacerbations after treatment, and improvement in FEV1 of at least 10% after treatment. A diagnosis of nasal polyps by an ear, nose, and throat specialist and a diagnosis of or by a were This study was approved by the of the Centre Hospitalier Universitaire of and all for The study is at This study to the airway of mediators of the type 2 cascade as predictors of remission after anti-IL-5 treatment in a cohort of patients with severe eosinophilic asthma. a between with a of to 80% and a level of the was as to patients per group These were on a of sputum IL-5 as in the if no consensus exists on the remission definition in the asthma is of a percentage of of patients a response to anti-IL-5 treatment. with a cohort of 52 patients, we a of at least patients in the remission group. Feno was measured at a of 50 was performed before and after according to the American Thoracic Society and European Respiratory Society J. et of Respir J. PubMed Scopus Google Scholar of patients were analyzed by the of the of for and The sputum was induced and as and the sputum was before the addition of which the M. M. et sputum in patients with PubMed Scopus Google J. S. M. et for sputum and Scholar was by and the count was performed by on with Eosinophil peroxidase was measured by was IgE levels were measured with the IgE from The was Finally, IL-3, IL-4, IL-5, IL-13, IL-25, IL-33, granulocyte-macrophage colony-stimulating factor, thymic stromal lymphopoietin (TSLP), and eotaxin-1 were measured by This has been used with in sputum S. R. R. et exhaled nitric oxide type 2 in severe Respir Med. 2021; PubMed Scopus Google Scholar and was The lower of are in are as and and are as or as The of was by the test was found for BMI, ACQ score, asthma of questionnaire score, function and sputum neutrophil baseline characteristics of patients in the remission the P.P.W. Wener R.R. Amelink M. Zwinderman A.H. Bouvy M.L. Bel E.H. The prevalence of severe refractory asthma.J Allergy Clin Immunol. 2015; 135: 896-902Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar or test was used for and the test or test was performed for Univariate regression was to the between patient remission and and of regression were and performed were and a of < was were performed for for which was The values associated with the the that the the Among the 52 patients treated with anti-IL-5 11 patients were classified as being in remission at 1 year according to our criteria characteristics are in 1 and These 11 patients baseline characteristics as the for the linked to more were in the group of patients in remission compared with the group not in remission of patients an control of asthma we looked at the ACQ and ACT as well as asthma of questionnaire The function parameters were and the blood counts, IgE, and were in the same A a of patients treated with OCS maintenance was found in the group of patients in remission compared with the group not in remission the inflammatory the Feno values were in The of patients with nasal or or were the of sputum eosinophil count were at baseline in the group of patients in remission as well as the sputum and lymphocyte counts and Finally, a lower of sputum was observed and of in Remission vs Those in Remission in < compared to patients not in not at duration, after after to to after eosinophil, IgE, or are as or ACQ asthma control ACT asthma control asthma of Feno fraction of exhaled nitric corticosteroids; OCS oral < compared to patients not in remission. in a new of in Remission vs Those in Remission in < compared to patients not in < compared to patients not in < compared to patients not in < compared to patients not in < compared to patients not in remission. < compared to patients not in < compared to patients not in are as or EPX eosinophil granulocyte-macrophage colony-stimulating thymic stromal < compared to patients not in remission. in a new are as or ACQ asthma control ACT asthma control asthma of Feno fraction of exhaled nitric corticosteroids; OCS oral are as or EPX eosinophil granulocyte-macrophage colony-stimulating thymic stromal the mediators at protein eotaxin-1, TSLP, IL-5, EPX, and IgE sputum levels were higher in the remission group compared with the other group and whereas IL-3, IL-4, IL-13, IL-25, IL-33, and granulocyte-macrophage colony-stimulating were not between the A was to the of these sputum type 2 markers to predict remission after anti-IL-5 therapy markers seemed to well in between patients in remission at 1 year vs those who were not ≥ with EPX and IL-5 the of and with the In the of the blood eosinophil count a lower to the and was not eosinophil eosinophil the EPX eosinophil thymic stromal in a new the EPX eosinophil thymic stromal the improvement after treatment was analyzed for parameters one at a we observed that patients with improved ACT score also showed a higher sputum EPX protein level at baseline vs vs patients who showed an in FEV1 before by at least 10% a higher baseline sputum IL-5 protein level vs 3 vs These results are in was for the other for potential of asthma regression was performed on baseline and These results are shown in with the and found that male vs female sputum neutrophil percentage eotaxin-1 level IL-5 level and EPX level were potential predictors of of of Asthma male vs vs vs of vs at to vs vs or vs vs vs vs vs vs vs vs vs vs vs vs asthma control ACT asthma control asthma of EPX eosinophil Feno fraction of exhaled nitric granulocyte-macrophage colony-stimulating corticosteroids; all patients were no analysis was OCS oral corticosteroids; thymic stromal < in a new ACQ asthma control ACT asthma control asthma of EPX eosinophil Feno fraction of exhaled nitric granulocyte-macrophage colony-stimulating corticosteroids; all patients were no analysis was OCS oral corticosteroids; thymic stromal a < In this study, we that of patients were to be in remission 1 year after anti-IL-5 treatment. These patients more were and were characterized by higher sputum eosinophil counts at baseline as well as higher sputum type 2 biomarkers such as eotaxin-1, TSLP, IL-5, EPX, and IgE protein observed a higher of in the group achieving remission. previously that patients an in local and systemic eosinophilic inflammation more were A. et of local and systemic eosinophilia in asthma.Eur Respir J. 2014; PubMed Scopus Google Scholar and eosinophilic inflammation previously was associated with the response to anti-IL-5 and in severe H.G. Yancey S.W. Mayer B. et al.Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies.Lancet Respir Med. 2016; 4: 549-556Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar,14FitzGerald J.M. Bleecker E.R. Menzies-Gow A. et al.Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies.Lancet Respir Med. 2018; 6: 51-64Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar In addition, patients achieving remission were characterized by a for a lower of patients treated with OCS a also observed by another E.S. Langton D. Katelaris C. et al.Mepolizumab effectiveness and identification of super-responders in severe asthma.Eur Respir J. 2020; 551902420Crossref PubMed Scopus (110) Google Scholar The higher airway and lymphocyte observed in our study a lower neutrophil compared with the group not in remission. to anti-IL-5 therapy are linked to a more intense local inflammation, as shown previously in in our F. Graff S. Nekoee H. et al.Real-word experience with mepolizumab: does it deliver what it has promised?.Clin Exp Allergy. 2020; 50: 687-695Crossref PubMed Scopus (55) Google Scholar but not J.E. d’Ancona G. Elstad M. et al.Real-world effectiveness and the characteristics of a “super-responder” to mepolizumab in severe eosinophilic asthma.Chest. 2020; 158: 491-500Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar that blood eosinophil count was with anti-IL-5 general response. However, the systemic eosinophilic inflammation has been shown to be from local eosinophilic A. et of local and systemic eosinophilia in asthma.Eur Respir J. 2014; PubMed Scopus Google Scholar and on the we that with a blood eosinophil level at baseline before biotherapy, the response can be In this sputum and sputum type 2 markers levels be surrogate markers of response. is an and an of type 2 inflammatory IL-5 is a in the severe eosinophilic asthma IL-5 is the responsible for eosinophil and which can the high sputum eosinophil count and EPX sputum the higher eotaxin-1 protein which is a for was higher at baseline in the sputum of patients in remission. it a systemic of these mediators in the blood was not in this study, but because the patients combined systemic and airway eosinophilic a recent study not in blood eosinophil and IL-5 levels in responders (no exacerbation, ≥ 50% OCS dose reduction at or vs in a cohort of patients before mepolizumab M. P. et response of airway eosinophilia to anti-IL-5 biologics in severe asthma Med. 2022; Scholar the of those mediators in the sputum of patients with local eosinophilic inflammation is of because those patients represent of the patients with asthma eosinophilic A. et of local and systemic eosinophilia in asthma.Eur Respir J. 2014; PubMed Scopus Google Scholar for a higher sputum eosinophil count in the current patients who remission at 1 year be that in those with an an of eosinophil exists in the because of the of such as The higher sputum IgE levels in patients achieving remission are more the group with remission not a higher of patients with compared with the patients not in and blood IgE levels not between However, it has been shown that local of IgE exists in of asthma and was not linked to J. B. C. F. C. in sputum of IgE antibodies in Respir Med. PubMed Scopus Google Scholar In addition, our previously observed that sputum IL-5 levels also were in of high sputum IgE levels and that higher sputum IgE levels were in patients eosinophilic airway M. G. K. F. C. R. Sputum IgE and in asthma: with sputum Scholar Univariate showed between these baseline sputum mediators and the of achieving and all sputum markers performed better than blood eosinophil These results the that anti-IL-5 are more in patients with a local type 2 high In addition, the regression analysis male sex, sputum neutrophil percentage, eotaxin-1 IL-5 and EPX level as potential predictors of but not sputum eosinophil because of the presence of However, these results need to be validated in a larger cohort in a sputum neutrophil percentage is associated with a suboptimal response also The of this study are that the criteria of remission in asthma are not the of patients have the of the to between an analysis on or suboptimal response predictors be of and be performed in another In addition, it be interesting to at other markers in but we on type 2 markers because a type 2 disease was Finally, the sputum also not be in all but its use in be because it the of in the of patients with severe eosinophilic asthma. if and this study to the of our the to local airway of mediators of the type 2 cascade as predictors of remission after anti-IL-5 treatment in a cohort of patients with severe eosinophilic asthma. Sputum type 2 markers levels be surrogate markers of response 1 year after anti-IL-5 treatment. Sputum is by American Thoracic Society and European Respiratory Society guidelines in the of severe asthma and be by local because it predict patients who achieve remission after of these very costly Study and for this study