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====== 恢復期血漿治療 ======

=====簡介=====

恢復期血漿療法通常被稱為被動抗體療法，構成一種治療干預，其中使用來自特定傳染病恢復期的個體的血漿來治療同時患病的患者。 這種療法的主要目的在於通過針對致病病原體的預製抗體賦予接受者立即被動免疫力，從而有可能改善正在發生的疾病的病程。

=====歷史背景=====

恢復期血漿療法的起源可以追溯到 19 世紀下半葉，並在 1918 年西班牙流感大流行期間首次應用。自誕生以來，這種治療方式已在一系列傳染病爆發中被引用，包括2009 年的H1N1 流感大流行、2014 年西非的埃博拉病毒災難，以及最近的全球COVID-19 大流行。

=====作用機制=====

恢復期血漿是從目標傳染病恢復期的個體中採集的。 這种血漿成分富含抗體，這是免疫系統響應特定致病實體的存在而引發的特殊蛋白質。 當被引入患有活動性感染的患者體內時，這些抗體充當警惕的哨兵，中和病原體，阻礙其複制能力，並支持宿主的免疫反擊。

=====收集與處理=====

恢復期血漿的獲取需要有條不紊的程序。 康復者要接受嚴格的篩選標準，以確保資格，包括必要的抗體滴度和不存在並發感染因子。 隨後，通過血漿置換過程獲得血漿，其中抽取血液，將血漿與細胞成分分離，然後將細胞成分返回給捐獻者。

=====適應症=====

恢復期血漿療法的主要應用是對抗病毒感染，通常在替代治療方式受到限製或不可用時採用。 它在流感、埃博拉病毒，尤其是在可怕的 COVID-19 大流行中取得了顯著的成功。

=====功效與爭論=====

恢復期血漿治療的功效仍然是持續科學探究和討論的主題。 其效力取決於多種因素，包括特定的傳染原、給藥的時間性以及所獲得血漿的質量。

===== COVID-19 和超免疫恢復期血漿療法 =====

2019 年，一種被稱為嚴重急性呼吸綜合徵冠狀病毒2 (SARS-CoV-2) 的新型冠狀病毒導致了2019 年冠狀病毒病(COVID-19) 的爆發，該病毒在中國武漢首次發現後在全球範圍內迅速傳播。 2020年初，中國和意大利開始在特定病例和小規模病例中應用恢復期血漿。 [(RefNote1>>
authors:李麗，張文，胡Y，童X，鄭S，楊J，等。
title:恢復期血漿治療對嚴重和危及生命的 COVID-19 患者臨床改善時間的影響：一項隨機臨床試驗
url:https://doi.org/10.1001/jama.2020.10044
published:2020 年 8 月
journal:美國醫學會雜誌。 324（5）：460-470。
)]
[(RefNote2>>
authors:沉春，王澤，趙峰，楊Y，李J，袁J，等。
title:使用恢復期血漿治療 5 名 COVID-19 重症患者
url:https://doi.org/10.1001/jama.2020.4783
published:2020 年 4 月
journal:美國醫學會雜誌。 323（16）：1582–1589。
)]
[(RefNote3>>
authors:Perotti C、Baldanti F、Bruno R、Del Fante C、Seminari E、Casari S 等人。
title:使用超免疫血漿治療 46 名重症 Covid-19 患者，死亡率降低。 概念驗證單臂多中心試驗
url:https://doi.org/10.3324/haematol.2020.261784
published:2020 年 12 月
journal:血液學。 105（12）：2834-2840。
)]
梅奧診所領導的恢復期血漿擴大獲取計劃促進了美國恢復期血漿治療的更廣泛實施，[(RefNumber4>>
authors:Senefeld JW、Johnson PW、Kunze KL、Bloch EM、van Helmond N、Golafshar MA 等。
title:美國 COVID-19 恢復期血漿的獲取和安全性擴展獲取計劃：國家登記研究
url:https://doi.org/10.1371/journal.pmed.1003872
published:2021 年 12 月
journal:公共科學圖書館醫學。 18（12）：e1003872。
)]
隨後獲得美國食品和藥物管理局授予的緊急使用授權。 [(RefNote5>>
title: FDA 發布恢復期血漿緊急使用授權，作為潛在有前景的 COVID-19 治療方法
發布: 2020 年 8 月 23 日
出版者：食品藥品監督管理局。
url:https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-pottial-promising-covid-19-treatment
)]
來自擴展訪問計劃的數據表明，與接受低滴度恢復期血漿的患者相比，不需要機械通氣且接受高滴度恢復期血漿的患者死亡率較低（14.2% vs. 22.2%）。 [(RefNote15>>
authors:Joyner MJ、Carter RE、Senefeld JW、Klassen SA、Mills JR、Johnson PW 等。
title:恢復期血漿抗體水平和 Covid-19 死亡風險
url:https://doi.org/10.1056/NEJMoa2031893
published:2021 年 3 月
journal:新英格蘭醫學雜誌。 384（11）：1015-1027。
)]

在大流行的初期階段，幾項隨機對照試驗得出的結論是，恢復期血漿療法對 COVID-19 無效。 值得注意的是，這些試驗大多數集中於已經血清反應呈陽性或處於疾病晚期的患者和/或使用抗體水平不足的血漿單位。 [(RefNote6>>
authors:Simonovich VA、Burgos Pratx LD、Scibona P、Beruto MV、Vallone MG、Vázquez C 等。
title:Covid-19 重症肺炎恢復期血漿的隨機試驗
url:https://doi.org/10.1056/NEJMoa2031304
published:2021 年 2 月
journal:新英格蘭醫學雜誌。 384（7）：619-629。
)]
[(RefNote7>>
authors:Abani O、Abbas A、Abbas F、Abbas M、Abbasi S、Abbass H 等。 （RECOVERY協作組）
title:COVID-19 入院患者恢復期血漿（RECOVERY）：一項隨機對照、開放標籤平台試驗
url:https://doi.org/10.1016/S0140-6736(21)00897-7
published:2021 年 5 月
journal:柳葉刀。 397（10289）：2049–2059。
)]
[(RefNote8>>
authors:Agarwal A、Mukherjee A、Kumar G、Chatterjee P、Bhatnagar T、Malhotra P
title:恢復期血漿在印度成人中度 covid-19 管理中的應用：開放標籤 II 期多中心隨機對照試驗（PLACID 試驗）
url:https://doi.org/10.1136/bmj.m3939
published:2020 年 10 月
journal:英國醫學雜誌。 371：m3939。
)]
[(RefNote9>>
authors:Bégin P、Callum J、Heddle NM、Cook R、Zeller MP、Tinmouth A 等人。
title:成人急性 COVID-19 呼吸道疾病恢復期血漿 (CONCOR-1)：國際、多中心、隨機、開放標籤試驗的研究方案
url:https://doi.org/10.1186/s13063-021-05235-3
published:2021 年 5 月
日記：審判。 22（1）：323。
)]
[(RefNote10>>
authors:Estcourt LJ、Turgeon AF、McQuilten ZK、McVerry BJ、Al-Beidh F、Annane D 等人。
title:恢復期血漿對 COVID-19 危重患者無器官支持日的影響：一項隨機臨床試驗
url:https://doi.org/10.1001/jama.2021.18178
published:2021 年 11 月
journal:美國醫學會雜誌。 326（17）：1690-1702。
)]
[(RefNote11>>
authors:Focosi D、Franchini M、Pirofski LA、Burnouf T、Paneth N、Joyner MJ、Casadevall A
title:COVID-19 恢復期血漿和臨床試驗：了解相互衝突的結果
url:https://doi.org/10.1128/cmr.00200-21
published:2022 年 3 月
journal:臨床微生物學評論。 35（3）：e0020021。
)]
相反，將注意力集中在診斷後早期給予高滴度恢復期血漿的隨機對照試驗表明，住院人數大幅減少，約減少 50-80%。 [(RefNote16>>
authors:Libster R、Pérez Marc G、Wappner D、Coviello S、Bianchi A、Braem V 等。
title:早期高滴度血漿治療可預防老年人出現嚴重的 Covid-19
url:https://doi.org/10.1056/NEJMoa2033700
published:2021 年 2 月
journal:新英格蘭醫學雜誌。 384（7）：610-618。
)]
[(RefNote12>>
authors:Sullivan DJ、Gebo KA、Shoham S、Bloch EM、Lau B、Shenoy AG 等。
title:Covid-19 恢復期血漿的早期門診治療
url:https://doi.org/10.1056/NEJMoa2119657
published:2022 年 5 月
journal:新英格蘭醫學雜誌。 386（18）：1700–1711。
)]
這一結果與單克隆抗體和小分子抗病毒藥物所取得的效果相一致。 [(RefNote13>>
authors:Sullivan DJ、Focosi D、Hanley D、Franchini M、Ou J、Casadevall A、Paneth N
title:減少 COVID-19 住院治療的有效抗病毒方案：隨機對照試驗的系統比較
url:https://doi.org/10.1101/2022.05.24.22275478
published:2022 年 5 月
journal:medRxiv。
)]

一項流行病學分析檢查了美國恢復期血漿的使用情況和隨後的死亡率，結果顯示出強大的負相關性，提供了令人信服的證據證明其在全人群水平上的有效性。 根據這些數據，據估計，恢復期血漿的使用可能會在美國避免大約 10 萬人死亡。 [(RefNote14>>
authors:Casadevall A、Dragotakes Q、Johnson PW、Senefeld JW、Klassen SA、Wright RS 等。
title:美國恢復期血漿的使用與 COVID-19 死亡率呈負相關
url:https://doi.org/10.7554/eLife.69866
published:2021 年 6 月
journal:eLife。 10：e69866。
)]


===== 生活 =====

~~REFNOTES~~

====== Convalescent Plasma Therapy ======

===== Introduction =====

Convalescent plasma therapy, often referred to as passive antibody therapy, constitutes a therapeutic intervention wherein blood plasma derived from individuals convalescing from a specific infectious ailment is employed to treat contemporaneously afflicted patients. The principal objective of this therapy lies in conferring immediate passive immunity to the recipient by means of preformed antibodies against the causative pathogen, thereby potentially ameliorating the course of the ongoing malady. 

===== Historical Background =====

The genesis of convalescent plasma therapy can be traced to the latter part of the 19th century, finding its inaugural application during the ravages of the Spanish flu pandemic in 1918. Since its inception, this therapeutic modality has been invoked in a spectrum of infectious disease outbreaks, encompassing the H1N1 influenza pandemic of 2009, the Ebola virus scourge in West Africa in 2014, and most recently, amidst the global COVID-19 pandemic.

===== Mechanism of Action =====

Convalescent plasma is culled from individuals convalescent from the targeted infectious malady. This plasma component is enriched with antibodies, specialized proteins elicited by the immune system in response to the presence of a particular pathogenic entity. When introduced into a patient harboring an active infection, these antibodies function as vigilant sentinels, effecting the neutralization of the pathogen, impeding its replicative capacity, and buttressing the host's immune riposte.

===== Collection and Processing =====

The acquisition of convalescent plasma entails a methodical procedure. Convalescent individuals are subjected to stringent screening criteria to ensure eligibility, encompassing requisite antibody titers and the absence of concurrent infectious agents. Subsequently, plasma is garnered through the process of plasmapheresis, wherein blood is drawn, plasma is segregated from cellular constituents, and the latter are subsequently returned to the donor.

===== Indications =====

Convalescent plasma therapy finds its principal application in the combat against viral infections, typically resorted to when alternative therapeutic modalities are constrained or unavailable. It has garnered notable successes in the context of influenza, Ebola, and most prominently, amidst the formidable COVID-19 pandemic.

===== Efficacy and Contentions =====

The efficacy of convalescent plasma therapy remains a subject of sustained scientific inquiry and discourse. Its potency is contingent upon multifarious factors, including the specific infectious agent, the temporality of administration, and the quality of the procured plasma.

===== COVID-19 and Hyperimmune Convalescent Plasma Therapy =====

In 2019, a new type of coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to the outbreak of coronavirus disease 2019 (COVID-19), rapidly spreading worldwide after its initial identification in Wuhan, China. In the early months of 2020, the application of convalescent plasma began in specific cases and small-scale instances in both China and Italy. [(RefNumber1>>
authors: Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al.
title: Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial
url: https://doi.org/10.1001/jama.2020.10044
published: August 2020
journal: JAMA. 324 (5): 460–470.
)]
[(RefNumber2>>
authors: Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al.
title: Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma
url: https://doi.org/10.1001/jama.2020.4783
published: April 2020
journal: JAMA. 323 (16): 1582–1589.
)]
[(RefNumber3>>
authors: Perotti C, Baldanti F, Bruno R, Del Fante C, Seminari E, Casari S, et al.
title: Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial
url: https://doi.org/10.3324/haematol.2020.261784
published: December 2020
journal: Haematologica. 105 (12): 2834–2840.
)]
The broader implementation of convalescent plasma therapy in the United States was facilitated through a Mayo Clinic-led Expanded Access Program for convalescent plasma, [(RefNumber4>>
authors: Senefeld JW, Johnson PW, Kunze KL, Bloch EM, van Helmond N, Golafshar MA, et al.
title: Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study
url: https://doi.org/10.1371/journal.pmed.1003872
published: December 2021
journal: PLOS Medicine. 18 (12): e1003872.
)]
followed by an Emergency Use Authorization granted by the United States Food & Drug Administration. [(RefNumber5>>
title: FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment
published: August 23, 2020
publisher: Food and Drug Administration.
url: https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
)]
Data derived from the Expanded Access Program indicated that patients not requiring mechanical ventilation who received high-titer convalescent plasma exhibited lower mortality rates compared to those administered low-titer convalescent plasma (14.2% vs. 22.2%). [(RefNumber15>>
authors: Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al.
title: Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19
url: https://doi.org/10.1056/NEJMoa2031893
published: March 2021
journal: The New England Journal of Medicine. 384 (11): 1015–1027.
)]

During the initial stages of the pandemic, several randomized controlled trials concluded that convalescent plasma therapy was not effective for COVID-19. Notably, most of these trials focused on patients who were already seropositive or in the advanced stages of the disease and/or used plasma units with inadequate antibody levels. [(RefNumber6>>
authors: Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al.
title: A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia
url: https://doi.org/10.1056/NEJMoa2031304
published: February 2021
journal: The New England Journal of Medicine. 384 (7): 619–629.
)]
[(RefNumber7>>
authors: Abani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, et al. (RECOVERY Collaborative Group)
title: Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial
url: https://doi.org/10.1016/S0140-6736(21)00897-7
published: May 2021
journal: Lancet. 397 (10289): 2049–2059.
)]
[(RefNumber8>>
authors: Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P
title: Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)
url: https://doi.org/10.1136/bmj.m3939
published: October 2020
journal: BMJ. 371: m3939.
)]
[(RefNumber9>>
authors: Bégin P, Callum J, Heddle NM, Cook R, Zeller MP, Tinmouth A, et al.
title: Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial
url: https://doi.org/10.1186/s13063-021-05235-3
published: May 2021
journal: Trials. 22 (1): 323.
)]
[(RefNumber10>>
authors: Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, et al.
title: Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial
url: https://doi.org/10.1001/jama.2021.18178
published: November 2021
journal: JAMA. 326 (17): 1690–1702.
)] 
[(RefNumber11>>
authors: Focosi D, Franchini M, Pirofski LA, Burnouf T, Paneth N, Joyner MJ, Casadevall A
title: COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes
url: https://doi.org/10.1128/cmr.00200-21
published: March 2022
journal: Clinical Microbiology Reviews. 35 (3): e0020021.
)]
Conversely, randomized controlled trials that directed their attention towards the early administration of high-titer convalescent plasma following diagnosis demonstrated a substantial reduction in hospital admissions, ranging from approximately 50-80%. [(RefNumber16>>
authors: Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al.
title: Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults
url: https://doi.org/10.1056/NEJMoa2033700
published: February 2021
journal: The New England Journal of Medicine. 384 (7): 610–618.
)]
[(RefNumber12>>
authors: Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, et al.
title: Early Outpatient Treatment for Covid-19 with Convalescent Plasma
url: https://doi.org/10.1056/NEJMoa2119657
published: May 2022
journal: The New England Journal of Medicine. 386 (18): 1700–1711.
)]
This outcome aligns with the effectiveness achieved with monoclonal antibodies and small-molecule antiviral agents. [(RefNumber13>>
authors: Sullivan DJ, Focosi D, Hanley D, Franchini M, Ou J, Casadevall A, Paneth N
title: Effective antiviral regimens to reduce COVID-19 hospitalizations: a systematic comparison of randomized controlled trials
url: https://doi.org/10.1101/2022.05.24.22275478
published: May 2022
journal: medRxiv.
)]

An epidemiological analysis examining the utilization of convalescent plasma and subsequent mortality rates in the United States revealed a robust inverse correlation, presenting compelling evidence of its effectiveness at a population-wide level. Based on this data, it was estimated that the deployment of convalescent plasma potentially averted roughly 100,000 fatalities in the United States. [(RefNumber14>>
authors: Casadevall A, Dragotakes Q, Johnson PW, Senefeld JW, Klassen SA, Wright RS, et al.
title: Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality
url: https://doi.org/10.7554/eLife.69866
published: June 2021
journal: eLife. 10: e69866.
)]


===== Riferimenti =====

~~REFNOTES~~