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Published in: Respiratory Research 1/2018

Open Access 01-12-2018 | Research

Serum sST2 levels predict severe exacerbation of asthma

Authors: Masato Watanabe, Keitaro Nakamoto, Toshiya Inui, Mitsuru Sada, Kojiro Honda, Masaki Tamura, Yukari Ogawa, Takuma Yokoyama, Takeshi Saraya, Daisuke Kurai, Haruyuki Ishii, Hajime Takizawa

Published in: Respiratory Research | Issue 1/2018

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Abstract

Background

Neutrophilic inflammation is associated with poorly controlled asthma. Serum levels of sST2, a soluble IL-33 receptor, increase in neutrophilic lung diseases. We hypothesized that high serum sST2 levels in stable asthmatics are a predictor for exacerbation within a short duration.

Methods

This prospective observational study evaluated the serum sST2 levels of 104 asthmatic patients who were treated by a lung disease specialist with follow-ups for 3 months.

Results

High serum sST2 levels (> 18 ng/ml) predicted severe asthma exacerbation within 3 months. Serum sST2 levels correlated positively with asthma severity (treatment step), airway H2O2 levels, and serum IL-8 levels. High serum sST2 levels and blood neutrophilia (> 6000 /μl) were independent predictors of exacerbation. We defined a post-hoc exacerbation-risk score combining high serum sST2 level and blood neutrophilia, which stratified patients into four groups. The score predicted exacerbation-risk with an area under curve of 0.91 in the receiver operating characteristic curve analysis. Patients with the highest scores had the most severe phenotype, with 85.7% showing exacerbation, airflow limitation, and corticosteroid-insensitivity.

Conclusions

High serum sST2 levels predicted exacerbation within the general asthmatic population and, when combined with blood neutrophil levels, provided an exacerbation-risk score that was an accurate predictor of exacerbation occurring within 3 months.
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Literature
2.
go back to reference Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716–25.CrossRefPubMed Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716–25.CrossRefPubMed
3.
go back to reference Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol. 2015;135:299–310. quiz 311CrossRefPubMed Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol. 2015;135:299–310. quiz 311CrossRefPubMed
4.
go back to reference Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D'Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181:315–23.CrossRefPubMed Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D'Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181:315–23.CrossRefPubMed
5.
go back to reference Hastie AT, Moore WC, Li H, Rector BM, Ortega VE, Pascual RM, Peters SP, Meyers DA, Bleecker ER. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013;132:72–80.CrossRefPubMedPubMedCentral Hastie AT, Moore WC, Li H, Rector BM, Ortega VE, Pascual RM, Peters SP, Meyers DA, Bleecker ER. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013;132:72–80.CrossRefPubMedPubMedCentral
6.
go back to reference Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–9.CrossRefPubMed Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–9.CrossRefPubMed
7.
8.
go back to reference Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965–76.CrossRefPubMed Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965–76.CrossRefPubMed
9.
go back to reference Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, Wenzel SE, Peters SP, Meyers DA, Bleecker ER. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133:1557–63. e1555CrossRefPubMed Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, Wenzel SE, Peters SP, Meyers DA, Bleecker ER. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133:1557–63. e1555CrossRefPubMed
10.
go back to reference Nadif R, Siroux V, Boudier A, le Moual N, Just J, Gormand F, Pison C, Matran R, Pin I. Blood granulocyte patterns as predictors of asthma phenotypes in adults from the EGEA study. Eur Respir J. 2016;48:1040–51.CrossRefPubMed Nadif R, Siroux V, Boudier A, le Moual N, Just J, Gormand F, Pison C, Matran R, Pin I. Blood granulocyte patterns as predictors of asthma phenotypes in adults from the EGEA study. Eur Respir J. 2016;48:1040–51.CrossRefPubMed
11.
go back to reference Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, Saito H, Matsuda A. IL-33 mediates inflammatory responses in human lung tissue cells. J Immunol. 2010;185:5743–50.CrossRefPubMed Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, Saito H, Matsuda A. IL-33 mediates inflammatory responses in human lung tissue cells. J Immunol. 2010;185:5743–50.CrossRefPubMed
12.
go back to reference Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369–80.CrossRefPubMed Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369–80.CrossRefPubMed
13.
go back to reference Hristova M, Habibovic A, Veith C, Janssen-Heininger YM, Dixon AE, Geiszt M, van der Vliet A. Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses. J Allergy Clin Immunol. 2016;137:1545–56. e1511CrossRefPubMed Hristova M, Habibovic A, Veith C, Janssen-Heininger YM, Dixon AE, Geiszt M, van der Vliet A. Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses. J Allergy Clin Immunol. 2016;137:1545–56. e1511CrossRefPubMed
14.
go back to reference Luthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P, et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31:84–98.CrossRefPubMed Luthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P, et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31:84–98.CrossRefPubMed
15.
go back to reference Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.CrossRefPubMed Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.CrossRefPubMed
16.
go back to reference Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H. IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol. 2012;188:1503–13.CrossRefPubMed Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H. IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol. 2012;188:1503–13.CrossRefPubMed
17.
go back to reference Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009;41:342–7.CrossRefPubMed Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009;41:342–7.CrossRefPubMed
18.
go back to reference Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363:1211–21.CrossRefPubMedPubMedCentral Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363:1211–21.CrossRefPubMedPubMedCentral
19.
go back to reference Mildner M, Storka A, Lichtenauer M, Mlitz V, Ghannadan M, Hoetzenecker K, Nickl S, Dome B, Tschachler E, Ankersmit HJ. Primary sources and immunological prerequisites for sST2 secretion in humans. Cardiovasc Res. 2010;87:769–77.CrossRefPubMed Mildner M, Storka A, Lichtenauer M, Mlitz V, Ghannadan M, Hoetzenecker K, Nickl S, Dome B, Tschachler E, Ankersmit HJ. Primary sources and immunological prerequisites for sST2 secretion in humans. Cardiovasc Res. 2010;87:769–77.CrossRefPubMed
20.
go back to reference Watanabe M, Takizawa H, Tamura M, Nakajima A, Kurai D, Ishii H, Takata S, Nakamoto K, Sohara E, Honda K, et al. Soluble ST2 as a prognostic marker in community-acquired pneumonia. J Inf Secur. 2015;70:474–82. Watanabe M, Takizawa H, Tamura M, Nakajima A, Kurai D, Ishii H, Takata S, Nakamoto K, Sohara E, Honda K, et al. Soluble ST2 as a prognostic marker in community-acquired pneumonia. J Inf Secur. 2015;70:474–82.
21.
go back to reference Xia J, Zhao J, Shang J, Li M, Zeng Z, Wang J, Xu Y, Xie J. Increased IL-33 expression in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2015;308:L619–27.CrossRefPubMed Xia J, Zhao J, Shang J, Li M, Zeng Z, Wang J, Xu Y, Xie J. Increased IL-33 expression in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2015;308:L619–27.CrossRefPubMed
22.
go back to reference Hoogerwerf JJ, Tanck MW, van Zoelen MA, Wittebole X, Laterre PF, van der Poll T. Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med. 2010;36:630–7.CrossRefPubMedPubMedCentral Hoogerwerf JJ, Tanck MW, van Zoelen MA, Wittebole X, Laterre PF, van der Poll T. Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med. 2010;36:630–7.CrossRefPubMedPubMedCentral
23.
go back to reference Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S, Tominaga SI, Sugiyama Y. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med. 2001;164:277–81.CrossRefPubMed Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S, Tominaga SI, Sugiyama Y. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med. 2001;164:277–81.CrossRefPubMed
24.
go back to reference Global Strategy for Asthma Management and Prevention (GINA). Global Initiative for Asthma 2015. Global Strategy for Asthma Management and Prevention (GINA). Global Initiative for Asthma 2015.
25.
go back to reference Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, Taylor DR. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184:602–15.CrossRefPubMedPubMedCentral Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, Taylor DR. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184:602–15.CrossRefPubMedPubMedCentral
26.
go back to reference Oshikawa K, Kuroiwa K, Tokunaga T, Kato T, Hagihara SI, Tominaga SI, Sugiyama Y. Acute eosinophilic pneumonia with increased soluble ST2 in serum and bronchoalveolar lavage fluid. Respir Med. 2001;95:532–3.CrossRefPubMed Oshikawa K, Kuroiwa K, Tokunaga T, Kato T, Hagihara SI, Tominaga SI, Sugiyama Y. Acute eosinophilic pneumonia with increased soluble ST2 in serum and bronchoalveolar lavage fluid. Respir Med. 2001;95:532–3.CrossRefPubMed
27.
go back to reference Loukides S, Bouros D, Papatheodorou G, Panagou P, Siafakas NM. The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity. Chest. 2002;121:338–46.CrossRefPubMed Loukides S, Bouros D, Papatheodorou G, Panagou P, Siafakas NM. The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity. Chest. 2002;121:338–46.CrossRefPubMed
28.
go back to reference Zhang XY, Simpson JL, Powell H, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, et al. Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy. 2014;44:1137–45.CrossRefPubMed Zhang XY, Simpson JL, Powell H, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, et al. Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy. 2014;44:1137–45.CrossRefPubMed
30.
go back to reference Ho JE, Chen WY, Chen MH, Larson MG, McCabe EL, Cheng S, Ghorbani A, Coglianese E, Emilsson V, Johnson AD, et al. Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. J Clin Invest. 2013;123:4208–18.CrossRefPubMedPubMedCentral Ho JE, Chen WY, Chen MH, Larson MG, McCabe EL, Cheng S, Ghorbani A, Coglianese E, Emilsson V, Johnson AD, et al. Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. J Clin Invest. 2013;123:4208–18.CrossRefPubMedPubMedCentral
31.
go back to reference Alves-Filho JC, Sonego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M, Basile-Filho A, McKenzie AN, Xu D, Cunha FQ, Liew FY. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med. 2010;16:708–12.CrossRefPubMed Alves-Filho JC, Sonego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M, Basile-Filho A, McKenzie AN, Xu D, Cunha FQ, Liew FY. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med. 2010;16:708–12.CrossRefPubMed
32.
go back to reference Le Goffic R, Arshad MI, Rauch M, L'Helgoualc'h A, Delmas B, Piquet-Pellorce C, Samson M. Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol. 2011;45:1125–32.CrossRefPubMed Le Goffic R, Arshad MI, Rauch M, L'Helgoualc'h A, Delmas B, Piquet-Pellorce C, Samson M. Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol. 2011;45:1125–32.CrossRefPubMed
33.
go back to reference Kearley J, Silver JS, Sanden C, Liu Z, Berlin AA, White N, Mori M, Pham TH, Ward CK, Criner GJ, et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity. 2015;42:566–79.CrossRefPubMed Kearley J, Silver JS, Sanden C, Liu Z, Berlin AA, White N, Mori M, Pham TH, Ward CK, Criner GJ, et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity. 2015;42:566–79.CrossRefPubMed
34.
go back to reference Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J Immunol. 2012;188:3488–95.CrossRefPubMed Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J Immunol. 2012;188:3488–95.CrossRefPubMed
35.
go back to reference Lefrancais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP, Cayrol C. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A. 2012;109:1673–8.CrossRefPubMedPubMedCentral Lefrancais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP, Cayrol C. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A. 2012;109:1673–8.CrossRefPubMedPubMedCentral
Metadata
Title
Serum sST2 levels predict severe exacerbation of asthma
Authors
Masato Watanabe
Keitaro Nakamoto
Toshiya Inui
Mitsuru Sada
Kojiro Honda
Masaki Tamura
Yukari Ogawa
Takuma Yokoyama
Takeshi Saraya
Daisuke Kurai
Haruyuki Ishii
Hajime Takizawa
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2018
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-018-0872-2

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