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Shanghai Experience of COVID-19 Management





Speaker：Dr. Hu Bijie

Member of the Shanghai Combined Task Force on COVID-19

Chief, Department of Infectious Disease Department of Infection Control

Zhongshan Hospital Affiliated to Shanghai Fudan University

讲者：上海医疗救治专家组成员、复旦大学附属中山医院感染病科主任胡必杰教授





Editor's Notes: Under the stress of this COVID-19 pandemic, physicians around the world are struggling on finding the plan for prevention and treatment of COVID-19. In Shanghai, all the diagnosed COVID-19 cases go to Shanghai Public Health Clinical Center. Since Jan 2020, the expert physicians in Shanghai have taken care of 371 cases and most of these patients recovered. The Shanghai Experts have accumulated tremendous experiences and knowledge. We would like to share one lecture with all the physicians around the world. Together we can beat the virus.



The speaker Professor Hu Bijie is a member of the Shanghai Combined Task Force on COVID-19. He is also the chief of Department of Infectious Disease and chief of Department of Infection Control of Zhongshan hospital affiliated to Shanghai Fudan University.

COVID-19 has caused many death and critical cases all over the world. “Shanghai Plan” has focused on risk assessment, prognosis prediction, and combination therapy for early intervention to prevent the development of severe cases. According to Professor Hu among all the medications used, hydroxychloroquine was found to effectively and safely prevent the progression of disease and minimize the numbers of severe and critical patients. The fact is new severe and critical COVID-19 cases in Shanghai have decreased significantly since February 5th, suggesting Hydroxychloroquine might be one of the correct medications to reverse this pandemic.

Considering the strategic value of prevention and intervention of severe COVID-19 cases, we believe that the initial observational data from Shanghai might provide reference for physicians around the world although the effectiveness and safety of the Hydroxychloroquine in the “Shanghai Plan” needs to be further evaluated through randomized control studies.

COVID-19 is one of the most challenging pandemic diseases in the history of modern medicine. We are seeing a little ray of hope now and with the joint efforts from all over the world, it is believed that this pandemic will soon hit a turning point.

Dr. Kathy Shi, MD, Ph.D, CEO, SinoUnited Health







On March 19, US President Donald trump urged the FDA to speed up the approval of the COVID-19 medication. Hydroxychloroquine may soon be used to treat COVID-19.

The Shanghai epidemic prevention and control press conference said: hydroxychloroquine ranked as the first drug in "Shanghai Plan" therapeutic drugs, Shanghai’s experience in diagnosing and treating COVID-19 is worth sharing. Up until March 15, the clinical study of hydroxychloroquine in treating COVID-19 has enrolled a total of 184 cases, involving 21 hospitals. The preliminary results showed that the hydroxychloroquine treatment was effective and safer. Just yesterday, trump announced that hydroxychloroquine and Remdesivir have been approved by the FDA for special use. Hydroxychloroquine might be the “special medication”, the hope for the public, to reverse the pandemic trend of COVID-19 for real. The scale of the COVID-19 being so large and the impact being so deep, we haven’t seen something like this for hundreds years. This outbreak has made us realize that the world is closely connected; no country can be alone; and no one can live without another. Only by working together can we beat the virus.



Following is summary of Pro. Bijie Hu's report on COVID-19. The discussions is based on Chinese National Health Commission Diagnosis and Treatment Protocol (Trial Version 7) and on the consensus of the Shanghai Combined Task Force on COVID-19.

Content: Early detection and prevention of deterioration of COVID-19 Pneumonia

Antiviral treatment and applications

Corticosteroid and antibiotic applications

Maintenance and support of the immune system

Management of Severe Pneumonia and Critical Pneumonia

Diagnostic criteria for COVID-19 Pneumonia

Discharge criteria and RT-PCR re-test positivity

Here in Shanghai, we take the treatment measures of concentrate patients, concentrate experts and concentrate resources to treat COVID-19. We collect all adult cases and collectively put them in Shanghai Public Health Clinical Center for treatment. A total of 300 plus cases were treated.

These cases belong to "Severe Pneumonia" category, they need close clinical monitoring. In recent period, the ratio of severe pneumonia among COVID-19 diagnosed cases has almost diminished to zero. The reason for this result was due to our cumulative experiences in the effective treatment modalities and the application to clinical use. On daily basis, we go through each case as we treat and review their possible clinical & laboratory indicators that would indicate impending deterioration. We have to double our efforts to prevent the occurrence of severe clinical situations. If we could successfully prevent the occurrence of severe cases, we could conserve our medical resources significantly.





We have been able to sort out the early alarm indicators for severe COVID-19 pneumonia.

Clinical Indicators for deterioration of COVID-19 Pneumonia

Advanced age( age> 65y/o)

Complicated with other systemic diseases: diabetes mellitus, coronary heart disease, hypertension, obesity

Progressive worsening of lung parenchymal pathology > 50% for 2-3 days

CD4+ T lymphocytes number < 250/uL

Significant increase in serum IL-6 level

Lactate Dehydrogenase (LDH) level > 2x normal range upper limit

Serum Lactic Acid >/= 3 mmol/L, with metabolic alkalosis





Major systematic diseases/old age -- a very important indicator/rapid progression of clinical symptoms and signs are the major factors.In addition, Shanghai team was the earliest group that took notice that CD4+ T cells subgroups are also very important severe disease early indicators.





CD4+ cut off value is probably at 250/μL, it is less likely to see severe cases with CD4>400/μL, CT scan of the chest with CD4>2000/μL cases almost showed no pathological findings. Here is a patient with progressive dropping of CD4+ level, reflecting its's clinical severity.





CD4+ and COVID-19 infections have close relationship. We are not sure the exact cause-effect of the two. There is a possibility that the virus specifically attack CD4+, caused CD4 level to drop significantly, therefore severely destroyed the immune system. There is also a relationship with the CD4+ cell count and the timing of viral shedding. The lower the CD4 count, the longer the viral shedding period.





Combined Approaches toward Prevention of Disease Progression(Mild cases and Common cases):

Antiviral drugs

Oxygen Therapy and supplementation/ Oxygen saturation monitoring

Maintenance of Immune system: Medications, Sleep, Mood management

Enhance supportive care, guarantee adequate caloric intake

Focusing on water & electrolyte balance, maintenance homeostasis.

Avoidance of antibiotics and glucocorticoids.

Anticoagulants and large dose of Vitamin C





First of all, we are focusing on antiviral drugs, Oxygen Therapy and supplementation/Oxygen saturation monitoring, Maintenance of Immune system: Some patients have high anxieties, we have also been focusing in the easing of their stress & terror and try to maintain and provide a good sleep quality routine.





We are also concerned about maintenance of patients’ energy level, keeping a stable environment. We have also noticed that large quantity of Vitamin C (10-20 gram daily) use seemed beneficial.





In regard to the use of antiviral drugs, anti-HIV medication Lopinavir/Ritonavir, and a broad spectrum anti-viral drug, Abitor, the overall result compared to placebo group showed no significant difference. We, clinical physicians, felt that Arbitor has a slightly better response than Lopinavir/Ritonavir. One reason is that Lopinavir/Ritonavir has caused toxic side effects onto some patients, with severe GI reactions and further reduce patients’ immune responses.





We, the Shanghai COVID-19 special medical task force members have a stronger and stronger believe that Hydroxychloroquine could be a good choice. After patients’ use of Hydroxychloroquine, The number of our patient’s clinical progression from “mild” class to “severe” class and from “severe” to “critical” class have been significantly reduced. Furthermore, the side effects of Hydroxychloroquine has not been as severe as we had imagined.









Some experts suggest that among the family of chloroquines, the toxic side effect of Hydroxychloroquine is quite low. We have been using the maximum dose as per manufacturer’s insert, 400mg QD. We have also consulted with rheumatology experts, they agree that Hydroxychloroquine is comparatively safe to use in a normal situations.





Therefore, the recommended medications in our Shanghai COVID-19 medical treatment guidelines was quite simple. Besides Hydroxychloroquine, there are also National treatment guidelines’ recommended Chloroquine Phosphate, Arbitor and Interfron. Some people have questioned us as to why we do not recommend more drugs to use. The reason is that we truly felt Hydroxychloroquine is the specific drug of choice for COVID-19.





We have compared Phase I epidemic period and Phase II epidemic period patient outcomes. In Phase I period, there were high ratio of severe cases and critical cases. In Phase II period (admission after Feb 5th), There is a significant drop in the number of severe cases and critical cases, we have attributed this outcome to our extensive use of Hydroxychloroquine. We have basically reached our conclusion on this finding.





The usage of glucocorticoid and antibiotic drugs have been tightly restricted for COVID-19 patients in Shanghai. Experts have different opinions about the usage of glucocorticoid. But one uniform consensus had been reached that if it is to be used, only small dosage and short-term application should be applied.





Data showed that a group of patients who had use glucocorticoid, their viral shedding time were prolonged. We have also observed that thee group of patients who had used glucocorticoid, their nasopharyngeal swab viral shedding time compared to non-users were 15 days vs 8 days. Stool nucleic acid shedding time were also prolonged. Steroid-user vs non-users were 20 days vs 11 days. Therefore, we should refrain from the urge to use steroid.





With Hydroxychloroquine treatment, the use of antibiotics were significantly reduced. According to statistics, our “mild” case patients needed much less antibiotic drugs with our knowledge of the disease nature. We have boldly discontinued all the use of antibiotics. The result has been satisfactory.





For maintenance and support of patient’s immune system functions, we propose the use of Thymosin in some cases, it has shown beneficial results, especially in patients with low CD4+ and younger age group in early stage use shown more obvious beneficial effects.





On the other hand, we had used gamma-Globulin in Phase I period, but in Phase II period, we have stopped it’s usage. In theory and combined with our present experiences, gamma-Globulin effect is limited.





In the management of severe and critical pneumonia cases, we have 5 teams consist of 5 ICU experts. We have been using advanced technology and now treatment modalities. (I will skip this topic here.) For those patients who continue to shed virus, we used plasma extracted from convalescent patients and transfused to these patients. We are having some hope for this therapeutic approach.









Indeed, some patients presented with negative RT-PCR test results at convalescent stage, but later, turned positive again in 3 days. For this, we have to be cautious and we have to accumulate more experiences before putting it into routine use.





For the diagnostic Criteria for COVID-19 pneumonia, which is more important? Laboratory findings or Clinical findings?





Actually, we found that the clinical presentations of respiratory symptoms and fever are not that significant. These symptoms are not specific enough for us to detect it early in its highly infectious phase. On the other hand, Chest CT scan has more specificity for COVID -19. RT-PCR testing does present with false negative results. For Chest CT scan, we need to learn more and we must avoid accidentally omitting cases with typical findings.





Cases that are definitely not COVID-19, we must have the confidence to exclude them. As for serum findings, In Shanghai, this is now added as a supplementary tool to the diagnosis of this viral disease. At current stage, it is a worthwhile direction for further development., But the stability and reliability of the test kits --false-positive , false-negative--issues are not solved yet. In addition, the serum tests can only give qualitative , not quantitative results. We still need to work more and accumulate more experiences on these technical issues before its widespread use.





In our clinical practices, in epidemiological studies, with the findings of respiratory symptoms and signs, with the findings of disease toxicity, with chest imaging findings, with RT-PCR findings, with specific antibody testing and monitoring, how do we make the final diagnosis for COVID-19 ? Under different circumstances, some we could be sure, but some still needs further considerations.





National Guidelines for Discharge from Hospitals:

Normal body temperature for 3 consecutive days Significant improvement with respiratory symptoms Chest imaging studies showed significant improvement compared with acute stage findings. Two consecutive negative results from respiratory tract secretion swabs ( sampling must be 24 hours apart) Shanghai: After two consecutive negative respiratory secretion swabs, stool sample must also show negative viral nucleic acid test result. Shanghai: entire illness course > 2 weeks.





As noted, our Shanghai COVID-19 Hospital Discharge Criteria has two additional requirements compared to National COVID-19 Hospital Discharge Criteria.





The reasons for these additional requirements are based on the following: After two consecutive respiratory tract secretion swab tested negative, we are also looking for stool specimen testing negative. Shanghai team experts have postulated that if after 4 weeks of positive stool results, the possibility of COVID-19 contagiousness through feces to others are low. Obviously, we still need further data to support this. We do allow patients to be discharged, but we give instructions as to how to handle their excretions after returning back to the community.





Illness duration exceed 2 weeks before discharge—we postulate that most of viral infections are still contagious within 2 weeks, after 2 weeks, some viruses are self- limited and self- resolving, even without any medication. In Shanghai, Discharge orders are given with more strict requirements. Besides the two above listed criteria, we also require Task Force expert physicians to review patients’ chest imaging films and confirm the resolution of the lung parenchymal pathologies prior to discharge.





After two consecutive negative respiratory secretion swabs, stool sample must also show negative viral nucleic acid test result. We have also accumulated the following experience: The viral shedding duration for respiratory tract secretion swab test is indeed different from the stool specimen. Viral shedding duration is much longer in stool compared to respiratory tract pathway.













《新冠病毒肺炎上海诊治实践的热点话题》讲座视频

讲者：上海医疗救治专家组成员、复旦大学附属中山医院感染病科主任和感染管理科科长 胡必杰教授





编者按 COVID-19大流行，全球医生致力于寻找高效安全的防治方法，目前还没有找到早期干预重症化病程的特效药。这段演讲中胡必杰教授对“上海方案”的介绍，给我们以极大信心。

讲者胡必杰教授系上海市新型冠状病毒肺炎临床救治专家组成员，同时担任复旦大学附属中山医院感染病科主任和感染管理科科长。他与上海相关学科最优秀的专家们合作，汇聚于上海公共卫生临床中心，进行上海COVID-19患者的集中诊疗。

COVID-19病毒传染性强，重症和危重症病例多，治疗成本高，疗效欠佳，易引发医疗资源挤兑。针对这些特点，“上海方案”提出对确诊患者进行风险评估，制定早期干预方案，预防病情由轻症转重症，由重症转危重症，初效令人瞩目。

在第一阶段，上海团队完成了对本病诊疗规律的初步摸索，在2月5号以后的诊疗中，结合国家版指南，上海制定了操作程序，对患者重症化高危风险因素进行系统性评估，选择羟氯喹对轻型和普通型患者进行积极干预，对象包括存在糖尿病等合并疾病、老年人或各项指标显示存在重症化倾向人群，同时严密随访药物副反应。结果显示：自2月5号以后，上海新发病例中重症及危重症显著减少，提示羟氯喹很可能在真正意义上保护COVID-19轻型和普通型患者。

此外，胡必杰教授还详细解释了上海团队评估风险因素的方法，使用其它抗病毒药物的心得，对糖皮质激素和抗菌药物的经验，并提供了粪便和咽拭子核酸检测的一些重要解读。

“上海方案”中羟氯喹所见疗效和相对安全性，需要进一步的随机对照研究去验证。法国科学家Didier Raoulta的团队在今天被同行评审的科学杂志International Journal of Antimicrobial Agents接受发表的一篇临床研究论文中显示硫酸羟基氯喹对于治疗COVID-2019病人有显著疗效。在这项36名患者的研究中，第6天患者鼻咽拭子病毒转阴率：接受羟氯喹和阿奇霉素联合治疗的为100％；而仅接受羟氯喹单药治疗的患者为57.1％；对照组为12.5％（p <0.001）。

考虑到预防和干预重症新型冠状病毒肺炎对COVID-19存在战略意义价值，我们认为上海的初期数据可以为全球医生提供富有实战意义的样本，特此推荐给同行参考，稍后我们将分享各国语言版本。

COVID-19是现代医学史上所经历的最困难的疫情。曙光初现，在全球同行的共同努力下，相信很快会迎来全球疫情折点。

曜影医疗CEO：史浩颖医生，医学博士



3月19日美国总统特朗普急宣：敦促FDA加速针对新冠肺炎药物的审批工作，羟氯喹有可能很快应用于治疗新冠肺炎。

上海疫情防控新闻发布会上称：羟氯喹位列“上海方案”治疗性药物首位，上海对于新冠病毒肺炎的诊治经验值得分享。截至到3月15日，羟氯喹治疗新冠肺炎的临床研究，累计入组184例，参与医院21家，初步结果显示羟氯喹治疗有效且更安全。就在昨天，川普宣布药物羟氯喹和瑞德西韦（Remdesivir）已经被美国FDA特批可以同情用药。羟氯喹可能成为真正意义上逆转COVID-19疫情趋势的“特效药”，大众的希望。新冠肺炎疫情规模之大，影响之深，百年未遇。这次疫情更让我们意识到这个世界是紧密相连，没有一个国家可以成为孤岛，谁也离不开谁，只有携手才能战胜病毒！



以下为上海医疗救治专家组成员、复旦大学附属中山医院感染病科主任胡必杰教授《新冠病毒肺炎上海诊治实践的热点话题》视频的文字摘录。本讨论基于国家卫健委：《新冠肺炎诊疗方案（试行第七版）》和《上海市2019冠状病毒综合救治专家共识》。

上海自新型冠状病毒肺炎（新冠肺炎）爆发以来，前后共收治300余例患者，采取集中患者、集中专家、集中资源和集中救治的方式，把所有成人确诊案例，集中于上海市公共卫生临床中心进行诊治。



1.早期识别和遏制肺炎重症化

新冠病毒肺炎患者中一部分为重症肺炎，临床需要关注。值得庆幸的是，最近一段时间，上海的重症新冠病毒肺炎比例非常低，这大部分要归功于我们在临床应用中积累的有效的经验措施，我们一直在思考，哪些临床指标可以预测新冠病毒肺炎中的重症病例，如何来阻止重症化的发生，尽管目前还没有大规模的对照研究证实，我们非常愿意和大家分享这些经验，以便于及时救治和预防重症新冠病毒肺炎患者，而预防和治疗重症新冠病毒肺炎的方案有效的话，每减少一例重症，可以节省很多医疗资源，新冠病毒肺炎就没有那么可怕了。









我们摸索了哪些是新冠肺炎重症化的预警指标：基础疾病、老年是非常重要的指标。





此外上海最早摸索出，CD4+T淋巴细胞亚群也是重要的重症化预警指标，CD4+ cut off值可能在250/μL，400/μL以上重症化机会相对少，CD4+>2000/μL的案例（CT片中）几乎看不到任何病灶。但是有患者，CD4+进行性下降，出现了肺炎向重症演变。





CD4+和新冠病毒感染存在相关性，因果关系是什么还不敢说，有可能病毒专门攻击CD4+，所以导致CD4+显著下降，严重摧毁免疫功能。也能看到患者CD4+细胞的计数和排毒时间有关，CD4+数越低，排毒时间越长。





2.抗病毒治疗的应用

如何阻止重症化，我们主张选用有效的抗病毒药物，采用正确的氧疗，还有免疫功能的良好维护。有一部分病人恐慌心理很严重，缓解他们的恐惧心理，解决改善睡眠质量的问题，也有助于提高免疫力。我们也非常关注机体能量的保持，内环境的稳定，这次感觉大剂量维生素C，10g~20g的使用似乎有价值。





关于抗病毒的治疗，治疗艾滋病的药物克力芝（洛匹那韦利托那韦片），以及广谱抗病毒药阿比多尔，整体来看效果和空白对照组差不多。我们的临床体会是阿比多尔似乎有一点作用。但克力芝副反应较为明显，特别是消化道反应，可能影响免疫功能。





我们上海团队感受到，我们能不能说，羟氯喹是新冠肺炎的“特效药”吗？因为我们真的是越来越感受到，用了羟氯喹以后，我们的病人（由轻症转向）重症化，或重症转向危重症的比例明显减少。其次，羟氯喹的副作用较小，（有专家建议）在氯喹系列里，羟氯喹的毒副反应比较低。而且我们用了说明书里的最大剂量，即每天400mg，我们咨询了风湿科专家，他们认为羟氯喹在通常情况下比较安全。所以我们在上海指南里推荐的药物其实不多，除了羟氯喹，还有国家指南里推荐的磷酸氯喹，还有阿比多尔和干扰素。有人问我们为什么没有推荐其它药物。因为我们觉得这个药物真的是特效药。









我们比较了第一阶段和第二阶段的病人差别，其中第一阶段病人重症和危重症比例非常高。第二阶段（2月5号以后入住）的病人， 重症和危重症的比例明显下降了。我们最大的经验积累是用了羟氯喹，这方面的数据总结基本已完成。





3.糖皮质激素和抗菌药物的应用

糖皮质激素和抗菌药物（的使用）在上海受到严格控制。（对是否使用糖皮质激素）专家内部意见不完全一致，但有一点是肯定的，大家都认为：如果要用激素，需要小剂量短疗程使用。另一组数据显示，（使用糖皮质激素的患者）排毒时间明显延长。我们也看到了，咽拭子检测，用激素组和不用激素组相比，排毒时间，一个15天，一个8天，粪便核酸排毒时间也一样，一个是20天，一个是11天。所以我们现在说，经常要克制使用激素的欲望。





抗菌药物的使用机会也是明显减少。据统计，我们的普通型患者尤其抗菌药物第一周使用比例明显减少，得益于我们对这个疾病的正确认识，我们就大着胆子把抗菌药物全部停掉了，但是停了抗菌药物以后效果还是不错的。





4.免疫功能支持和维护

我们主张胸腺肽还是用一些，有一点帮助。尤其是胸腺肽对CD4+比较低的病人，年纪轻的，早期使用，好像感觉效果比较明显一点。另一个，丙种球蛋白，第一阶段我们用得比较多，第二阶段我们基本放弃，丙种球蛋白，从理论机制上，以及我们现在的实际经验看，丙种球蛋白效果不理想。





5.重型和危重型肺炎的处理

重型和危重型肺炎的处理，我们由5个重症医学专家组负责，用了先进的新技术、新方法，这方面我不展开。康复者的血清输注，对一些病毒持续不能消除的病人，我们使用了这个方法，寄予了一些希望，确实有一部分病人病毒转阴了，但是过了三天又复阳了。所以现在对康复期的血清使用，我们觉得还需要积累更多的经验。





（以上图片均来源于网络）







6.新冠肺炎诊断标准

新冠肺炎的诊断标准方面，到底实验室的检查和临床表现哪个更重要？其实咳嗽等呼吸道症状以及毒性症状的发烧，我们认为意义不是很大，新冠肺炎的毒性症状不明显，导致了这个疾病在传染性比较强的时候我们没有及时发现。而胸部CT有相对比较强的特异性。核酸的监测确实存在假阴性的问题。但是反过来说，胸部CT我们需要学习，尽量避免典型或者比较典型的病人被漏诊，也有一些肯定不是的，你要有足够自信排除它。血清学的问题，上海市对这个新加进去的血清学作为病原学的诊断标准，（认为它是）病原学诊断的补充，目前这是一个发展的方向，但是目前试剂盒的稳定性，或者是假阳性、假阴性的问题还没有完全解决，甚至目前是一个定性，还没有定量，我们对这个技术的广泛使用需要积累经验。





7.出院标准与核酸复阳

国家指南的出院标准：

1. 体温恢复正常>3d；

2. 呼吸道症状明显好转；

3. 肺部影像学检查显示急性病变明显改善；

4. 连续两次呼吸道标本核酸检测阴性（采样至少间隔1d）；

上海增加的标准：

5. 呼吸道标本核酸检测阴性后，粪便病原核酸检测也阴性；

6. 总病程超过2周。





我们的出院标准和全国的出院标准相比，增加了两项。第一个，呼吸道标本阴性以外，粪便标本监测也阴性才可出院。上海专家组认为如果粪便阳性超过4周，传染性可能不大，当然缺少数据依据，所以如果超过4周粪便还是阳性的话，我们允许患者出院，但是出院时我们会要求病人回去以后处理粪便以避免污染 。第二个增加的标准，是要求病程超过2周。之前在想好多病毒2周之内可能还会有传染性，有些病毒有自限性，超过2周自己可能会好转，即便没有有效药物也可自愈，所以当时定了这两个附加的标准。





所以，对出院指征，上海把控比较严格。我们还重点控制了出院前的影像学评估，同时我们也要进行核酸复查，只有咽拭子和粪便同时阴性，才可出院。我们也发现，确实是粪便核酸阳性比咽拭子核酸阳性持续时间要长很多。







