Serum YKL-40 levels may help distinguish exacerbation of post-infectious bronchiolitis obliterans from acute bronchiolitis in young children
Identifieur interne : 000255 ( Pmc/Corpus ); précédent : 000254; suivant : 000256Serum YKL-40 levels may help distinguish exacerbation of post-infectious bronchiolitis obliterans from acute bronchiolitis in young children
Auteurs : Yoon Young Jang ; Hye Jin Park ; Hai Lee ChungSource :
- European Journal of Pediatrics [ 0340-6199 ] ; 2017.
Abstract
Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty-seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (
Url:
DOI: 10.1007/s00431-017-2940-x
PubMed: 28567534
PubMed Central: 7087271
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Serum YKL-40 levels may help distinguish exacerbation of post-infectious bronchiolitis obliterans from acute bronchiolitis in young children</title><author><name sortKey="Jang, Yoon Young" sort="Jang, Yoon Young" uniqKey="Jang Y" first="Yoon Young" last="Jang">Yoon Young Jang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Park, Hye Jin" sort="Park, Hye Jin" uniqKey="Park H" first="Hye Jin" last="Park">Hye Jin Park</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Chung, Hai Lee" sort="Chung, Hai Lee" uniqKey="Chung H" first="Hai Lee" last="Chung">Hai Lee Chung</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28567534</idno><idno type="pmc">7087271</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087271</idno><idno type="RBID">PMC:7087271</idno><idno type="doi">10.1007/s00431-017-2940-x</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000255</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000255</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Serum YKL-40 levels may help distinguish exacerbation of post-infectious bronchiolitis obliterans from acute bronchiolitis in young children</title><author><name sortKey="Jang, Yoon Young" sort="Jang, Yoon Young" uniqKey="Jang Y" first="Yoon Young" last="Jang">Yoon Young Jang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Park, Hye Jin" sort="Park, Hye Jin" uniqKey="Park H" first="Hye Jin" last="Park">Hye Jin Park</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Chung, Hai Lee" sort="Chung, Hai Lee" uniqKey="Chung H" first="Hai Lee" last="Chung">Hai Lee Chung</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">European Journal of Pediatrics</title><idno type="ISSN">0340-6199</idno><idno type="eISSN">1432-1076</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty-seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (<italic>N</italic> = 30) and in age-matched controls (<italic>N</italic> = 20). Only YKL-40 levels were found to be significantly higher in PIBO patients with exacerbation compared with that in bronchiolitis patients and showed a positive correlation with the severity of disease before diagnosis of PIBO.</p><p id="Par2"><italic>Conclusion</italic>: Our results suggest that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.<table-wrap id="Taba"><table frame="hsides" rules="groups"><tbody><tr><td><p><bold>What is Known:</bold></p><p><italic>• The children with post-infectious BO (PIBO) usually have recurrent wheezing and need frequent hospitalization due to acute exacerbation during the first disease years.</italic></p><p><italic>• Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment.</italic></p></td></tr><tr><td><p><bold>What is New:</bold></p><p><italic>• Measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.</italic></p></td></tr></tbody></table></table-wrap></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Moonnumakal, Sp" uniqKey="Moonnumakal S">SP Moonnumakal</name></author><author><name sortKey="Fan, Ll" uniqKey="Fan L">LL Fan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barker, Af" uniqKey="Barker A">AF Barker</name></author><author><name sortKey="Bergeron, A" uniqKey="Bergeron A">A Bergeron</name></author><author><name sortKey="Rom, Wn" uniqKey="Rom W">WN Rom</name></author><author><name sortKey="Hertz, Mi" uniqKey="Hertz M">MI Hertz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fischer, Gb" uniqKey="Fischer G">GB Fischer</name></author><author><name sortKey="Sarria, Ee" uniqKey="Sarria E">EE Sarria</name></author><author><name sortKey="Mattiello, 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Eur J Pediatr</journal-id><journal-id journal-id-type="iso-abbrev">Eur. J. Pediatr</journal-id><journal-title-group><journal-title>European Journal of Pediatrics</journal-title></journal-title-group><issn pub-type="ppub">0340-6199</issn><issn pub-type="epub">1432-1076</issn><publisher><publisher-name>Springer Berlin Heidelberg</publisher-name><publisher-loc>Berlin/Heidelberg</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28567534</article-id><article-id pub-id-type="pmc">7087271</article-id><article-id pub-id-type="publisher-id">2940</article-id><article-id pub-id-type="doi">10.1007/s00431-017-2940-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Serum YKL-40 levels may help distinguish exacerbation of post-infectious bronchiolitis obliterans from acute bronchiolitis in young children</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jang</surname><given-names>Yoon Young</given-names></name><address><email>yyjang0117@gmail.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Hye Jin</given-names></name><address><email>grapfarm@daum.net</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Chung</surname><given-names>Hai Lee</given-names></name><address><email>hlchung@cu.ac.kr</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9370 7312</institution-id><institution-id institution-id-type="GRID">grid.253755.3</institution-id><institution>Department of Pediatrics, School of Medicine,</institution><institution>Catholic University of Daegu,</institution></institution-wrap>Namgu Duryugongwon Ro 17-33, Daegu, 42472 South Korea</aff></contrib-group><author-notes><fn fn-type="com"><p>Communicated by Peter de Winter</p></fn></author-notes><pub-date pub-type="epub"><day>1</day><month>6</month><year>2017</year></pub-date><pub-date pub-type="ppub"><year>2017</year></pub-date><volume>176</volume><issue>7</issue><fpage>971</fpage><lpage>978</lpage><history><date date-type="received"><day>8</day><month>12</month><year>2016</year></date><date date-type="rev-recd"><day>18</day><month>5</month><year>2017</year></date><date date-type="accepted"><day>22</day><month>5</month><year>2017</year></date></history><permissions><copyright-statement>© Springer-Verlag Berlin Heidelberg 2017</copyright-statement><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty-seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (<italic>N</italic> = 30) and in age-matched controls (<italic>N</italic> = 20). Only YKL-40 levels were found to be significantly higher in PIBO patients with exacerbation compared with that in bronchiolitis patients and showed a positive correlation with the severity of disease before diagnosis of PIBO.</p><p id="Par2"><italic>Conclusion</italic>: Our results suggest that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.<table-wrap id="Taba"><table frame="hsides" rules="groups"><tbody><tr><td><p><bold>What is Known:</bold></p><p><italic>• The children with post-infectious BO (PIBO) usually have recurrent wheezing and need frequent hospitalization due to acute exacerbation during the first disease years.</italic></p><p><italic>• Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment.</italic></p></td></tr><tr><td><p><bold>What is New:</bold></p><p><italic>• Measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.</italic></p></td></tr></tbody></table></table-wrap></p></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>YKL-40</kwd><kwd>Growth factor</kwd><kwd>Post-infectious bronchiolitis obliterans</kwd><kwd>Children</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer-Verlag GmbH Germany 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Introduction</title><p id="Par9">Bronchiolitis obliterans (BO) is an uncommon and irreversible form of chronic obstructive lung disease secondary to severe insults to lower respiratory tract [<xref ref-type="bibr" rid="CR1">1</xref>]. Various kinds of lung injuries due to infection, allogeneic transplantation, and exposure to toxic fumes have been reported to cause BO [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>]. It is known that these diverse medical conditions share some common pathways that result in a characteristic histopathology of BO, subepithelial inflammation, and fibrotic narrowing of bronchioles [<xref ref-type="bibr" rid="CR2">2</xref>]. In young children, BO occurs most often after respiratory infection and common pathogens including adenovirus, influenza virus, and <italic>Mycoplasma pneumoniae</italic> have been associated with the development of post-infectious BO (PIBO) [<xref ref-type="bibr" rid="CR3">3</xref>]. Many children diagnosed with PIBO, in contrast to those with post-transplant BO, show clinical improvement during lung development. However, radiological findings and impaired lung function are persistent or sometimes progressive [<xref ref-type="bibr" rid="CR4">4</xref>–<xref ref-type="bibr" rid="CR6">6</xref>].</p><p id="Par10">The children with PIBO usually have recurrent wheezing, coughing, and shortness of breath on exertion. They also need frequent hospitalization because of acute exacerbation due to respiratory infection during the first disease years. Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment [<xref ref-type="bibr" rid="CR7">7</xref>].</p><p id="Par11">YKL-40, also called chitinase-3-like1 (CHI3L1) glycoprotein, is shown to have a role in various human diseases associated with infection, inflammation, and/or tissue remodeling [<xref ref-type="bibr" rid="CR8">8</xref>]. Recently, serum concentration of YKL-40 was reported to be a predictive biomarker for development of BO in lung transplant recipients [<xref ref-type="bibr" rid="CR9">9</xref>], but it has not been studied in the children with PIBO.</p><p id="Par12">Vascular endothelial growth factor (VEGF) is a key mediator of vascular neogenesis and is known to play a role in airway inflammation and remodeling [<xref ref-type="bibr" rid="CR10">10</xref>]. Transforming growth factor (TGF)-β1 and platelet-derived growth factor (PDGF) are important fibrogenic cytokines and are known to contribute to lung fibrosis [<xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR12">12</xref>]. These growth factors were shown to be involved in the pathogenesis of bronchiolitis obliterans syndrome following transplantation [<xref ref-type="bibr" rid="CR13">13</xref>–<xref ref-type="bibr" rid="CR15">15</xref>], but have not been studied yet in the children with PIBO.</p><p id="Par13">In the present study, we measured serum concentrations of YKL-40 and growth factors in children with PIBO admitted with exacerbation. All values measured were compared to those from children with acute bronchiolitis who served as positive controls. We hypothesized that YKL-40 and growth factors may be increased in the patients with PIBO and could be non-invasive biomarkers for distinguishing exacerbation of PIBO from acute bronchiolitis in young children.</p></sec><sec id="Sec2"><title>Materials and methods</title><sec id="Sec3"><title>Patients and controls</title><p id="Par14">The patients who were admitted with acute exacerbation of PIBO or acute bronchiolitis between March 2013 and February 2015 were enrolled. We retrospectively reviewed the medical records of the two patient groups and investigated their clinical characteristics.</p><p id="Par15">Diagnosis of PIBO was made based on both clinical and radiologic findings according to the previously described criteria [<xref ref-type="bibr" rid="CR16">16</xref>]: (1) history of acute lower respiratory infection in previously healthy children; (2) unresolved respiratory symptoms associated with airway obstruction (cough, shortness of breath on exertion, and/or abnormal breath sounds) that last for more than 6 weeks after the initial episode despite treatment; (3) mosaic perfusion with air trapping, bronchiectasis, or atelectasis on pulmonary high-resolution computed tomography (HRCT); (4) exclusion of any underlying diseases including other chronic lung diseases. This study included the patients with PIBO whose clinical data including age at onset of persistent respiratory disease, interval between onset of disease and diagnosis, and severity of disease before diagnosis were available.</p><p id="Par16">The patients admitted with acute bronchiolitis served as positive controls. Diagnosis of bronchiolitis was made clinically on the basis of a thorough history and physical examination [<xref ref-type="bibr" rid="CR17">17</xref>]. The present study included the patients who were age-matched to the patients with PIBO and it was confirmed that they did not develop BO during a 1-year follow-up period after discharge through a retrospective review of the outpatient medical records. The patients who had persistent respiratory symptoms associated with previous respiratory infection were excluded.</p><p id="Par17">Twenty age-matched control subjects, who were admitted with minor surgical problems, were also enrolled. They had no respiratory symptoms on admission and no previous history of recurrent respiratory illnesses.</p></sec><sec id="Sec4"><title>Review of clinical characteristics and laboratory findings in the patients</title><p id="Par18">The severity of disease before diagnosis in PIBO group was assessed on sum of scores (with maximum severity score 8) based on their medical history before admission, that is, from 1 to 2 for each of the following clinical findings: (1) cough, shortness of breath on exertion, and/or abnormal breath sounds (1 intermittent; 2 daily); (2) limitation of normal activity (1 none; 2 any); (3) frequency of respiratory disease requiring hospitalization or emergency department visits (1 once; 2 ≥twice); (4) frequency of unscheduled outpatient visits (1 once; 2 ≥twice) [<xref ref-type="bibr" rid="CR18">18</xref>].</p><p id="Par19">The severity of symptom during current admission was assessed on the symptom score from 0 to 4 according to the number of the following clinical findings: (1) fever over 38.5 °C; (2) tachypnea (age-specific) and/or lower chest wall indrawing; (3) oxygen saturation less than 92% breathing room air; (4) more than 7 days hospitalization [<xref ref-type="bibr" rid="CR19">19</xref>].</p><p id="Par20">Atopic sensitization was defined as having at least one serum-specific IgE >0.35 kU/L (ImmunoCAP, Phadia, Uppsala, Sweden) to common allergens. Common allergens used for our patients were <italic>Dermatophagoides farinae</italic>, <italic>Dermatophagoides pteronyssinus</italic>, pollen mixtures (grass pollen mixture, tree pollen mixture, weed pollen mixture), and food allergens (egg, milk, soybean, peanut).</p><p id="Par21">Nasopharyngeal aspirates were obtained from the patients on admission to detect respiratory viral pathogens using multiplex RT-PCR (Seeplex™ RV Detection kit, Seegene, Seoul, Korea). Respiratory syncytial virus, rhinovirus, human bocavirus, human metapneumovirus, influenza virus, adenovirus, corona virus, and parainfluenza virus were studied.</p></sec><sec id="Sec5"><title>Evaluation of YKL-40, VEGF, PDGF-BB, and TGF-β1</title><p id="Par22">Serum samples from the two patient groups, PIBO and bronchiolitis, and controls were collected immediately after admission and stored at −70 °C until analysis.</p><p id="Par23">Levels of YKL-40, VEGF, PDGF-BB, and TGF-β1 were measured using quantitative colorometric sandwich ELISA kits (R&D, Minneapolis, MN, USA) according to the manufacturer’s instruction. ELISA sensitivity was 1.25 pg/mL for YKL-40, 5.0 pg/mL for VEGF, 15 pg/mL for PDGF-BB, and 1.7 pg/mL for TGF-β1, respectively. All assays were performed in duplicate for each sample, and the mean values were reported.</p><p id="Par24">Serum levels of YKL-40, VEGF, PDGF-BB, and TGF-β1 were evaluated in relation to the clinical characteristics and laboratory findings including peripheral neutrophil and eosinophil counts in the two patient groups.</p></sec><sec id="Sec6"><title>Statistical analysis</title><p id="Par25">Analysis of data was done using IBM SPSS ver. 19.0 (SPSS Inc., Chicago, IL, USA). For comparison of serum levels of YKL-40, VEGF, PDGF-BB, and TGF-β1 between two patient groups and controls, since not all distributions were normal, Mann-Whitney <italic>U</italic> test was used. The serum levels are presented as medians with interquartile ranges (IQRs). Fisher’s exact test was used to test for equality of proportions between two groups. Pearson’s or Spearman’s rank correlation analysis was used to evaluate the relationship of biomarker levels with clinical findings. A receiver operating characteristic (ROC) curve was used to assess the cutoff values of YKL-40 which might help distinguish PIBO exacerbation form acute bronchiolitis. A <italic>P</italic> < 0.05 was considered statistically significant.</p></sec></sec><sec id="Sec7"><title>Results</title><sec id="Sec8"><title>Clinical characteristics of the subjects</title><p id="Par26">Thirty-seven patients with PIBO exacerbation and 30 patients with acute bronchiolitis were enrolled in this study. The clinical characteristics of the two patient groups and controls are presented in Table <xref rid="Tab1" ref-type="table">1</xref>. There was no intergroup difference in age distribution and sex ratio. Mean interval between onset of disease and diagnosis of PIBO was 8.1 months (range 2–24 months), and 16 patients were atopic.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Clinical characteristics of two patient groups and controls</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th>PIBO group<break></break>(<italic>N</italic> = 37)</th><th>Bronchiolitis group (<italic>N</italic> = 30)</th><th>Controls<break></break>(<italic>N</italic> = 20)</th><th><italic>P</italic></th></tr></thead><tbody><tr><td>Age, months, mean (range)</td><td>26.2 (5–51)</td><td>22.7 (5–38)</td><td>21.5 (9–45)</td><td>0.4</td></tr><tr><td>Sex, male (%)</td><td>15 (41)</td><td>16 (53)</td><td>11 (55)</td><td>0.3</td></tr><tr><td>Atopic patients (%)</td><td>16 (44)</td><td>11 (37)</td><td>ND</td><td>0.5</td></tr><tr><td><p>Age at initial episode,</p><p>months, mean (range)</p></td><td>16.1 (2–37)</td><td>NA</td><td></td><td></td></tr><tr><td>Interval between initial episode/diagnosis, months, mean (range)</td><td>8.1 (2–24)</td><td>NA</td><td></td><td></td></tr><tr><td>Symptom score during admission, median (range)</td><td>2 (1–4)</td><td>2 (0–4)</td><td></td><td>0.9</td></tr></tbody></table><table-wrap-foot><p><italic>PIBO</italic> post-infectious bronchiolitis obliterans, <italic>ND</italic> not done, <italic>NA</italic> not available</p></table-wrap-foot></table-wrap></p><p id="Par27">There was no difference in viral pathogens detected in nasopharyngeal specimens between the two patient groups (data not shown).</p></sec><sec id="Sec9"><title>Serum levels of YKL-40, VEGF, PDGF-BB, and TGF-β1</title><p id="Par28">Serum YKL-40 levels in the PIBO group were significantly higher than control group levels [1172.2 (IQR 807.7–1569.9) vs. 196.7 (IQR 147.4–570.2) pg/mL, <italic>P</italic> = 0.0001] and also higher than the bronchiolitis group levels [1172.2 (IQR 807.7–1569.9) vs. 687.7 (IQR 406.9–1231.6) pg/mL, <italic>P</italic> = 0.01]. Serum YKL-40 levels in the bronchiolitis group were significantly higher compared with those in controls [687.7 (IQR 406.9–1231.6) vs. 196.7 (IQR 147.4–570.2) pg/mL, <italic>P</italic> = 0.02] (Fig. <xref rid="Fig1" ref-type="fig">1</xref>a).<fig id="Fig1"><label>Fig. 1</label><caption><p>Increased serum YKL-40 levels in both PIBO and bronchiolitis groups compared with those in the controls, which were significantly higher in the PIBO group than in the bronchiolitis group (<bold>a</bold>). Increased VEGF levels with no difference between two patient groups (<bold>b</bold>). PDGF-BB levels with no significant difference among the PIBO, bronchiolitis, and control groups (<bold>c</bold>). Increased TGF-β1 levels in the PIBO group with no difference compared with those in the bronchiolitis group (<bold>d</bold>)</p></caption><graphic xlink:href="431_2017_2940_Fig1_HTML" id="MO1"></graphic></fig></p><p id="Par29">Serum VEGF levels were significantly increased in both PIBO and bronchiolitis groups compared with control group levels [557.9 (IQR 371.1–793.4) vs. 276.7 (IQR 127.3–511.9) pg/mL, <italic>P</italic> = 0.007, and 524.7 (IQR 311.1–841.2) vs. 276.7 (IQR 127.3–511.9) pg/mL, <italic>P</italic> = 0.03, respectively], but showed no difference between those in the PIBO and bronchiolitis groups [557.9 (IQR 371.1–793.4) vs. 524.7 (IQR 311.1–841.2) pg/mL, <italic>P</italic> = 0.63] (Fig. <xref rid="Fig1" ref-type="fig">1</xref>b).</p><p id="Par30">Serum PDGF-BB levels in the PIBO group did not differ from control group levels [161.1 (IQR 139.2–204.9) vs. 166.4 (IQR 107.8–269.1) pg/mL, <italic>P</italic> = 0.96] and were slightly lower than those in the bronchiolitis group [161.1 (IQR 139.2–204.9) vs. 214.1 (IQR 138.3–291.6) pg/mL, <italic>P</italic> = 0.07]. PDGF-BB levels in the bronchiolitis group showed no significant difference compared with control group levels [214.1 (IQR 138.3–291.6) vs. 166.4 (IQR 107.8–269.1) pg/mL, <italic>P</italic> = 0.22] (Fig. <xref rid="Fig1" ref-type="fig">1</xref>c).</p><p id="Par31">Serum levels of TGF-β1 in the PIBO group were significantly higher than those in controls [1087.2 (IQR 589.3–1601.1) vs. 601.3 (IQR 462.7–745.9) pg/mL, <italic>P</italic> = 0.02]. In the bronchiolitis group, TGF-β1 levels also increased but did not reach statistical significance compared with control group levels [848.9 (IQR 564.1–1210.3) vs. 601.3 (IQR 462.7–745.9) pg/mL, <italic>P</italic> = 0.06]. TGF-β1 levels showed no difference between those in the PIBO and bronchiolitis groups [1087.2 (IQR 589.3–1601.1) vs. 848.9 (IQR 564.1–1210.3) pg/mL, <italic>P</italic> = 0.26] (Fig. <xref rid="Fig1" ref-type="fig">1</xref>d).</p><p id="Par32">Only YKL-40 levels were found to be significantly higher in the PIBO group compared with those in the bronchiolitis group. ROC curve analysis showed that serum YKL-40 level of 1033.5 pg/mL best differentiated PIBO exacerbation from acute bronchiolitis with an area under the ROC curve of 0.702 (95% confidence interval (CI) 0.604 to 0.829, <italic>P</italic> < 0.01, Fig. <xref rid="Fig2" ref-type="fig">2</xref>), a sensitivity of 62.5%, and a specificity of 70.8%.<fig id="Fig2"><label>Fig. 2</label><caption><p>Receiver operating characteristic (ROC) curve for YKL-40 levels to distinguish PIBO exacerbation from acute bronchiolitis. Area under the ROC curve (AUC): 0.702 (95% confidence interval (CI), 0.604 to 0.829)</p></caption><graphic xlink:href="431_2017_2940_Fig2_HTML" id="MO2"></graphic></fig></p></sec><sec id="Sec10"><title>Relationship between the levels of YKL-40, VEGF, PDGF-BB, and TGF-β1 and clinical or laboratory parameters in the PIBO and bronchiolitis groups</title><p id="Par33">In the PIBO group, serum YKL-40 levels showed a significant correlation with the severity of disease, assessed as sum of scores, before diagnosis of PIBO (<italic>r</italic> = 0.40, <italic>P</italic> = 0.03) (Fig. <xref rid="Fig3" ref-type="fig">3</xref>). However, severity of acute symptom during current admission showed no significant relationship with YKL-40 levels. Serum YKL-40 levels showed a significant correlation with neutrophil counts in peripheral blood (<italic>r</italic> = 0.40, <italic>P</italic> = 0.04). Serum levels of VEGF, PDGF-BB, and TGF-β1 showed no relationship with any clinical or laboratory findings (Table <xref rid="Tab2" ref-type="table">2</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Correlations between levels of YKL-40 and growth factors and clinical parameters in the patients with PIBO</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th>YKL-40</th><th>VEGF</th><th>PDGF-BB</th><th>TGF-β1</th></tr></thead><tbody><tr><td>Correlation coefficient</td><td><italic>r</italic></td><td><italic>r</italic></td><td><italic>r</italic></td><td><italic>r</italic></td></tr><tr><td>Age</td><td><p>0.17</p><p><italic>P</italic> = 0.46</p></td><td><p>−0.12</p><p><italic>P</italic> = 0.58</p></td><td><p>0.29</p><p><italic>P</italic> = 0.17</p></td><td><p>0.41</p><p><italic>P</italic> = 0.07</p></td></tr><tr><td>Interval between initial episode/diagnosis</td><td><p>0.04</p><p><italic>P</italic> = 0.86</p></td><td><p>−0.19</p><p><italic>P</italic> = 0.39</p></td><td><p>0.26</p><p><italic>P</italic> = 0.24</p></td><td><p>−0.28</p><p><italic>P</italic> = 0.19</p></td></tr><tr><td><p>Severity score</p><p>before diagnosis</p></td><td><p>0.40</p><p><italic>P</italic> = 0.03*</p></td><td><p>0.13</p><p><italic>P</italic> = 0.53</p></td><td><p>−0.01</p><p><italic>P</italic> = 0.19</p></td><td><p>0.26</p><p><italic>P</italic> = 0.98</p></td></tr><tr><td><p>Symptom score</p><p>during admission</p></td><td><p>0.10</p><p><italic>P</italic> = 0.63</p></td><td><p>0.15</p><p><italic>P</italic> = 0.89</p></td><td><p>0.14</p><p><italic>P</italic> = 0.16</p></td><td><p>0.07</p><p><italic>P</italic> = 0.62</p></td></tr><tr><td>Log[serum total IgE]</td><td><p>0.02</p><p><italic>P</italic> = 0.95</p></td><td><p>−0.21</p><p><italic>P</italic> = 0.35</p></td><td><p>0.43</p><p><italic>P</italic> = 0.05</p></td><td><p>−0.02</p><p><italic>P</italic> = 0.92</p></td></tr><tr><td>Blood eosinophils</td><td><p>0.17</p><p><italic>P</italic> = 0.71</p></td><td><p>−0.18</p><p><italic>P</italic> = 0.37</p></td><td><p>−0.14</p><p><italic>P</italic> = 0.59</p></td><td><p>0.11</p><p><italic>P</italic> = 0.48</p></td></tr><tr><td>Blood neutrophils</td><td><p>0.40</p><p><italic>P</italic> = 0.04*</p></td><td><p>0.41</p><p><italic>P</italic> = 0.06</p></td><td><p>0.13</p><p><italic>P</italic> = 0.45</p></td><td><p>−0.15</p><p><italic>P</italic> = 0.54</p></td></tr></tbody></table><table-wrap-foot><p><italic>PIBO</italic> post-infectious bronchiolitis obliterans</p><p>*<italic>P</italic> < 0.05</p></table-wrap-foot></table-wrap></p><p id="Par34">In the bronchiolitis group, serum levels of YKL-40, VEGF, PDGF-BB, and TGF-β1 showed no relationship with any clinical and laboratory findings (data not shown).<fig id="Fig3"><label>Fig. 3</label><caption><p>A significant correlation between serum YKL-40 levels and the severity of disease before diagnosis of PIBO</p></caption><graphic xlink:href="431_2017_2940_Fig3_HTML" id="MO3"></graphic></fig></p></sec><sec id="Sec11"><title>Serum levels of YKL-40, VEGF, PDGF-BB, and TGF-β1 in relation to atopic status in the PIBO group</title><p id="Par35">There was no difference in demographic findings between atopic and non-atopic patients. Interval between onset of disease and diagnosis, severity score before diagnosis, and symptom score during current admission did not show any difference in relation to atopic status of the patients (data not shown).</p><p id="Par36">Serum levels of PDGF-BB and TGF-β1 were significantly higher in atopic patients compared with those in non-atopic patients [174.2 (IQR 149.9–234.0) vs. 143.6 (IQR 108.7–164.5) pg/mL, <italic>P</italic> = 0.03, and 783.2 (IQR 744.8–1655.6) vs. 743.1 (IQR 275.5–1250.8) pg/mL, <italic>P</italic> = 0.04, respectively]. YKL-40 and VEGF levels showed no difference between atopic and non-atopic patients [1093.2 (IQR 1093.2–1614.1) vs. 1329.3 (IQR 1066.8–1921.9) pg/mL, <italic>P</italic> = 0.6, and 495.6 (IQR 344.3–730.4) vs. 590.9 (IQR 362.4–814.0) pg/mL, <italic>P</italic> = 0.5, respectively].</p></sec></sec><sec id="Sec12"><title>Discussion</title><p id="Par37">The present study showed that serum YKL-40 levels were increased during exacerbation of pediatric PIBO and were significantly higher compared with those in children with acute bronchiolitis. YKL-40 levels in children with PIBO were positively correlated with the severity of disease before diagnosis.</p><p id="Par38">BO is characterized by peribronchial fibrosis which results in concentric narrowing and obliteration of small airways regardless of the antecedent causes [<xref ref-type="bibr" rid="CR2">2</xref>]. The children with PIBO are frequently hospitalized with acute exacerbation due to respiratory infection and so were the patients enrolled in this study. However, clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which might cause treatment delay [<xref ref-type="bibr" rid="CR7">7</xref>]. The search for non-invasive biomarkers for early diagnosis is needed to prevent chronic lung function impairment associated with PIBO.</p><p id="Par39">Increased serum concentrations of YKL-40 are observed in chronic lung diseases such as asthma, pulmonary fibrosis, and chronic obstructive lung disease (COPD) [<xref ref-type="bibr" rid="CR20">20</xref>–<xref ref-type="bibr" rid="CR22">22</xref>]. A recent study suggested that serum YKL-40 could be a biomarker for the development of BO after lung transplantation [<xref ref-type="bibr" rid="CR9">9</xref>]. In the present study, serum YKL-40 levels were significantly increased in the children with PIBO and showed a good correlation with disease severity before diagnosis. Taken together with the previous results, our study seems to support the assumption that YKL-40 might be involved in the development of PIBO and there might be a common pathway through which various insults could lead to similar pathologic and clinical features in the patients with BO as indicated before [<xref ref-type="bibr" rid="CR2">2</xref>]. Further investigation including histopathological studies will be needed to clarify the active role of YKL-40 in the pathogenesis of PIBO.</p><p id="Par40">YKL-40 is known as an important regulator of oxidant-induced lung injury [<xref ref-type="bibr" rid="CR8">8</xref>]. Our results seem to be supported by other studies which have shown that oxidative stress is increased in both post-transplant [<xref ref-type="bibr" rid="CR23">23</xref>] and post-infectious BO [<xref ref-type="bibr" rid="CR24">24</xref>].</p><p id="Par41">We examined the children who were admitted with acute bronchiolitis during the same period as the positive controls. Serum YKL-40 levels were also increased in bronchiolitis patients compared with those in the controls, but they were significantly lower compared with those in the patients with PIBO exacerbation. ROC curve analysis showed that measuring serum YKL-40 levels might help distinguish PIBO exacerbation from acute bronchiolitis in young children.</p><p id="Par42">Our study showed a significant correlation between serum YKL-40 levels and peripheral blood neutrophil counts in PIBO patients. This result seems to be in line with that in a previous study that reported a good correlation between serum YKL-40 levels and peripheral neutrophils in the children with severe asthma [<xref ref-type="bibr" rid="CR25">25</xref>]. Although the major source of YKL-40 is known to be alveolar macrophages and epithelial cells [<xref ref-type="bibr" rid="CR26">26</xref>, <xref ref-type="bibr" rid="CR27">27</xref>], it has been reported that YKL-40 can be stored in the specific granules of neutrophils and released upon activation [<xref ref-type="bibr" rid="CR25">25</xref>].</p><p id="Par43">It has been suggested that VEGF, a potent angiogenic factor, may enhance airway obliteration in post-transplant BO by increasing the proliferation of airway smooth muscle cells through inducing PDGF signaling [<xref ref-type="bibr" rid="CR14">14</xref>]. TGF-β1<sub>,</sub> an important mediator of lung fibrosis and remodeling, was reported to be associated with the development of BO after human lung transplantation [<xref ref-type="bibr" rid="CR15">15</xref>] and overexpressed in the patients with BO caused by toxic-fume inhalation [<xref ref-type="bibr" rid="CR28">28</xref>]. VEGF and TGF-β<sub>1</sub> have also been reported to be increased during acute viral respiratory infections in other studies [<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR30">30</xref>]. In our study, serum levels of VEGF and TGF-β<sub>1</sub> were significantly higher in the PIBO group than those in the controls. These results suggest that those growth factors might also be involved in the pathogenesis of PIBO in young children. However, unlike YKL-40, there was no difference in growth factor levels between the patients with PIBO exacerbation and those with acute bronchiolitis. We think more studies including serial measurement might be needed to clarify the role of growth factors as possible biomarkers for PIBO in children.</p><p id="Par44">In our study, TGF-β1 and PDGF-BB levels were significantly higher in atopic than in non-atopic patients. Those growth factors are known to be involved in remodeling of asthmatic airways. Although thickening of reticular basement membrane and subepithelial fibrosis are components of airway remodeling in asthma, similar changes are observed in BO [<xref ref-type="bibr" rid="CR31">31</xref>]. A previous study reported that the structural changes were observed only in atopic but not in non-atopic subjects with asymptomatic airway hyperresponsiveness [<xref ref-type="bibr" rid="CR32">32</xref>]. A recent study also showed that atopy was associated with increased airway smooth muscle area in preschool children with severe recurrent wheeze [<xref ref-type="bibr" rid="CR33">33</xref>]. Although there was no significant difference in clinical findings, taken together with these previous results, our study seems to suggest that the molecular pathogenesis might be different between atopic and non-atopic children with PIBO. We think a future long-term follow-up study is needed to determine the outcome of PIBO in relation to atopic status of the children.</p><p id="Par45">The present study has limitations. YKL-40 and growth factor levels were not measured repeatedly over time and were not studied in the patients without exacerbation, which would be necessary to demonstrate their prolonged effects in the airways of young children and development of PIBO. Although our results showed some relationship between YKL-40 levels and clinical severity of disease, histopathological findings will be needed to clarify the role of YKL-40 in the pathogenesis of PIBO. However, to our knowledge, our study showed for the first time that YKL-40, known to play a role in the development of BO after lung transplantation or other lung injuries, is also increased in the serum of the children who developed BO after respiratory infection.</p><p id="Par46">In conclusion, our study showed that serum YKL-40 levels were significantly increased in the children admitted with acute exacerbation of PIBO and had a positive correlation with the severity of disease before diagnosis of PIBO. It suggests that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children and seems to support the assumption that YKL-40 might be involved in the pathogenesis of PIBO.</p></sec></body><back><glossary><title>Abbreviations</title><def-list><def-item><term>PDGF</term><def><p id="Par3">Platelet-derived growth factor</p></def></def-item><def-item><term>ROC</term><def><p id="Par4">Receiver operating characteristic</p></def></def-item><def-item><term>PIBO</term><def><p id="Par5">Post-infectious bronchiolitis obliterans</p></def></def-item><def-item><term>TGF</term><def><p id="Par6">Transforming growth factor</p></def></def-item><def-item><term>VEGF</term><def><p id="Par7">Vascular endothelial growth factor</p></def></def-item><def-item><term>IQR</term><def><p id="Par8">Interquartile range</p></def></def-item></def-list></glossary><fn-group><fn><p>Revisions received: 4 January 2017 / 18 May 2017</p></fn></fn-group><notes notes-type="author-contribution"><title>Authors’ contributions</title><p>Jang YY, Park HJ, and Chung HL had full access to all of the data in the present study and took responsibility for the integrity of the data and also contributed to the study design, data analysis and interpretation, and writing of the manuscript.</p></notes><notes notes-type="ethics"><title>Compliance with ethical standards</title><notes notes-type="COI-statement"><title>Conflict of interest</title><p id="Par47">The authors declare that they have no conflict of interest.</p></notes><notes><title>Ethical approval</title><p id="Par48">Informed written consents were obtained from all the parents and this study was approved by the Daegu Catholic University Medical Center Institutional Review Board (IRB No. CR-16-015) and was performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.</p></notes></notes><ref-list id="Bib1"><title>References</title><ref 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