COVID-19: Convalescent plasma as a potential therapy.
COVID-19: Convalescent plasma as a potential therapy.
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DOI：
10.7196/samj.2020.v110i7.14983
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发表时间：
2020-06
期刊：
影响因子：
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通讯作者：
K. V. D. Berg;M. Vermeulen;T. Glatt;S. Wasserman;C. Barrett;J. Peter;D. Brittain;V. Louw
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文献类型：
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作者：
K. V. D. Berg;M. Vermeulen;T. Glatt;S. Wasserman;C. Barrett;J. Peter;D. Brittain;V. Louw
562 2020 年 7 月，卷。 110，第 7 期 COVID-19：恢复期血浆作为一种潜在疗法致编辑：SARS-CoV-2 是导致 COVID-19 的原因，对全球健康构成了重大威胁。目前尚未制定具体的治疗方法或有效的预防措施，对重症患者的护理在很大程度上是支持性的，而需要入住 ICU 的患者预后较差。实验疗法包括抗病毒药物，如瑞德西韦、[1] 洛匹那韦/利托那韦[2] 和法匹拉韦、[3] 羟氯喹/氯喹、[4] 白细胞介素 6 抑制剂，如托珠单抗、[5] 西妥昔单抗 [6] 和沙里鲁单抗 [7] 以及 COVID-19 恢复期血浆 (CCP)。 [8] CCP 已被纳入中国重症 COVID-19 的治疗指南中，[9] 并且美国食品和药物管理局最近批准其在临床试验中并通过美国的扩大准入计划用于重症 COVID-19 患者。 [10]南非 (SA) 对使用 CCP 治疗 COVID-19 表现出了兴趣。 CCP 是指从已从 COVID-19 中康复并可能产生 SARS-CoV-2 中和抗体的捐献者收集的血浆。据推测，注入带有病毒特异性抗体的血浆可以立即将被动免疫转移给接受者，并可以通过加速病毒清除和受感染细胞的抗体依赖性细胞介导的细胞毒性来改善临床病程和结果。 [11]使用恢复期血浆（CP）作为被动免疫来治疗病毒感染并不新鲜。 [12]事实证明，早期施用CP可成功降低严重流感[13,14]以及相关流行性冠状病毒严重急性呼吸综合征（SARS）-CoV[15]的死亡率，并已成功用于中东呼吸综合征（MERS）-CoV[16]和埃博拉病毒病[17]。在各种病毒感染中使用CP的研究表明，实验室和临床参数均得到改善，[13,18-22]包括过度炎症细胞因子反应的减少，这似乎是COVID-19发病率和死亡率的关键驱动因素。[23,24]当CP用于治疗SARS-CoV感染时，死亡率的绝对风险降低范围在7%至23%之间，[25-30]并且CP与较早出院有关。 [15,26,27,30]正是由于这些试验的积极结果，加上目前缺乏成功的治疗方案，才在当前的 SARS-CoV-2 大流行中考虑使用 CCP。使用中国 CCP 的研究显示出潜在的益处，包括提高生存率、[31,32] 降低病毒载量[31-33] 和改善放射学特征。[31,32,34] 这些研究有各种局限性，包括患者数量少、缺乏盲法、随机或安慰剂对照试验，以及患者接受多种不同的治疗。一项涉及 6 名危重患者的研究[33]发现，虽然所有患者在注射 CCP 后 3 天内变为 SARSCoV-2 RNA 阴性，但最终有 5 名患者死亡。因此，在 CCP 被视为有效的治疗选择之前，建议在大型随机对照试验中测试其安全性和有效性，[8,35] 并且美国、英国、加拿大、巴西和意大利以及其他几个欧洲国家正在进行试验。早期安全性[36]和治疗[37]结果似乎令人鼓舞，不通气的患者比需要通气的患者受益更多。 CP 的历史使用表明，用作预防或早期治疗时最有效，并且需要为 CCP 建立这些发现。大流行期间 CP 的收集面临着独特的挑战。其中包括生物学方面的，例如确保捐献者在临床和病毒上不感染 SARS-CoV-2，并且具有足够的抗体滴度以达到治疗效果；后勤，例如旅行/行动禁令；法律，例如捐赠者的同意和资格，以及临床试验中 CP 管理的监管要求；科学方面，例如用于抗体滴度测试的经验证测定的商业可用性有限。国家血液服务机构在应对和管理这些挑战方面具有独特的优势，因为它们可能已经拥有适当的基础设施和网络来支持 CP 等血液制品的快速采集、检测和存储。虽然研究表明 CP 是安全的，但需要考虑接受任何血液制品的理论上的风险，包括输血传播感染和输血相关急性肺损伤 (TRALI)，特别是在呼吸道病毒的情况下。需要通过确保 CCP 献血者遵守为定期献血制定的所有标准资格和测试标准来减轻这些风险；排除已产女性捐献者以减少 TRALI 的发生率；并利用减少病原体来针对输血传播感染。此外，理论上存在其他非抗 SARSCoV-2 中和抗体可能导致抗体依赖性感染增强的风险。在国际上，康复患者捐赠CCP的意愿保证了CCP的可持续供应。由于南澳州尚无经过证实的针对 COVID-19 的有效疗法，并且在为危重病患者提供护理的资源有限的情况下，评估南澳州人群中潜在的治疗干预措施是研究的重点。需要一种有效的疫苗来维持人群的免疫力，但开发、生产和扩大规模可能还需要几个月的时间。因此，考虑 CCP 很有吸引力，它可以提供立即的被动免疫力，并且其生产可以在几周内迅速扩大规模，以便在全国范围内广泛使用。然而，我们需要提醒的是，鉴于目前数据匮乏以及潜在的风险和复杂性，在推荐使用 CCP 之前，需要进行随机对照试验来确定对 COVID-19 疾病的治疗效果和安全使用。
562 July 2020, Vol. 110, No. 7 COVID-19: Convalescent plasma as a potential therapy To the Editor: SARS-CoV-2, the cause of COVID-19, has posed a significant threat to global health. No specific treatment or effective prophylaxis has been established, and care of severely ill patients is largely supportive, with poor outcomes in those requiring ICU admission. Experimental therapies include antiviral agents such as remdesivir,[1] lopinavir/ritonavir[2] and favipiravir,[3] hydroxychloroquine/chloroquine,[4] interleukin-6 inhibitors such as tocilizumab,[5] siltuximab[6] and sarilumab,[7] and COVID-19 convalescent plasma (CCP).[8] CCP has been included in the treatment guidelines for severe COVID-19 in China,[9] and the Food and Drug Administration has recently approved its use for critically ill COVID-19 patients in the context of clinical trials and through the expanded access programme in the USA.[10] Interest has been expressed in the use of CCP for COVID-19 treatment in South Africa (SA). CCP refers to plasma collected from donors who have recovered from COVID-19 and are likely to have produced neutralising antibodies to SARS-CoV-2. It is hypothesised that the infusion of plasma with virus-specific antibodies confers immediate transfer of passive immunity to the recipient and may improve the clinical course and outcomes by accelerating viral clearance and antibodydependent cell-mediated cytotoxicity of infected cells.[11] The use of convalescent plasma (CP) as passive immunisation to treat viral infections is not novel.[12] Early administration of CP has proved successful in reducing mortality from severe influenza[13,14] as well as the related epidemic coronavirus severe acute respiratory syndrome (SARS)-CoV,[15] and has been used successfully in Middle East respiratory syndrome (MERS)-CoV[16] and Ebola virus disease.[17] Studies using CP in various viral infections have shown improvement of both laboratory and clinical parameters,[13,18-22] including a reduction in the hyperinflammatory cytokine response, which appears to be a critical driver of morbidity and mortality in COVID-19.[23,24] Where CP was used to treat SARS-CoV infections, the absolute risk reduction in mortality ranged between 7% and 23%,[25-30] and CP was associated with earlier discharge from hospital. [15,26,27,30] It is because of the positive results of these trials, in addition to the lack of successful treatment options available at present, that the use of CCP has been considered in the current SARS-CoV-2 pandemic. Studies of the use of CCP from China have shown potential benefit, including improved survival,[31,32] reductions in viral load[31-33] and improved radiological features.[31,32,34] These studies have various limitiations, including small numbers of patients, lack of blinded, randomised or placebo-controlled trials, and patients receiving a multitude of different therapies. One study involving 6 critically ill patients[33] found that although all the patients became SARSCoV-2 RNA-negative within 3 days of CCP infusion, 5 eventually died. Consequently, before CCP can be considered as an effective treatment option, testing of its safety and efficacy in large randomised controlled trials has been recommended,[8,35] and trials are underway in the USA, the UK, Canada, Brazil and Italy, as well as several other European countries. Early safety[36] and treatment[37] outcomes appear encouraging, with non-ventilated patients benefiting more than those requiring ventilation. Historical use of CP has shown that it is most effective when used as prophylaxis or early in treatment, and these findings need to be established for CCP. There are unique challenges around the collection of CP during a pandemic. These include biological, such as ensuring that donors are clinically and virally free of SARS-CoV-2 and with a sufficient antibody titre to be therapeutically effective; logistical, such as travel/movement bans; legal, such as donor consent and eligibility, and regulatory requirements for administration of CP in a clinical trial; and scientific, such as limited commercial availability of validated assays for antibody titre testing. National blood services are uniquely positioned to address and manage these challenges, as they are likely to already have appropriate infrastructure and networks to support the rapid collection, testing and storage of blood products such as CP. While studies have shown that CP is safe, the theoretical risks of receiving any blood products need to be considered, including transfusion-transmissible infections and transfusion-related acute lung injury (TRALI), specifically in the setting of a respiratory virus. These risks need to be mitigated by ensuring that CCP donors comply with all standard eligibility and testing criteria established for regular blood donations; excluding parous female donors to reduce the incidence of TRALI; and using pathogen reduction to target transfusion-transmissible infections. Furthermore, there is a theoretical risk that other non-anti-SARSCoV-2-neutralising antibodies may cause antibody-dependent enhancement of infection. Internationally, the willingness of recovered patients to donate CCP has ensured a sustainable CCP supply. With no proven effective therapy against COVID-19 available in SA, and in the context of limited resources to provide care to patients with critical illness, it is a research priority to evaluate potential therapeutic interventions in an SA population. An effective vaccine is required for sustained population immunity, but development, manufacture and scale-up are likely to be several months away. It is therefore appealing to consider CCP, which may offer immediate passive immunity, and production of which could be rapidly scaled to be widely available throughout the country in a matter of weeks. However, we would caution that given the current paucity of data and potential risks and complexities, before the use of CCP can be recommended, randomised controlled trials are needed to establish therapeutic efficacy and safe use for COVID-19 disease.