Use of Convalescent Plasma Therapy in Severe Coronavirus Disease 2019: The Yale-New Haven Health System Experience
Use of Convalescent Plasma Therapy in Severe Coronavirus Disease 2019: The Yale-New Haven Health System Experience
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DOI：
10.1182/blood-2020-137352
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发表时间：
2021-08-03
期刊：
影响因子：
20.3
通讯作者：
Desruisseaux MS
中科院分区：
文献类型：
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作者：
Browning SL;Gormally M;Briggs N;Li M;Zakko A;Laurent-Rolle M;Ladines-Lim J;Morrison A;Kandel P;Khan M;McLeod GX;Buller GK;Owusu KA;Treggiari MM;Hendrickson JE;Tormey CA;Desruisseaux MS
背景资料：2019冠状病毒病（COVID-19）是一种由严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）感染引起的多系统疾病，已影响美国500万人，导致超过16万人死亡。目前，除了支持性治疗外，还没有被证明有效的治疗SARS-CoV-2感染的方法。从SARS-CoV-2感染康复者身上收集的恢复期血浆（CP）已被安全地用于将病毒中和抗体转移给因COVID-19住院的患者。在此，我们报告了在我们的卫生系统中接受CP治疗COVID-19的患者的临床病程和结局。研究方法：耶鲁-纽黑文卫生系统5家医院的≥ 18岁确诊SARS-CoV-2感染和重度或危及生命疾病的住院患者（图1）入组美国COVID-19扩大使用计划（EAP），并输注1单位CP。在CP输注后7、14和28天评估患者结局。此外，我们试图确定该患者队列的死亡率预测因素。结果：105例入组EAP的患者在2020年4月12日至2020年6月14日期间输注了CP。中位年龄为62岁（28-88岁）。62.9%的患者为男性。非白人种族的个体占我们队列的56.2%，33.3%被确定为西班牙裔或拉丁裔。47.6%的患者体重指数大于30，13.3%被归类为极度肥胖。糖尿病、高血压和高脂血症在我们的人群中高度流行。COVID-19的伴随治疗包括羟氯喹（79.0%）、托珠单抗（79.0%）和瑞德西韦（23.8%）（表1）。91例患者在住院期间需要重症监护室（ICU），其中87例患者在CP输注时在ICU。CP输血后第7天，42.9%的患者的世界卫生组织（WHO）有序量表评分改善（中位改善时间为4天），而9.5%的患者的WHO评分增加，表明CP后7天内氧合恶化（图2）。CP输血后7天、14天和28天的死亡率分别为10.48%、20.95%和28.57%（图2）。CP时在ICU的患者中，56例（64.4%）在输血后中位8天后降级为非ICU护理，55例（63.2%）最终出院。存活者从CP输血到出院的中位时间为14天（2-103天），而非存活者从CP到死亡的中位时间为10天（1-76天）。与存活者相比，非存活者从入院到CP和从SARS-CoV-2聚合酶链反应（PCR）阳性到CP的平均天数趋势略长（分别为8.6 vs 6.9天，p=0.218和9.7 vs 7.3天，p=0.85）。D-二聚体水平>5毫克/升纤维蛋白原当量单位（mg/L FEU）与CP输血后24小时（OR 2.79，95% CI 1.18-6.72）、48小时（OR 3.64，95% CI 1.44-9.70）和72小时（OR 2.99，95% CI 1.23-7.66）的死亡率增加相关（图3）。12例（11.4%）接受预防性或中等剂量抗凝治疗的患者随后在CP输注后7天内递增至治疗剂量。此外，CP当天铁蛋白水平>3000纳克/毫升（ng/mL）与死亡率增加相关（OR 5.14，95%CI 1.34-19.68）。结论：CP治疗通过EAP对患有严重疾病和高龄、肥胖频率高和广泛合并症的COVID-19患者进行。在这一预期死亡率较高的COVID-19人群中，42.9%的患者在CP输注后7天内按WHO顺序量表评分改善，52.4%的患者存活并在28天出院。CP后24、48和72小时的基线铁蛋白和d-二聚体水平是死亡率的预测因子，后者增加了与COVID-19相关的血栓形成风险增加可能因给予可能处于残留促凝状态的供体血液制品而加剧的可能性。我们小组正在进行进一步的研究，以评估供体CP的止血平衡，通过比较接受CP的患者与未接受CP的COVID-19患者的匹配对照队列来估计与结局的相关性，并在随机安慰剂对照临床试验中评估CP的疗效。麦克劳德：吉利德制药公司：其他：医学顾问。在本摘要中，我们描述了我们卫生系统中接受研究性恢复期血浆治疗的患者，这些患者通过入组“扩大恢复期血浆治疗COVID-19患者”方案接受治疗，该方案由巴尔达资助，并由持有主要IRB方案的马约诊所运行。FDA此前发布的关于COVID-19恢复期血浆研究使用的指南包括对扩大获取计划的建议，作为促进全国范围内获取这种血液制品的方法。到目前为止，从扩大使用项目中报告的安全性数据表明没有相关结果，严重不良事件的发生率非常低。因此，鉴于恢复期血浆的总体耐受性以及缺乏其他经证实的COVID-19疗法，我们认为即使在目前尚未批准恢复期血浆输注用于COVID-19管理的情况下，报告这些发现也很重要。
Background: Coronavirus disease 2019 (COVID-19), a multi-system disorder resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 5.0 million individuals in the United States (US) resulting in more than 160,000 deaths. There is currently no proven effective therapy for SARS-CoV-2 infection beyond supportive care. Convalescent plasma (CP), collected from individuals who have recovered from SARS-CoV-2 infection, has been safely used to transfer virus-neutralizing antibodies to patients hospitalized with COVID-19. Herein we report on the clinical course and outcomes of patients who received CP for the treatment of COVID-19 across our health system. Methods: Hospitalized patients ≥ 18 years of age at 5 hospitals in the Yale-New Haven Health System with confirmed SARS-CoV-2 infection and severe or life-threatening disease (Figure 1) were enrolled in the US COVID-19 Expanded Access Program (EAP) and transfused 1 unit of CP. Patient outcomes were assessed at 7, 14, and 28 days after CP transfusion. Furthermore, we sought to determine mortality predictors in this patient cohort. Results: 105 patients enrolled in the EAP were transfused CP from 4/12/2020 to 6/14/2020. Median age was 62 years (28-88 years). 62.9% of patients were male. Individuals of a non-white race comprised 56.2% of our cohort and 33.3% identified as Hispanic or Latinx. 47.6% of patients had a body mass index greater than 30, with 13.3% classified as extremely obese. Diabetes mellitus, hypertension, and hyperlipidemia were highly prevalent in our population. Concomitant therapy for COVID-19 included hydroxychloroquine (79.0%), tocilizumab (79.0%), and remdesivir (23.8%) (Table 1). 91 patients required the intensive care unit (ICU) during their hospital course, with 87 patients in the ICU at the time of CP transfusion. 42.9% of patients had an improvement in their World Health Organization (WHO) Ordinal Scale score by day 7 post-CP transfusion (median 4 days to improvement), while 9.5% demonstrated an increase in their WHO score indicating worsening oxygenation during the 7 days following CP (Figure 2). Mortality was 10.48% at 7 days, 20.95% at 14 days, and 28.57% at 28 days post-CP transfusion (Figure 2). Of the patients in the ICU at the time of CP, 56 (64.4%) de-escalated to non-ICU care after a median of 8 days from transfusion and 55 (63.2%) were ultimately discharged from the hospital. The median time from CP transfusion to discharge in survivors was 14 days (2-103 days), while median time from CP to death in non-survivors was 10 days (1-76 days). The mean time in days both from hospital admission to CP and from positive SARS-CoV-2 polymerase chain reaction (PCR) to CP trended slightly longer in non-survivors when compared to survivors (8.6 vs 6.9 days, p=0.218 and 9.7 vs 7.3 days, p=0.85, respectively). D-dimer levels >5 milligrams per liter fibrinogen equivalent units (mg/L FEU) were associated with increased mortality at 24 (OR 2.79, 95% CI 1.18-6.72), 48 (OR 3.64, 95% CI 1.44-9.70), and 72 hours (OR 2.99, 95% CI 1.23-7.66) post-CP transfusion (Figure 3). Twelve patients (11.4%) on prophylactic or intermediate dose anticoagulation were subsequently escalated to therapeutic dosing during the 7 days after CP transfusion. Furthermore, a ferritin level of >3000 nanograms per milliliter (ng/mL) on the day of CP was associated with increased mortality (OR 5.14, 95% CI 1.34-19.68). Conclusions: CP therapy was administered through the EAP to COVID-19 patients with severe disease and with advanced age, high frequency of obesity, and extensive co-morbidity. In this COVID-19 population with high expected mortality, 42.9% of patients improved by WHO Ordinal Scale score within 7 days of CP transfusion and 52.4% were alive and discharged at 28 days. Baseline ferritin and d-dimer levels at 24, 48, and 72 hours post-CP were predictors of mortality, the latter raising the possibility that the increased thrombotic risk associated with COVID-19 may be exacerbated by administration of blood products from donors potentially in a residual procoagulant state. Further studies by our group are underway to assess hemostatic balance in donor CP, to estimate associations with outcomes by comparing patients who received CP with a matched control cohort of COVID-19 patients who did not receive CP, and to evaluate efficacy of CP in a randomized, placebo-controlled clinical trial. McLeod:Gilead Pharmaceuticals: Other: Medical Advisor . We have described in this abstract patients across our health system who received investigational convalescent plasma therapy through enrollment in the “Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19” protocol that is funded by BARDA and run by the Mayo Clinic, where primary IRB protocol is held. Previous guidance issued by the FDA regarding investigational use of COVID-19 convalescent plasma included recommendations for the expanded access program as a method by which to facilitate access to this blood product across the nation. Safety data reported thus far from the expanded access program has demonstrated no concerning findings, with a very low rate of serious adverse events. Therefore given the overall tolerability of convalescent plasma and the lack of other proven therapies for COVID-19, we believe it is important to report these findings even in the absence of current approval for convalescent plasma transfusion in the management of COVID-19.