Human recombinant soluble ACE2 in severe COVID-19.
Human recombinant soluble ACE2 in severe COVID-19.
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DOI：
10.1016/s2213-2600(20)30418-5
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发表时间：
2020-11
期刊：
影响因子：
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通讯作者：
Penninger JM
中科院分区：
文献类型：
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作者：
Zoufaly A;Poglitsch M;Aberle JH;Hoepler W;Seitz T;Traugott M;Grieb A;Pawelka E;Laferl H;Wenisch C;Neuhold S;Haider D;Stiasny K;Bergthaler A;Puchhammer-Stoeckl E;Mirazimi A;Montserrat N;Zhang H;Slutsky AS;Penninger JM
血管紧张素转换酶2（ACE 2）是严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的重要受体，并作为肾素-血管紧张素系统的调节剂保护包括肺在内的多种组织免受损伤。1因此，ACE 2已成为COVID-19研究和大量药物开发工作的重点。正在开发的新型化合物包括人重组可溶性ACE 2（hrsACE 2 [APN 01; Apeiron Biologics，维也纳，奥地利]），它具有两种作用机制，理论上应该对COVID-19有益。2第一个涉及结合病毒刺突蛋白，从而中和SARS-CoV-2，3，第二个是最大限度地减少对多个器官的损伤，包括肺，肾脏和心脏，因为未减弱的肾素-血管紧张素系统过度活化和血管紧张素II浓度增加。4-6 hrsACE 2已在89例患者中进行了测试，即在1期研究中的健康志愿者和在2期临床研究中的急性呼吸窘迫综合征（ARDS）患者中进行了测试，具有可接受的安全性特征。7，8此外，hrsACE 2可以在体外细胞培养实验和工程类器官中将SARS-CoV-2负载降低1000-5000倍，直接证明ACE 2可以有效中和SARS-CoV-2。3我们在本病例报告中描述了一名严重COVID-19患者的第一个疗程的hrsACE 2治疗。一名45岁女性因咳嗽、虚弱、肌痛、发热和呼吸困难7天以及恶心和腹泻4天而入院。既往病史显示2型糖尿病，通过运动和饮食控制未复发，以及已行甲状腺切除术的格雷夫斯病;患者甲状腺激素治疗后甲状腺功能正常。她有一个正常的体重指数，并报告良好的运动耐力之前，她目前的疾病。入院时，患者发热（38.1 ℃），轻度低氧血症（PaO 2 56 mm Hg，室内空气），开始鼻插管吸氧。胸部X线检查显示双侧斑片状实变，提示病毒性肺炎（附录第6页）。通过鼻咽拭子的RT-PCR诊断为SARS-CoV-2感染，并开始羟氯喹（400 mg，每日两次）治疗和那屈肝素抗凝治疗（0.4 mg，每日一次）。第二天，患者的胸部X线片显示双侧、多灶性和外周毛玻璃样影增加（附录第6页）。她的吸入空气中的氧浓度分数（FiO 2）为153 mm Hg，她在使用高流量鼻插管时显示出衰竭迹象，FiO 2为70%。因此，我们对她进行了插管，并采用了肺保护性治疗策略。初步实验室检查显示轻度白细胞减少和血小板减少伴严重淋巴细胞减少（0·54g/L）;血清乳酸脱氢酶（636 U/L）、铁蛋白（880 µg/L），C反应蛋白（103 mg/L）和D-二聚体（1· 3 mg/L）浓度均明显升高症状发作后9天（基线，入院后第2天），开始用hrsACE 2（APN 01; 0.4 mg/kg）静脉输注治疗，每天两次，每次5 min。在主治医生、患者家属和外部传染病和ARDS专家协商后，开始指定患者使用。首次hrsACE 2给药后，患者在数小时内无发热。第二天，她的体温升高，呼吸道分泌物呈脓性，这表明她患有细菌性肺炎，并接受了头孢呋辛治疗。气管抽吸物中有甲氧西林敏感金黄色葡萄球菌（MSSA）。肾素-血管紧张素系统
Angiotensin converting enzyme 2 (ACE2) is the crucial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor and protects multiple tissues, including the lung, from injury as a regulator of the renin–angiotensin system. 1 Therefore, ACE2 has become the focus of COVID-19 research and a plethora of drug development efforts. Among the novel compounds under development is human recombinant soluble ACE2 (hrsACE2 [APN01; Apeiron Biologics, Vienna, Austria]), which has two mechanisms of action that theoretically should be of benefit in COVID-19. 2 The first involves binding the viral spike protein and thereby neutralising SARS-CoV-2, 3 and the second is minimising injury to multiple organs, including the lungs, kidneys, and heart, because of unabated renin–angiotensin system hyperactivation and increased angiotensin II concentrations. 4–6 hrsACE2 has been tested in 89 patients, namely in healthy volunteers in phase 1 studies and in patients with acute respiratory distress syndrome (ARDS) in phase 2 clinical studies, with an acceptable safety profile. 7, 8 Moreover, hrsACE2 can reduce SARS-CoV-2 load by a factor of 1000–5000 in in-vitro cell-culture experiments and engineered organ oids, directly demonstrating that ACE2 can effectively neutralise SARS-CoV-2. 3 We describe in this Case Report the first course of treatment with hrsACE2 of a patient with severe COVID-19. A 45-year-old woman was admitted to hospital with a 7-day history of cough, weakness, myalgia, fever, and dyspnoea, and a 4-day history of nausea and diarrhoea. Past medical history revealed type 2 diabetes, controlled non-pharmacologically by exercise and diet, and Grave’s disease for which thyroidectomy had been done; the patient was euthyroid on thyroxin. She had a normal body-mass index and reported good exercise tolerance before her present illness. On admission she was febrile (38· 1 C), mildly hypoxaemic (PaO2 56 mm Hg on room air), and was started on oxygen by nasal cannula. A chest x-ray showed bilateral patchy consolidations indicative of viral pneumonia (appendix p 6). Diagnosis of SARS-CoV-2 infection was made by RT-PCR from a nasopharyngeal swab, and treatment with hydroxychloroquine (400 mg twice daily) and anticoagulation with nadroparin (0· 4 mg once daily) were started. The following day, the patient’s chest x-ray showed increasing bilateral, multifocal, and peripheral ground glass patterns (appendix p 6). Her fractional concentration of oxygen in inspired air (FiO2) was 153 mm Hg, and she showed signs of exhaustion while on high flow nasal cannula, with a FiO2 of 70%. We therefore intubated her and used a lung protective ventilatory strategy. Initial laboratory tests showed mild leukopenia and thrombocytopenia with a profound lymphopenia (0· 54 g/L); serum lactate dehydrogenase (636 U/L), ferritin (880 µg/L), C-reactive protein (103 mg/L), and D-dimer (1· 3 mg/L) concen trations were all markedly elevated (appendix p 4).9 days after symptom onset (baseline, day 2 after hospital admission), treatment with hrsACE2 (APN01; 0· 4 mg/kg) intravenous infusion for 5 min twice daily was started. This named patient use was initiated after consultations among attending physicians, the patient’s family, and external infectious disease and ARDS experts. After administration of the first hrsACE2 dose, the patient became afebrile within hours. Her temperature increased the following day with purulent respiratory secretions, suggesting a bacterial pneumonia, which was treated with cefuroxime. A tracheal aspirate sub sequently grew methicillin-sensitive Staphylococcus aureus (MSSA). Renin–angiotensin system …