Examination of the relationship between endotype and exacerbation in severe asthma

• Project/Area Number: 20K17206
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hokkaido University
• Principal Investigator: Kimura Hirokazu 北海道大学, 大学病院, 助教 (90789330)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 重症喘息 / 増悪 / エンドタイプ / バイオマーカー / 難治性喘息 / 2型気道炎症 / 好酸球 / FeNO / 喘息増悪

Outline of Research at the Start

重症喘息において増悪を繰り返す病型の存在が報告されているが、増悪の抑制は喘息の治療における重要課題であり、その予測が重要である。申請者らは、重症喘息患者における頻回増悪と2型気道炎症との関連性について報告した。一方で、2型気道炎症のメカニズムは多様であり、様々なバイオマーカーの関与が予想される。
本研究では、血液、喀痰などの検体におけるバイオマーカーの表現型（エンドタイプ）と増悪の状況を調べ、そのバイオマーカーをターゲットとした新規治療の開発へ繋げることが最終的な目的である。

Outline of Final Research Achievements

Various analyzes were performed using data from a prospective 6-year refractory asthma cohort study, including smokers. In particular, we focused on the relationship between the endotype, which is a phenotype of cytokines in blood, sputum, and urine, and the situation of exacerbation, but no significant results have been obtained so far. We would like to continue the analysis in the future.
On the other hand, it was shown that when the three items of high peripheral blood eosinophil count, high exhaled nitric oxide level, which is reflecting eosinophil airway inflammation, and positive atopic status were all present, the exacerbation occurred frequently. Regarding nitric oxide in exhaled breath, the period until the first exacerbation was short when the fluctuation was large.

Academic Significance and Societal Importance of the Research Achievements

本研究では喫煙者を含む集団を対象として、より実臨床を反映している質の高いコホート研究である。吸入ステロイド薬の普及により、多くの喘息患者のコントロールは良くなったが、治療が難しい「難治性喘息」の患者をどのように診療するかは、今なお多くの問題が残っている。
難治性喘息患者の中でも、増悪を繰り返しやすい群が存在することがわかってきた。本研究結果からは、この対象を早期に見つけ出して介入することに繋がると考えられる。

Research Products

• [Journal Article] Further evidence for association of YKL-40 with severe asthma airway remodeling (2022)
  • Author(s): Kimura H, Shimizu K, Tanabe N, Makita H, Taniguchi N, Kimura H, Suzuki M, Abe Y, Matsumoto-Sasaki M, Oguma A, Takimoto-Sato M, Takei N, Matsumoto M, Goudarzi H, Sato S, Ono J, Izuhara K, Hirai T, Nishimura M, Konno S
  • Journal Title: Annals of Allergy, Asthma & Immunology Volume: - Issue: 6 Pages: 682-688
  • DOI: 10.1016/j.anai.2022.03.016
  • Peer Reviewed / Open Access
• [Journal Article] Determination of the cutoff values of Th2 markers for the prediction of future exacerbation in severe asthma: An analysis from the Hokkaido Severe Asthma Cohort Study (2021)
  • Author(s): Kimura Hirokazu、Makita Hironi、Taniguchi Natsuko、Takei Nozomu、Matsumoto Munehiro、Kimura Hiroki、Goudarzi Houman、Shimizu Kaoruko、Suzuki Masaru、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Allergology International Volume: 70 Issue: 1 Pages: 68-73
  • DOI: 10.1016/j.alit.2020.09.001
  • NAID: 130007966772
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Annual Fractional Exhaled Nitric Oxide Measurements and Exacerbations in Severe Asthma (2020)
  • Author(s): Abe Yuki、Suzuki Masaru、Kimura Hirokazu、Shimizu Kaoruko、Makita Hironi、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Journal of Asthma and Allergy Volume: Volume 13 Pages: 731-741
  • DOI: 10.2147/jaa.s289592
  • Peer Reviewed
• [Presentation] Annual fractional exhaled nitric oxide measurements and exacerbations in severe asthma (2021)
  • Author(s): Abe Y, Suzuki M, Kimura H, Shimizu K, Makita H, Nishimura M, Konno S
  • Organizer: ATS congress 2021
  • Int'l Joint Research
• [Presentation] Association of longitudinal changes in quality of life with comorbidities and exacerbations in patients with severe asthma (2021)
  • Author(s): Matsumoto-Sasaki M, Suzuki M, Kimura H, Shimizu K ,Makita H, Nishimura M, Konno S
  • Organizer: APSR 2021
  • Int'l Joint Research