Hemorrhage and venous thromboembolism in critically ill patients with COVID-19.

OBJECTIVE: The majority of patients with COVID-19 showed mild symptoms. However, approximately 5% of them were critically ill and require intensive care unit admission for advanced life supports. Patients in the intensive care unit were high risk for venous thromboembolism and hemorrhage due to the immobility and anticoagulants used during advanced life supports. The aim of the study was to report the incidence and treatments of the two complications in such patients. METHOD: Patients with COVID-19 (Group 1) and patients with community-acquired pneumonia (Group 2) that required intensive care unit admission were enrolled in this retrospective study. Their demographics, laboratory results, ultrasound findings and complications such as venous thromboembolism and hemorrhage were collected and compared. RESULTS: Thirty-four patients with COVID-19 and 51 patients with community-acquired pneumonia were included. The mean ages were 66 and 63 years in Groups 1 and 2, respectively. Venous thromboembolism was detected in 6 (18%) patients with COVID-19 and 18 (35%) patients with community-acquired pneumonia (P = 0.09). The major type was distal deep venous thrombosis. Twenty-one bleeding events occurred in 12 (35%) patients with COVID-19 and 5 bleeding events occurred in 5 (10%) patients with community-acquired pneumonia, respectively (P = 0.01). Gastrointestinal system was the most common source of bleeding. With the exception of one death due to intracranial bleeding, blood transfusion with or without surgical/endoscopic treatments was able to manage the bleeding in the remaining patients. Multivariable logistic regression showed increasing odds of hemorrhage with extracorporeal membrane oxygenation (odds ratio: 13.9, 95% confidence interval: 4.0-48.1) and COVID-19 (odds ratio: 4.7, 95% confidence interval: 1.2-17.9). CONCLUSION: Venous thromboembolism and hemorrhage were common in both groups. The predominant type of venous thromboembolism was distal deep venous thrombosis, which presented a low risk of progression. COVID-19 and extracorporeal membrane oxygenation were risk factors for hemorrhage. Blood transfusion with or without surgical/endoscopic treatments was able to manage it in most cases.

GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown activity in treating relapsed or refractory multiple myeloma; however, relapse is still common, and new targets are needed. We aimed to assess the activity and safety profile of G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma. METHODS: POLARIS was a first-in-human, single-centre, single-arm, phase 1 trial of GPRC5D-targeted CAR T cells (OriCAR-017) done at the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. Eligible patients were adults aged 18-75 years with a diagnosis of relapsed or refractory multiple myeloma and an ECOG performance status of 0-2, had GPRC5D expression in bone marrow plasma cells greater than 20% or were positive for GPRC5D by immunohistochemistry, and had received at least three previous lines of treatment including proteasome inhibitors, immunomodulatory drugs, and chemotherapy. Patients were consecutively assigned to receive a single dose of intravenous OriCAR-017 at 1 × 106 CAR T cells per kg, 3 × 106 CAR T cells per kg, or 6 × 106 CAR T cells per kg in the dose-escalation phase. In the expansion phase, patients received the recommended phase 2 dose. Recruitment to the expansion phase terminated early due to the COVID-19 pandemic on May 1, 2022. The primary endpoints were safety, the maximum tolerated dose and the recommended phase 2 dose. Safety and activity analyses included all patients who received OriCAR-017. This trial is registered with ClinicalTrials.gov, NCT05016778. This trial has been completed and is entering long-term follow-up. FINDINGS: Between June 9, 2021, and Feb 28, 2022, we recruited 13 patients for inclusion into the study. One patient was excluded because of GPRC5D negativity and two patients discontinued after apheresis because of rapid progression. Nine patients were assigned to the dose escalation phase (three received 1 × 106 CAR T cells per kg, three received 3 × 106 CAR T cells per kg, and three received 6 × 106 CAR T cells per kg). The maximum tolerated dose was not identified, because no dose-limiting toxic effects were observed. On the basis of safety and preliminary activity, the recommended phase 2 dose was set at 3 × 106 CAR T cells per kg, which was received by one additional patient in the dose expansion phase. Five patients (50%) were female, five (50%) were male, and all were Chinese. Five patients (50%) were previously treated with BCMA-targeted CAR T-cell therapy. Median follow-up was 238 days (IQR 182-307). There were no serious adverse events and no treatment-related deaths. The most common grade 3 or worse adverse events were haematological, including neutropenia (ten [100%] of ten patients), thrombocytopenia (nine [90%]), leukopenia (nine [90%]), and anaemia (seven [70%]). All patients had cytokine release syndrome (nine [90%] grade 1 and one [10%] grade 2). No neurological toxic effects were reported. Ten (100%) of ten patients had an overall response, of whom six (60%) had a stringent complete response and four (40%) had very good partial response. Two patients discontinued due to disease progression (one GPRC5D-positive patient in the middle-dose group and one GPRC5D-negative patient in the low-dose group). INTERPRETATION: The results of this study suggest that GPRC5D is an active target for immunotherapy in multiple myeloma. GPRC5D-targeted CAR T-cell therapy is a promising treatment modality for patients with relapsed or refractory multiple myeloma and deserves further testing. FUNDING: OriCell Therapeutics.

2019冠状病毒病(COVID-19)诊疗浙江经验 Management of COVID-19: the Zhejiang experience

当前2019冠状病毒病（COVID-19）疫情仍处于胶着状态。浙江大学医学院附属第一医院是国家感染性疾病临床医学中心，浙江省COVID-19患者救治中心。疫情一线的专家集智攻关，以国家卫生健康委员会和国家中医药管理局发布的COVID-19诊治指南为依据，以抗病毒、抗休克、抗低氧血症、抗继发感染、维持水电解质和酸碱平衡、维持微生态平衡的“四抗二平衡”救治策略为核心，总结完善诊治方案，聚焦临床实践的一些具体问题，为COVID-19患者临床诊治提供借鉴。推荐以多学科协作诊治个性化治疗提高COVID-19患者救治质量。建议病原学检测、炎症指标监测和肺部影像学动态观察指导临床诊治。痰液的病毒核酸检测阳性率最高，约10%的急性期患者血液中检测到病毒核酸，50%的患者粪便中检测到病毒核酸，粪便中可分离出活病毒，须警惕粪便是否具有传染性；开展细胞因子等炎症指标监测有助于发现是否出现细胞因子风暴，判断是否需要人工肝血液净化治疗。通过以“四抗二平衡”为核心的综合治疗提高治愈率、降低病死率；早期抗病毒治疗能减少重症、危重症发生，前期使用阿比多尔联合洛匹那韦/利托那韦抗病毒显示出一定效果。休克和低氧血症多为细胞因子风暴所致，人工肝血液净化治疗能迅速清除炎症介质，阻断细胞因子风暴，对维持水电解质酸碱平衡也有很好的作用，可以提高危重型患者的疗效。重型病例疾病早期可适量、短程应用糖皮质激素。氧疗过程中，患者氧合指数小于200 mmHg时应及时转入重症医学科治疗；采用保守氧疗策略，不推荐常规进行无创通气；机械通气患者应严格执行集束化呼吸机相关性肺炎预防管理策略；氧合指数大于150 mmHg时，及早减、停镇静剂并撤机拔管。不推荐预防性使用抗菌药物，对于病程长，体温反复升高和血降钙素原水平升高的患者可酌情使用抗菌药物；要关注COVID-19患者继发真菌感染的诊治。COVID-19患者有肠道微生态紊乱，肠道乳酸杆菌、双歧杆菌等有益菌减少，推荐对所有患者进行营养和胃肠道功能评估，以营养支持和补充大剂量肠道微生态调节剂，纠正肠道微生态失衡，减少细菌移位和继发感染。COVID-19患者普遍存在焦虑和恐惧心理，应建立动态心理危机干预和处理。提倡中西医结合辨证施治；优化重型患者护理促进康复。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染后病毒清除规律仍不明了，出院后仍须居家隔离2周，并定期随访。以上经验和建议在本中心实行，取得较好效果，但COVID-19是一种新的疾病，其诊治方案及策略仍有待进一步探索与完善。

Running an Internet Hospital in China: Perspective Based on a Case Study.

Internet hospitals, as a new forum for doctors to conduct diagnosis and treatment activities based on the internet, are emerging in China and have become integral to the development of the medical field in conjunction with increasing reforms and policies in China's medical and health system. Here, we take the Internet Hospital of the First Affiliated Hospital, Zhejiang University (FAHZU Internet Hospital) as an example to discuss the operations and functional positioning of developing internet hospital medical services in relation to physical hospitals. This viewpoint considers the platform operation, management, and network security of FAHZU Internet Hospital, and summarizes the advantages and limitations in the operation to provide a reference for other areas with interest in developing internet hospitals.

Weathering the storm: COVID-19 infection in patients with hematological malignancies.

The coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a matter of months, this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents. In patients with COVID-19, underlying chronic diseases and comorbidities are associated with dismal treatment outcomes. Owing to their immunosuppressive status, patients with hematological malignancies (HMs) are at an increased risk of infection and have a worse prognosis than patients without HMs. Accordingly, intensive attention should be paid to this cohort. In this review, we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs. Furthermore, we briefly describe customized management strategies and interventions for this susceptible cohort. This review is intended to guide clinical practice.

Clinical characterization and risk factors associated with cytokine release syndrome induced by COVID-19 and chimeric antigen receptor T-cell therapy.

An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. This retrospective study evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by severe COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Grade 4 CRS was significantly more common in the COVID-19 group (15/40 (35.7%) vs. 5/41 (12.2%), P = 0.008). The CAR-T group had more dramatic increase in cytokines, including IL-2, IL-6, IL-10, and IFN-γ. Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml (16.1-70.0) vs. 3.3 (1.8-9.6), P < 0.001) and lg viral loads were correlated with lg IL-6 (R2 = 0.101; P < 0.001) and lg IL-10 (R2 = 0.105; P < 0.001). The independent risk factor for COVID-19-related sCRS was hypertension history (OR: 4.876, 95% CI: 2.038-11.668; P < 0.001). Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of severe COVID-19-related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.

CAR T-cell treatment during the COVID-19 pandemic: Management strategies and challenges.

The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly across the world. Currently, the COVID-19 pandemic is affecting the continuity of essential routine healthcare services and procedures, including chimeric antigen receptor T-cell (CAR-T) therapy, a life-saving option for patients with relapsed/refractory (R/R) hematologic malignancies. Due to the rapid disease progression of hematological malignancies, there is an urgent need to manufacture and utilize CAR T-cells. However, CAR-T treatment has become extraordinarily challenging during this COVID-19 pandemic. Thus, many medical and technical factors must now be taken into consideration before, during, and after CAR-T therapy. The purpose of this review is to provide brief suggestions for rational decision-making strategies in evaluating and selecting CAR T-cell treatment and appropriate CAR T-cell products, and protective strategies for medical staff and patients to prevent infection in the midst of the current COVID-19 pandemic.

Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.

OBJECTIVE: To evaluate viral loads at different stages of disease progression in patients infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first four months of the epidemic in Zhejiang province, China. DESIGN: Retrospective cohort study. SETTING: A designated hospital for patients with covid-19 in Zhejiang province, China. PARTICIPANTS: 96 consecutively admitted patients with laboratory confirmed SARS-CoV-2 infection: 22 with mild disease and 74 with severe disease. Data were collected from 19 January 2020 to 20 March 2020. MAIN OUTCOME MEASURES: Ribonucleic acid (RNA) viral load measured in respiratory, stool, serum, and urine samples. Cycle threshold values, a measure of nucleic acid concentration, were plotted onto the standard curve constructed on the basis of the standard product. Epidemiological, clinical, and laboratory characteristics and treatment and outcomes data were obtained through data collection forms from electronic medical records, and the relation between clinical data and disease severity was analysed. RESULTS: 3497 respiratory, stool, serum, and urine samples were collected from patients after admission and evaluated for SARS-CoV-2 RNA viral load. Infection was confirmed in all patients by testing sputum and saliva samples. RNA was detected in the stool of 55 (59%) patients and in the serum of 39 (41%) patients. The urine sample from one patient was positive for SARS-CoV-2. The median duration of virus in stool (22 days, interquartile range 17-31 days) was significantly longer than in respiratory (18 days, 13-29 days; P=0.02) and serum samples (16 days, 11-21 days; P<0.001). The median duration of virus in the respiratory samples of patients with severe disease (21 days, 14-30 days) was significantly longer than in patients with mild disease (14 days, 10-21 days; P=0.04). In the mild group, the viral loads peaked in respiratory samples in the second week from disease onset, whereas viral load continued to be high during the third week in the severe group. Virus duration was longer in patients older than 60 years and in male patients. CONCLUSION: The duration of SARS-CoV-2 is significantly longer in stool samples than in respiratory and serum samples, highlighting the need to strengthen the management of stool samples in the prevention and control of the epidemic, and the virus persists longer with higher load and peaks later in the respiratory tissue of patients with severe disease.