YKL-40 and adult-onset asthma: Elevated levels in clusters with poorest outcome
2019; Elsevier BV; Volume: 7; Issue: 7 Linguagem: Inglês
10.1016/j.jaip.2019.03.043
ISSN2213-2201
AutoresPinja Ilmarinen, Leena E. Tuomisto, Onni Niemelä, Mari Hämäläinen, Eeva Moilanen, Hannu Kankaanranta,
Tópico(s)Asthma and respiratory diseases
ResumoClinical Implications•This study shows that non-T2 marker YKL-40 could be used in identifying clinical phenotypes associated with poor prognosis in adult-onset asthma. •This study shows that non-T2 marker YKL-40 could be used in identifying clinical phenotypes associated with poor prognosis in adult-onset asthma. Asthma may be divided into different phenotypes. Adult-onset asthma constitutes of phenotypes including less allergic processes, poorer responsiveness to inhaled corticosteroid therapy, and poorer prognosis compared with childhood-onset asthma. We previously carried out a cluster analysis and identified 5 subphenotypes of adult-onset asthma with variable long-term prognosis, namely, smoking asthma, obese asthma, atopic asthma, nonrhinitic asthma, and female asthma.1Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Poorest 12-year prognosis was found in smoking and obese asthma. Novel targeted approaches are needed for these patient groups. YKL-40 (chitinase-3–like protein 1) is a secreted glycoprotein produced by macrophages, neutrophils, and airway epithelium. YKL-40 levels are increased in patients with asthma and chronic obstructive pulmonary disease when compared with levels in healthy controls, and a negative correlation was shown between lung function and serum YKL-40 level.2Chupp G.L. Lee C.G. Jarjour N. Shim Y.M. Holm C.T. He S. et al.A chitinase-like protein in the lung and circulation of patients with severe asthma.N Engl J Med. 2007; 357: 2016-2027Crossref PubMed Scopus (457) Google Scholar, 3James A.J. Reinius L.E. Verhoek M. Gomes A. Kupczyk M. Hammar U. et al.Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016; 193: 131-142Crossref PubMed Scopus (92) Google Scholar Furthermore, YKL-40 has been associated with asthma severity2Chupp G.L. Lee C.G. Jarjour N. Shim Y.M. Holm C.T. He S. et al.A chitinase-like protein in the lung and circulation of patients with severe asthma.N Engl J Med. 2007; 357: 2016-2027Crossref PubMed Scopus (457) Google Scholar and is a potential marker of asthma-chronic obstructive pulmonary disease overlap.4Shirai T. Hirai K. Gon Y. Maruoka S. Mizumura K. Hikichi M. et al.Combined assessment of serum periostin and YKL-40 may identify asthma-COPD overlap.J Allergy Clin Immunol Pract. 2019; 7: 134-145.e1Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Previous cluster analysis5Gomez J.L. Yan X. Holm C.T. Grant N. Liu Q. Cohn L. et al.Characterisation of asthma subgroups associated with circulating YKL-40 levels.Eur Respir J. 2017; 50: 1700800Crossref PubMed Scopus (43) Google Scholar identified 2 YKL-40–high clusters characterized by severe asthma and airflow obstruction but separated by age of asthma onset. Based on sputum and transcriptional profiling, it was suggested that YKL-40 might be a non-T2 biomarker.5Gomez J.L. Yan X. Holm C.T. Grant N. Liu Q. Cohn L. et al.Characterisation of asthma subgroups associated with circulating YKL-40 levels.Eur Respir J. 2017; 50: 1700800Crossref PubMed Scopus (43) Google Scholar In patients with severe asthma, YKL-40 was associated with neutrophilic inflammation and correlated with IL-8 and IL-6.6Hinks T.S. Brown T. Lau L.C. Rupani H. Barber C. Elliott S. et al.Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.J Allergy Clin Immunol. 2016; 138: 61-75Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar We aimed to study levels of plasma YKL-40 in our previously defined clusters of adult-onset asthma,1Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and the association of YKL-40 with clinical parameters and biomarkers. This study is part of Seinäjoki Adult Asthma Study (ClinicalTrials.gov ID NCT02733016), which is a prospective, single-center (Seinäjoki Central Hospital, Seinäjoki, Finland) study in which 203 patients with new-onset adult asthma were followed for 12 years. Asthma was diagnosed by respiratory specialists and confirmed by lung function measurements. Detailed methodology is presented in this article's Online Repository at www.jaci-inpractice.org. Main features of the clusters are as follows (Table I1Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar): (1) atopic well-controlled asthma with earliest age of onset, (2) female asthma with normal clinical parameters but high use of health care, (3) nonrhinitic partially controlled or controlled asthma with low use of medication and health care, (4) obese asthma with comorbidities, frequent symptoms, and use of medication and health care, and (5) smoking asthma or asthma-chronic obstructive pulmonary disease overlap with the poorest lung function, frequent symptoms, and use of medication and health care.Table IMain characteristics of clusters at 12-y follow-up visitCharacteristicCluster 1: AtopicCluster 2: FemaleCluster 3: NonrhiniticCluster 4: ObeseCluster 5: SmokingP valueSubjects3950382519Sex: female, n (%)18 (46.2)49 (98)∗P < .05 to all other clusters.15 (39.5)16 (64)2 (10.5)†P < .05 vs obese cluster.<.001Age of onset (y)33 ± 11∗P < .05 to all other clusters.43 ± 12∗P < .05 to all other clusters.50 ± 1257 ± 855 ± 9<.001BMI (kg/m2)26.8 ± 3.927.1 ± 4.829.9 ± 6.532.8 ± 5.3‡P < .05 vs smoking cluster.§P < .05 vs female cluster.‖P < .05 vs atopic cluster.28.1 ± 4.9<.001With smoking history, n (%)21 (53.8)18 (36)20 (52.6)11 (44)15 (78.9)§P < .05 vs female cluster.<.001Current smokers, n (%)8 (20.5)8 (16.0)7 (18.4)03 (15.8).225Atopic, n (%)22 (57.9)†P < .05 vs obese cluster.19 (40.4)9 (27.3)2 (9.1)5 (31.3)<.001Rhinitis, n (%)35 (89.7)44 (88)4 (10.5)∗P < .05 to all other clusters.24 (96)14 (73.7)<.001Uncontrolled asthma,¶Asthma control based on GINA 2010. n (%)6 (15.4)11 (22)#P < .05 vs nonrhinitic cluster.2 (5.3)12 (48)‖P < .05 vs atopic cluster.#P < .05 vs nonrhinitic cluster.16 (84.2)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.#P < .05 vs nonrhinitic cluster.<.001ICS dose of daily users (μg budesonide equivalent)800 (400-800)800 (575-1000)800 (400-1000)1000 (475-1525)900 (700-1400).163Pre-BD FEV1 (%ref)86 (12)96 (13)∗P < .05 to all other clusters.85 (14)79 (16)63 (19)∗P < .05 to all other clusters.<.001Blood eosinophils (×109/L)0.20 (0.12-0.28)0.16 (0.10-0.28)0.14 (0.09-0.25)0.13 (0.06-0.25)0.23†P < .05 vs obese cluster. (0.13-0.43).035No. of comorbidities0 (0-1)0.5 (0-1)1 (0-2)‖P < .05 vs atopic cluster.3 (2.5-4)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.#P < .05 vs nonrhinitic cluster.3 (1-4)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.#P < .05 vs nonrhinitic cluster.<.001Diabetes, n (%)2 (5.1)3 (6.0)4 (10.5)11 (44.0)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.#P < .05 vs nonrhinitic cluster.7 (36.8)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.<.001YKL-40 (ng/mL)37 (25-48)41 (28-63)53 (38-86)59 (40-96)‖P < .05 vs atopic cluster.83 (43-176)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.<.001IL-8 (pg/mL)5.4 (4.2-6.3)5.3 (4.3-8.1)6.8 (5.1-9.0)7.0 (5.5-8.4)8.1 (6.8-13.1)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.<.001IL-6 (pg/mL)1.2 (0.9-1.9)1.7 (1.0-2.5)1.8 (1.2-2.6)4.0§P < .05 vs female cluster.‖P < .05 vs atopic cluster.#P < .05 vs nonrhinitic cluster. (2.1-5.5)3.1 (2.1-4.9)§P < .05 vs female cluster.‖P < .05 vs atopic cluster.<.001BD, Bronchodilator; BMI, body mass index; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid.Part of data has been previously published.1Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (64) Google ScholarContinuous variables are shown as mean ± SD or median (interquartile range). Group comparisons were performed by 1-way ANOVA with Tukey post hoc test (age of onset, BMI, pre-BD FEV1), Kruskal-Wallis test adjusted by Bonferroni correction for multiple tests (ICS dose, blood eosinophils, number of comorbidities, YKL-40, IL-8, and IL-6), or χ2 test with comparison of column proportions by z test and adjusting P values by Bonferroni method (all categorical variables).∗ P < .05 to all other clusters.† P < .05 vs obese cluster.‡ P < .05 vs smoking cluster.§ P < .05 vs female cluster.‖ P < .05 vs atopic cluster.¶ Asthma control based on GINA 2010.# P < .05 vs nonrhinitic cluster. Open table in a new tab BD, Bronchodilator; BMI, body mass index; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid. Part of data has been previously published.1Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Continuous variables are shown as mean ± SD or median (interquartile range). Group comparisons were performed by 1-way ANOVA with Tukey post hoc test (age of onset, BMI, pre-BD FEV1), Kruskal-Wallis test adjusted by Bonferroni correction for multiple tests (ICS dose, blood eosinophils, number of comorbidities, YKL-40, IL-8, and IL-6), or χ2 test with comparison of column proportions by z test and adjusting P values by Bonferroni method (all categorical variables). In patients with adult-onset asthma, YKL-40 levels measured at 12-year follow-up visit were highest in the smoking cluster, second highest in the obese cluster, and lowest in atopic and female clusters (Figure 1, A; Table I). Plasma IL-8 levels behaved in a manner similar to YKL-40 levels in the clusters (Figure 1, B; Table I). Levels of IL-6 were highest in obese asthma (Figure 1, C; Table I). YKL-40 levels correlated with age (ρ = 0.402; P < .001), number of comorbidities (ρ = 0.376; P < .001), IL-6 level (ρ = 0.449; P < .001), and IL-8 level (ρ = 0.410; P < .001). Regarding traditional asthma-related parameters, YKL-40 level was found to correlate with increasing symptoms (Asthma Control Test: ρ = −0.228; P = .001; Airways Questionnaire 20: ρ = 0.256; P < .001) and negatively with lung function (pre-BD FEV1: ρ = −0.305; P < .001; post-BD FEV1: ρ = −0.317; P < .001). YKL-40 level also weakly correlated with number of add-on drugs, number of hospitalizations, and high sensitivity C-reactive protein, and negatively correlated with diagnostic lung function (see Table E1 in this article's Online Repository at www.jaci-inpractice.org). There was no correlation between YKL-40 and biomarkers of T2-asthma (blood eosinophils, fraction of exhaled nitric oxide, total IgE) (Table E1). Smoking and obese clusters shared many features such as older age, comorbidities, high respiratory symptoms, and reduced lung function. Linear regression analysis on clinical or physiological parameters associated with high YKL-40 levels in adult-onset asthma showed significant associations with age (β = 0.006; 95% CI, 0.003 to 0.009; P < .001), postbronchodilator FEV1 (β = −0.003; 95% CI, −0.006 to −0.001; P = .004), diabetes (β = 0.148; 95% CI, 0.037 to 0.259; P = .009), and Airways Questionnaire 20 score (β = 0.011; 95% CI, 0.002 to 0.021; P = .019). Sex, body mass index, smoking or pack years, blood eosinophils, neutrophils, IgE, fraction of exhaled nitric oxide, or lung function decline during 12-year follow-up were not associated with YKL-40 levels. Our previously defined clusters of adult-onset asthma based on long-term clinical data were distinguished by the levels of YKL-40. Smoking and obese clusters with the poorest 12-year outcome had the highest YKL-40 levels at 12-year follow-up visit and can be considered as "YKL-40 high" clusters. The result supports the association between YKL-40 and asthma severity,2Chupp G.L. Lee C.G. Jarjour N. Shim Y.M. Holm C.T. He S. et al.A chitinase-like protein in the lung and circulation of patients with severe asthma.N Engl J Med. 2007; 357: 2016-2027Crossref PubMed Scopus (457) Google Scholar previously defined by using cross-sectional data. Atopic and female clusters containing the highest proportion of atopic patients had the lowest YKL-40 levels, being "YKL-40 low" clusters. Previous studies have suggested YKL-40 as a biomarker of non-T2 inflammation,5Gomez J.L. Yan X. Holm C.T. Grant N. Liu Q. Cohn L. et al.Characterisation of asthma subgroups associated with circulating YKL-40 levels.Eur Respir J. 2017; 50: 1700800Crossref PubMed Scopus (43) Google Scholar, 7Jevnikar Z. Ostling J. Ax E. Calven J. Thorn K. Israelsson E. et al.Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.J Allergy Clin Immunol. 2019; 143: 577-590Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar and our study supports this concept. Furthermore, differing levels of YKL-40, IL-6, and IL-8 validate our previous cluster analysis1Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar by suggesting that the clusters originally defined on the basis of clinical parameters also share pathobiological features. Higher age, comorbidities (such as diabetes), symptoms, and poor lung function were common in the obese and smoking clusters and the main features associated with elevated YKL-40 levels. However, pack years of smoking was not associated with YKL-40, and body mass index only weakly (Table E1), as suggested previously.3James A.J. Reinius L.E. Verhoek M. Gomes A. Kupczyk M. Hammar U. et al.Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016; 193: 131-142Crossref PubMed Scopus (92) Google Scholar The association of YKL-40 level with diabetes was stronger when compared with body mass index or obesity, consistent with a previous study in subjects without asthma.8Catalan V. Gomez-Ambrosi J. Rodriguez A. Ramirez B. Rotellar F. Valenti V. et al.Increased circulating and visceral adipose tissue expression levels of YKL-40 in obesity-associated type 2 diabetes are related to inflammation: impact of conventional weight loss and gastric bypass.J Clin Endocrinol Metab. 2011; 96: 200-209Crossref PubMed Scopus (61) Google Scholar We previously showed worse respiratory symptoms in multimorbid patients with asthma, which might be related to higher level of IL-6.9Ilmarinen P. Tuomisto L.E. Niemelä O. Danielsson J. Haanpää J. Kankaanranta T. et al.Co-morbidities and elevated IL-6 associate with negative outcome in adult-onset asthma.Eur Respir J. 2016; 48: 1052-1062Crossref PubMed Scopus (62) Google Scholar Now we found an association between multimorbidity, higher symptoms, and YKL-40 level, adding YKL-40 as a possible player into this multifactorial phenomenon. Weak correlation between asthma symptom score and YKL-40 level has been shown before,3James A.J. Reinius L.E. Verhoek M. Gomes A. Kupczyk M. Hammar U. et al.Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016; 193: 131-142Crossref PubMed Scopus (92) Google Scholar but our study strengthens this relationship by showing that the association between YKL-40 level and symptoms remains after adjusting for age, sex, smoking, lung function, and comorbidities. The exact biological role of YKL-40 in asthma remains unknown, but it has consistently been shown to be associated with lung function3James A.J. Reinius L.E. Verhoek M. Gomes A. Kupczyk M. Hammar U. et al.Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016; 193: 131-142Crossref PubMed Scopus (92) Google Scholar (the present study) and parameters of airway remodeling.2Chupp G.L. Lee C.G. Jarjour N. Shim Y.M. Holm C.T. He S. et al.A chitinase-like protein in the lung and circulation of patients with severe asthma.N Engl J Med. 2007; 357: 2016-2027Crossref PubMed Scopus (457) Google Scholar YKL-40 was shown to be induced by IL-6/sIL-6R but not by IL-4/IL-13 pathway7Jevnikar Z. Ostling J. Ax E. Calven J. Thorn K. Israelsson E. et al.Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.J Allergy Clin Immunol. 2019; 143: 577-590Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar and stimulated IL-8 production in bronchial epithelial cells, presenting a possible pathway leading to bronchial smooth muscle proliferation and airway remodeling.10Tang H. Sun Y. Shi Z. Huang H. Fang Z. Chen J. et al.YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-kappaB pathways, causing bronchial smooth muscle proliferation and migration.J Immunol. 2013; 190: 438-446Crossref PubMed Scopus (91) Google Scholar Consistently, in our study, YKL-40 level correlated with IL-6 and IL-8 levels, supporting the mechanisms proposed. Even though sputum YKL-40 and sputum neutrophils have been reported to correlate in patients with severe asthma, in studies with all levels of severity included as the present study, no clear relationship has been found between airway or blood YKL-40 level and neutrophils.2Chupp G.L. Lee C.G. Jarjour N. Shim Y.M. Holm C.T. He S. et al.A chitinase-like protein in the lung and circulation of patients with severe asthma.N Engl J Med. 2007; 357: 2016-2027Crossref PubMed Scopus (457) Google Scholar, 3James A.J. Reinius L.E. Verhoek M. Gomes A. Kupczyk M. Hammar U. et al.Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016; 193: 131-142Crossref PubMed Scopus (92) Google Scholar, 5Gomez J.L. Yan X. Holm C.T. Grant N. Liu Q. Cohn L. et al.Characterisation of asthma subgroups associated with circulating YKL-40 levels.Eur Respir J. 2017; 50: 1700800Crossref PubMed Scopus (43) Google Scholar Altogether, highest YKL-40 levels were found in previously defined clinical clusters of adult-onset asthma with the poorest long-term outcomes and were associated with more severe symptoms, poor lung function, and multimorbidity. In this era where many attempts are being made to identify clinical phenotypes and their biomarkers, our study extends previous findings by showing a link between a biomarker, clinically defined phenotypes, and disease prognosis. Our study suggests that YKL-40 could be used in identifying asthma phenotypes with poor prognosis and support a role for YKL-40 in non-T2 asthma. Mrs Aino Sepponen, RN, is gratefully acknowledged for her help through all the stages of this work. Ms Terhi Salonen and Ms Heini Sood are acknowledged for excellent technical assistance. The present study was part of Seinäjoki Adult Asthma Study (SAAS). SAAS is a prospective, single-center (Seinäjoki Central Hospital, Seinäjoki, Finland) 12-year follow-up study of a cohort of patients having new-onset asthma that was diagnosed at adult age (≥15 years). The participants gave written informed consent to the study protocol approved by the Ethics Committee of Tampere University Hospital, Tampere, Finland (R12122). The protocol, inclusion and exclusion criteria, and the background data of SAAS have been published separately,E1Kankaanranta H. Ilmarinen P. Kankaanranta T. Tuomisto L.E. Seinajoki adult asthma study (SAAS): a protocol for a 12-year real-life follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialised care.NPJ Prim Care Respir Med. 2015; 25: 15042Crossref PubMed Scopus (27) Google Scholar as well as results of cluster analysis.E2Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Haanpää J. Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma.J Allergy Clin Immunol Pract. 2017; 5: 967-978Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Briefly, asthma was diagnosed by a respiratory physician during the period 1999-2002 on the basis of typical symptoms and confirmed by objective lung function measurements.E1Kankaanranta H. Ilmarinen P. Kankaanranta T. Tuomisto L.E. Seinajoki adult asthma study (SAAS): a protocol for a 12-year real-life follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialised care.NPJ Prim Care Respir Med. 2015; 25: 15042Crossref PubMed Scopus (27) Google Scholar After diagnosis, the patients were treated and monitored by their own treating physician either in specialized care or in primary care. The total cohort consisted of 257 patients and 203 patients returned to the follow-up visit 12 years (mean, 12.2 years; range, 10.8-13.9 years) after diagnosis. At follow-up visit, asthma status and control, comorbidities, and medication were evaluated using structured questionnaires and lung function and blood YKL-40, IL-8, and IL-6 levels were measured. Data on asthma-related visits to health care and hospitalizations were collected from primary care, occupational health care, private clinics, and hospitals from the whole 12-year follow-up period. All 203 patients were included in most correlation analyses but 171 patients in clinical clusters due to missing data. Lung function measurements were performed with a spirometer (Vmax Encore 22, Viasys Healthcare, Palm Springs, Calif) according to international recommendations.E3Miller M.R. Hankinson J. Brusasco V. Burgos F. Casaburi R. Coates A. et al.Standardisation of spirometry.Eur Respir J. 2005; 26: 319-338Crossref PubMed Scopus (11481) Google Scholar The spirometer was calibrated daily. Postbronchodilator measurements were taken 15 minutes after inhalation of salbutamol (400 μg). Finnish reference values were used.E4Viljanen A.A. Halttunen P.K. Kreus K.E. Viljanen B.C. Spirometric studies in non-smoking, healthy adults.Scand J Clin Lab Invest Suppl. 1982; 159: 5-20Crossref PubMed Google Scholar Fractional exhaled nitric oxide was measured with a portable rapid-response chemiluminescent analyzer according to ATS standardsE5American Thoracic Society, European Respiratory SocietyATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med. 2005; 171: 912-930Crossref PubMed Scopus (2819) Google Scholar (flow rate, 50 mL/s; NIOX System, Aerocrine, Sweden). Venous blood was collected and white blood cells differential counts were determined. Total IgE levels were measured by using ImmunoCAP (Thermo Scientific, Uppsala, Sweden). Plasma YKL-40 and IL-8 concentrations were measured by an ELISA using reagents from R&D Systems Europe Ltd, Abingdon, UK, and BD Biosciences, Erembodegem, Belgium, respectively.E6Väänänen T. Lehtimäki L. Vuolteenaho K. Hämäläinen M. Oksa P. Vierikko T. et al.Glycoprotein YKL-40 levels in plasma are associated with fibrotic changes on HRCT in asbestos-exposed subjects.Mediators Inflamm. 2017; 2017: 1797512Crossref PubMed Scopus (11) Google Scholar, E7Väänänen T. Kallio J. Vuolteenaho K. Ojala A. Luukkaala T. Hämäläinen M. et al.High YKL-40 is associated with poor survival in patients with renal cell carcinoma: a novel independent prognostic marker.Scand J Urol. 2017; 51: 367-372Crossref PubMed Scopus (8) Google Scholar, E8Väänänen T. Koskinen A. Paukkeri E.L. Hämäläinen M. Moilanen T. Moilanen E. et al.YKL-40 as a novel factor associated with inflammation and catabolic mechanisms in osteoarthritic joints.Mediators Inflamm. 2014; 2014: 215140Crossref PubMed Scopus (41) Google Scholar The detection limit and interassay coefficient of variation were 7.8 pg/mL and 2.7% for YKL-40 and 0.8 pg/mL and 7.5% for IL-8. Serum IL-6 levels were measured by using ELISA (R & D Systems, Minneapolis, Minn), and lower limit for detection was 0.7 pg/mL. High-sensitivity C-reactive protein was measured by using particle-enhanced immunoturbidometric method on Roche Cobas 8000 automated clinical chemistry analyzer (Roche Diagnostics, Basel, Switzerland) with lower limit of detection of 0.3 mg/L. Patients completed Airways Questionnaire 20E9Barley E.A. Quirk F.H. Jones P.W. Asthma health status measurement in clinical practice: validity of a new short and simple instrument.Respir Med. 1998; 92: 1207-1214Abstract Full Text PDF PubMed Scopus (114) Google Scholar and Asthma Control Test. Assessment of asthma control was performed according to the Global Initiative for Asthma report.E10Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2010http://www.ginasthma.org/Google Scholar Information on the conditions included as comorbidities has been previously published.E1Kankaanranta H. Ilmarinen P. Kankaanranta T. Tuomisto L.E. Seinajoki adult asthma study (SAAS): a protocol for a 12-year real-life follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialised care.NPJ Prim Care Respir Med. 2015; 25: 15042Crossref PubMed Scopus (27) Google Scholar A multivariate linear regression was performed when analyzing factors associated with YKL-40 levels. Because of skewed YKL-40 distribution, YKL-40 levels were log-transformed for linear regression analysis. The correlation matrix was analyzed and the explanatory variables not strongly correlated (R < 0.7) were included in the analysis. Predictors were selected on the basis of univariate analysis and the combination of variables giving the best R2 chosen by using the enter method. Also, forward and backward methods were carried out to aid selection of the best model. Statistical analyses were performed by using SPSS software, version 25 (IBM SPSS, Armonk, NY) .Table E1Correlations of plasma YKL-40 with clinical clusters/phenotypes of adult-onset asthma, basic characteristics, and clinical parameters of asthmaCharacteristicSpearman ρP valueAt 12-y follow-up visit Age0.402<.001 BMI0.213.002 Pack years0.099.171 No. of comorbidities0.376<.001 Pre-BD FEV1−0.305<.001 Post-BD FEV1−0.317<.001 Pre-BD FVC−0.218.002 Post-BD FVC−0.175.013 Post-BD FEV1/FVC ratio−0.238.001 FEV1 Reversibility0.078.270 ACT−0.228<.001 AQ200.256<.001 Blood eosinophils0.031.664 Blood neutrophils0.125.076 Total IgE−0.058.411 Feno−0.042.563 IL-60.449<.001 IL-80.410<.001 hsCRP0.248<.001 ICS dose0.119.144 No. of add-on drugs0.273<.001At diagnosis Pre-BD FEV1−0.225.001 Post-BD FEV1−0.232.001 Post-BD FEV1/FVC ratio−0.248.001During 12-y follow-up period Lung function decline∗Pre-FEV1 from maximum point of lung function within 2.5 y after start of therapy to 12-y follow-up visit.−0.154.020 Hospitalizations†Number of hospitalizations during the 12-y follow-up period.0.208.003 No. of oral steroid courses‡Within 2 y before 12-y follow-up visit. Most correlation analyses include 203 patients.0.063.377ACT, Asthma Control Test; AQ20, Airways Questionnaire 20; BD, bronchodilator; Feno, fractional exhaled nitric oxide; FVC, forced vital capacity; hsCRP, high sensitivity C-reactive protein; ICS, inhaled corticosteroid.∗ Pre-FEV1 from maximum point of lung function within 2.5 y after start of therapy to 12-y follow-up visit.† Number of hospitalizations during the 12-y follow-up period.‡ Within 2 y before 12-y follow-up visit. Most correlation analyses include 203 patients. Open table in a new tab ACT, Asthma Control Test; AQ20, Airways Questionnaire 20; BD, bronchodilator; Feno, fractional exhaled nitric oxide; FVC, forced vital capacity; hsCRP, high sensitivity C-reactive protein; ICS, inhaled corticosteroid.
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