維基百科

細胞介素放出症候羣

身體反應

細胞介素放出症候群（粵拼：sai3 baau1 gaai3 sou3 fong3 ceot1 zing3 hau6 kwan4；英文：Cytokine release syndrome，簡稱CRS）係一種 系統嚮應炎症（SIRS），佢會畀好幾種唔同嘅因素，譬如感染又或者一啲嘅藥促發。[2] 我哋有陣時會嗌佢做細胞介素風暴 症候群 (CSS)[3]，而佢係因爲有勁多嘅白血球畀呢啲因素激活咗，兼且放出炎症細胞介素嗰陣，導致有更多嘅白血球受到激活而引發嘅。細胞介素放出症候群亦係一啲單株抗體藥又或者抗原受容體T細胞療法嘅副作用。[4][5] 嚮由抗原受容體T細胞療法引起嗰陣，佢又屬於輸注反應。[6]

細胞介素放出症候羣
同義詞細胞介素風暴[1]
類型藥嘅副作用，免疫系統病
分類同拎
醫學專科免疫學
DiseasesDB34296
eMedicine2500111

細胞介素風暴呢個行話通常係可以同細胞介素放出症候羣兩家撈亂嚟用嘅。之不過呢，雖然佢哋的確係有著好似樣嘅臨牀特徵，但係佢哋係有分別嘅。當嚮畀某一種療法引起嗰陣，細胞介素放出症候羣可能會拖到幾日甚至乎幾個禮拜之後先至發作；而急性發作嘅細胞介素放出症候羣我哋就嗌佢細胞介素風暴。[7]不過有時我哋都會嗌嗰啲嚴重啲嘅細胞介素放出症候羣做細胞介素風暴。[1]

跡象同徵狀

編輯

細胞介素放出症候羣嘅徵狀包括反覆噉發燒、攰、冇胃口、肌肉同關節痛、心口悶、屙、嘔、皮疹、唞氣快、心跳快、低血壓、暈、頭痛、神智唔清、幻覺、手震同埋協調力降低。

病因

編輯

當勁多嘅白血球，包括B細胞、T細胞、自然冧友細胞、巨噬細胞、樹突細胞同埋單核細胞畀某啲因素激活咗兼且放出炎症細胞介素，然之後激活更多嘅白血球嗰陣，就會引起細胞介素放出症候羣，構成一個病原性發炎嘅正反饋循環。[8]免疫細胞會透過受到壓力抑或感染嗰啲細胞嘅受體配體相互作用而受到激活。[9]

當免疫系統同病原體打交嗰陣，免疫細胞產生嘅嗰啲細胞介素就會惹嚟更多嘅效應細胞，譬如T細胞同埋炎症單核細胞（可分化成巨噬細胞）去到發炎抑或感染嘅部位。仲有，當細胞介素同免疫細胞上邊相應嘅受體結合嗰時會引嚟進一步嘅細胞介素嘅放出。[10]當呢個過程失咗控，噉就會導致嚴重嘅系統性發炎、低血壓、休克同埋多器官衰竭，隨時會攞命。[11]

自體T細胞改造嘅抗原受容體T細胞療法(CAR-T細胞療法)亦都會引起細胞介素放出症候羣。由CAR-T引起嘅細胞介素放出症候羣嘅病人，佢哋血清樣本入邊嘅IL-6、IFN-γ、IL-8 (CXCL8)、IL-10、GM-CSF、MIP-1α/β、MCP-1 (CCL2)、CXCL9同埋CXCL10 (IP-10)嘅水平會升高。[12] CAR-T輸注36個鐘頭之後，最具預測性嘅標記係體溫高過38.9攝氏度(華氏102度)同埋血清入邊嘅MCP-1水平升高。[13]細胞介素放出症候羣病發嗰時，放出嘅細胞介素好多都唔係由CAR-T細胞嗰度出嚟嘅，而係由T細胞介導激活嘅骨髓系細胞產生嘅。譬如，體外共培養實驗就證明咗IL-6、MCP-1同埋MIP-1唔係由CAR-T細胞嗰度嚟嘅，而係由炎症骨髓系細胞產生嘅。[14]體內模型已經證明咗，缺乏淋巴細胞同埋骨髓系細胞嘅有NSG (NOD/SCID/γ鏈)缺陷嘅老鼠仔嚮CAR-T細胞輸注之後唔會出現細胞介素放出症候羣。[15]

除咗CAR-T療法之外，嚴重嘅細胞介素放出症候羣仲會嚮一啲感染或者非感染嘅病嗰度出現，譬如嚮移植物對宿主病（GVHD），2019新型冠狀病毒病（COVID-19），急性呼吸困壓症候羣，敗血病，伊波拉病毒，禽流感，天花同埋系統響應炎症。[16]

雖然2019新型冠狀病毒引起嘅急性呼吸症狀對多數病人嚟講會嚮一開始嘅急性免疫響應嗰時清晒，但係嚮一啲病人嗰度會發展成隨時攞命嘅高強度系統炎症，並且有肺部嘅捲入。呢啲噉樣嘅系統響應炎症導致咗啲淋巴細胞同埋單核細胞積晒嚮個肺度，仲影響埋個心臟，最後仲會發展成急性呼吸困壓症候羣同埋急性心臟衰竭。[17]呢一類嘅病人，佢哋血清入邊嘅CRP, LDH, IL-6, 同埋ferritin都會升高。[18]

血球吞食性淋巴組織細胞增生症候羣特別係EB病毒引起嘅血球吞食性淋巴組織細胞增生症候羣會將啲細胞介素數目提升得好犀利，正因為係噉，呢種情況都應該當佢係嚴重嘅細胞介素放出症候羣。[19]

斷症

編輯

細胞介素放出症候羣喺斷症嗰陣一定要同其它原因引起嘅症狀分清楚，譬如係個病人因為自己嘅病而經已有咗嘅病徵，又抑或啲藥嘅副作用等等。一個較為合適嘅例子係瘤溶症候羣，佢係由抗瘤藥引起嘅副作用，因而處理手法亦唔同。一直到2020年為止，細胞介素放出症候羣都係靠醫生嘅判斷嚟斷症，因為根本冇客觀同埋特異性好嘅測試。[20]

順便提提，除咗細胞介素放出症候羣之外，CAR-T療法仲可能會引起神經毒性，不過兩家嘅病徵完全唔同，而且唔一定會同一時間發病。[21]

預防

編輯

由藥引起嘅嚴重嘅細胞介素放出症候羣可以透過降低劑量，減慢輸注速度又或者嚮用藥之前或者用緊藥嗰陣使用抗組織胺或者類固醇嚟預防。[22]

有體外試驗就用嚟試下明解一啲開發緊嘅新藥會唔會引起細胞介素放出症候羣，同埋用嚟指導動物試驗嗰陣嘅用藥劑量。政府嘅監控部門都好想知道呢啲試驗嘅結果。[1][23]

接受咗CAR-T療法嘅病人一定要參加美國食物同藥物監管署（FDA）指定嘅風險評估同管控計劃（REMS）。呢個計劃要啱啱接受完CAR-T輸注嘅病人留院觀察一斷時間，出院之後要住嚮離同一間醫院兩個鐘車程之內。一出現細胞介素放出症候羣嘅症狀就要馬上由照顧嘅家人車去同一間醫院個急症室，並且出示一張俗稱「荷包卡」嘅卡片，卡片上便有晒病人嘅資料同啲指引。FDA要求醫院方面針對每個病人有兩劑嘅tocilizumab隨時救命。[24][25] [26] [27] [28]

流行性

編輯

嚴重嘅細胞介素放出症候羣係好少有嘅。作為主要嘅副作用，輕微或者中挺嘅細胞介素放出症候羣就嚮接受咗免疫療法或者CAR-T療法嘅病人度好常見。[29]

參攷

編輯
  1. ↑ 1.0 1.1 1.2 Vidal JM, Kawabata TT, Thorpe R, Silva-Lima B, Cederbrant K, Poole S, 等 (August 2010). "In vitro cytokine release assays for predicting cytokine release syndrome: the current state-of-the-science. Report of a European Medicines Agency Workshop". Cytokine. 51 (2): 213–5. doi:10.1016/j.cyto.2010.04.008. PMID 20471854.
  2. ↑ Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, 等 (June 2018). "Cytokine release syndrome". Journal for Immunotherapy of Cancer. 6 (1): 56. doi:10.1186/s40425-018-0343-9. PMC 6003181. PMID 29907163.
  3. ↑ Behrens EM, Koretzky GA (June 2017). "Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era". Arthritis & Rheumatology. 69 (6): 1135–1143. doi:10.1002/art.40071. PMID 28217930. S2CID 21925082.
  4. ↑ Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, 等 (July 2014). "Current concepts in the diagnosis and management of cytokine release syndrome". Blood. 124 (2): 188–95. doi:10.1182/blood-2014-05-552729. PMC 4093680. PMID 24876563.
  5. ↑ Kroschinsky F, Stölzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M, Schellongowski P (April 2017). "New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management". Critical Care. 21 (1): 89. doi:10.1186/s13054-017-1678-1. PMC 5391608. PMID 28407743.
  6. ↑ Vogel WH (April 2010). "Infusion reactions: diagnosis, assessment, and management". Clinical Journal of Oncology Nursing. 14 (2): E10-21. doi:10.1188/10.CJON.E10-E21. PMID 20350882.
  7. ↑ Porter D, Frey N, Wood PA, Weng Y, Grupp SA (March 2018). "Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel". Journal of Hematology & Oncology. 11 (1): 35. doi:10.1186/s13045-018-0571-y. PMC 5833070. PMID 29499750.
  8. ↑ Daniel WL, Rebecca Gardner, and Crystal LM. "Current concepts in the diagnosis and management of cytokine release syndrome". {{cite journal}}: Cite journal requires |journal= (help); Vancouver style error: punctuation in name 1 (help)
  9. ↑ Liu Q, Zhou YH, Yang ZQ (January 2016). "The cytokine storm of severe influenza and development of immunomodulatory therapy". Cellular & Molecular Immunology. 13 (1): 3–10. doi:10.1038/cmi.2015.74. PMC 4711683. PMID 26189369.
  10. ↑ Murphy K, Travers P, Walport M (2007). "Signaling Through Immune System Receptors". Janeway's Immunobiology (第7版). London: Garland. ISBN 978-0-8153-4123-9.
  11. ↑ "Cytokine Release Syndrome". National Cancer Institute Dictionary of Cancer Terms. 喺2023-03-07搵到.
  12. ↑ Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, 等 (June 2016). "Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia". Cancer Discovery. 6 (6): 664–79. doi:10.1158/2159-8290.CD-16-0040. PMC 5448406. PMID 27076371.
  13. ↑ Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, 等 (November 2017). "Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy". Blood. 130 (21): 2295–2306. doi:10.1182/blood-2017-06-793141. PMC 5701525. PMID 28924019.
  14. ↑ Barrett DM, 等 (2016). "Interleukin 6 Is Not Made By Chimeric Antigen Receptor T Cells and Does Not Impact Their Function". Blood. 128 (22): 654. doi:10.1182/blood.V128.22.654.654.
  15. ↑ Sentman ML, Murad JM, Cook WJ, Wu MR, Reder J, Baumeister SH, 等 (December 2016). "Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice". Journal of Immunology. 197 (12): 4674–4685. doi:10.4049/jimmunol.1600769. PMC 5136298. PMID 27849169.
  16. ↑ Drazen, Jeffrey M.; Cecil, Russell L.; Goldman, Lee; Bennett, J. Claude (2000). Cecil Textbook of Medicine (21st ed.). Philadelphia: W.B. Saunders. ISBN 978-0-7216-7996-9.
  17. ↑ Wadman M, Couzin-Frankel J, Kaiser J, Matacic C (April 2020). "A rampage through the body". Science. 368 (6489): 356–360. Bibcode:2020Sci...368..356W. doi:10.1126/science.368.6489.356. PMID 32327580. S2CID 216110951.
  18. ↑ Zhang C, Wu Z, Li JW, Zhao H, Wang GQ (March 2020). "The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality". International Journal of Antimicrobial Agents. 55 (5): 105954. doi:10.1016/j.ijantimicag.2020.105954. PMC 7118634. PMID 32234467.
  19. ↑ Rezk SA, Zhao X, Weiss LM (September 2018). "Epstein-Barr virus (EBV)-associated lymphoid proliferations, a 2018 update". Human Pathology. 79: 18–41. doi:10.1016/j.humpath.2018.05.020. PMID 29885408. S2CID 47010934.
  20. ↑ Lee, Dae Won; Gardner, Rebecca; Porter, David L.; Louis, Cyrus U.; Ahmed, Nabil; Jensen, Michael; Grupp, Stephanie A.; Mackall, Crystal L. (July 2014). "Current concepts in the diagnosis and management of cytokine release syndrome". Blood. 124 (2): 188–195. doi:10.1182/blood-2014-05-552729. PMID 24876563.
  21. ↑ "CAR T-Cell Therapy: Side Effects". Stanford Health Care. 喺2023-03-07搵到.
  22. ↑ Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-95. doi: 10.1182/blood-2014-05-552729. PMID: 24876563; PMCID: PMC4093680.
  23. ↑ "Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products" (PDF). FDA. August 2014.
  24. ↑ https://www.yescartatecartusrems.com/
  25. ↑ https://www.breyanzirems.com/
  26. ↑ https://www.kymriah-rems.com/
  27. ↑ https://www.abecmarems.com/
  28. ↑ https://carvyktirems.com/#Main
  29. ↑ Kroschinsky F, Stölzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M, Schellongowski P (April 2017). "New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management". Critical Care. 21 (1): 89. doi:10.1186/s13054-017-1678-1. PMC 5391608. PMID 28407743.
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