(7th Version)
Severe Acute Respiratory Syndrome Coronavirus-2
◼ Belong to the β genus; Have envelopes; Round or oval; diameter being 60 to 140 nm
◼ showed 79.0% nucleotide identity with the sequence of SARS-CoV and 51.8% identity with the sequence of MERS-CoV.
◼ Sensitive to ultraviolet and heat. 75% ethanol, chlorine-containing disinfectant, peracetic acid, and chloroform can effectively inactivate the virus.
◼ Chlorhexidine was not effective

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Epidemiology of COVID-19 globally
◼ COVID-19 has spread to the world rapidly. —— A threat of the word
  
https://www.who.i nt/doc s/de faul t-sou rc e /c oronavi ruse/si tua ti on-re por ts/20 200317-si t re p-57-c ovi d-19.pdf?sfv rsn=a 26922f2_4
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Pathogenic changes of severe COVID-19 in lung
◼ The pathological features in lungs greatly resemble those seen in SARS and MERS infection
◼ bilateral diffuse alveolar damage with cellular fibromyxoid exudates
Hyaline membrane Interstitial mononuclear Thrombus in pulmonary formation(blue arrow) inflammatory infiltrates arterioles (black arrow)
Xiaohong Yao et al. Chinese Journal of Pathology.2020,49 (2020-03-15).
  
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Severe Acute Respiratory Syndrome Coronavirus-2
◼ Viral particle in Alveolar type II cells (Electron microscopy)
Zhe Xu et al. Lancet Respir Med.2020. DOI: 10.1016/S2213-2600(20)30076-X
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Pathogenic changes of severe COVID-19 in other organs
◼ Degeneration and necrosis of parenchymal cells, formation of hyaline thrombus in small vessels, and pathological changes of chronic diseases were observed in other organs and tissues
◼ Decreased numbers of lymphocyte, cell degeneration and necrosis were observed in spleen
Zhe Xu et al. Lancet Respir Med.2020. DOI: 10.1016/S2213-2600(20)30076-X
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Diagnostic criteria of COVID-19——Suspected cases
Suspected cases
Epidemiological history (≤14 days)
Clinical symptoms
➢ travel /residence in Wuhan and its surrounding areas,or other communities where COVID-19 has been found
➢ fever and/or respiratory symptoms
➢ contact with COVID-19 patients
➢ imaging characteristics of COVID-19
➢ Contact with patients with fever or respiratory symptoms and from Wuhan and its surrounding areas, or from communities where COVID-19 has been found
➢ Normal or decreased of WBC ;Normal or decreased of Lymphocytes
➢ Clustered cases
◼ Any one criteria of Epidemiological history + Any two Clinical symptoms ◼ All three clinical symptoms
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Diagnostic criteria of COVID-19——Confirmed cases
Confirmed cases
Etiological or serological evidences
Nucleic acid testing
◼ SARS-CoV-2 RNA was positive detected by real time RT-PCR
◼ Viral gene sequence is highly homologous to known new coronaviruses
Serum antibody testing
◼ SARS-CoV-2 specific IgM and IgG are positive in serum
◼ SARS-CoV-2 specific IgG is detectable from negative to positive
◼ SARS-CoV-2 specific IgG antibody titer shows a 4-fold or higher change between the two sets of serum samples from acute and recovery phase
Suspect cases + one of etiological or serological evidences
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IgG/IgM Dynamic changes of Adults with COVID-19
 
Zhong Liu et al. unpublished data
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Transmission and incubation of COVID-19
    
Basic reproductive Median incubation period 4-5.2 days The 95th number R0=2.2-2.95 percentile of the distribution was 12.5 days
◼ COVID-19 patients including the asymptomatic infected people are the main source of infection
◼ Route of transmission
◼ Respiratorydropletsandclosecontact
◼ Long-timeexposuretotheenvironmentwithahighconcentrationsofaerosol ◼ Environmentcontaminatedbyfeces/urine→aerosolorcontacttransmission
◼ All the population are generally susceptible
Y Wang et al. Zhonghua Liu Xing Bing Xue Za Zhi.41 (4), 476-479; Qun Li et al. N Engl J Med. DOI: 10.1056/NEJMoa2001316
Guan WJ et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa2002032 10

Disease spectrum of COVID-19
◼ 81% were mild status
◼ No pneumonia or mild pneumonia
◼ 14% were severe status
◼ Dyspnea or Respiratory Rate ≥ 30/min or
SpO2 < 93% or PaO2/FiO2 <300 mmHg
◼ Lung infiltrates >50% within 24 to 48
hours
◼ 5% were critical ill status
◼ Needs mechanical ventilation
◼ Shock
◼ Complicated with other organ failure
required ICU admission
mild severe 5%
14%
critical
        
Zunyou Wu et al.JAMA.2020. DOI: 10.1001/jama.2020.2648
11
81%

Clinical features of COVID-19 patients
Symptoms and complications N%
Fever 98%
Cough 76%
Myalgia or fatigue 44%
Sputum production 28%
Diarrhea 3%
WBC ≤ 10 × 109/L 70% Lymphocytopnia 63%
  
ALT> 40U/L
Cr > 133 mmol/L
LDH > 243 U/L
HypersensitivetroponinI >28pg/ml
Procalcitonin < 0.1 ng/ml
37% Symptoms and complications N% 10% Acute cardiac injury 12% 73% Acute kidney injury 7% 12% Septic shock 7% 69% Secondary infection 10%

Acute respiratory distress syndrome 29%
Huang C et al. Lancet. 2020;395(10223):497-506. 12
Clinical course of COVID-19——Severe and critical illness
    
◼ Duration of dyspnea was 13 days in survivors
◼ 45% survivors still had cough on discharge
◼ Median duration of viral shedding was 20 days, could prolong as 37 days
◼ lymphocyte count was lowest on day 7 after illness onset and improved during hospitalisation in
survivors but whereas severe lymphopenia was observed until death in non-survivors.
Fei Zhou et al. Lancet.2020. DOI: 10.1016/S0140-6736(20)30566-3
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Inflammation of COVID-19——Severe and critical illness
25 20 15 10
5 0
IL-2
p = 0·26 p=0·02 p=0·04
                                                
Healthy control
ICU No ICU care care
                                                                                                                                  
                                                                                                        
 
◼ IL-1β, IL-6, G-SCF, IP-10, and MCP1 were significantly elevated
◼ Peripheral lymphocyte counts, mainly T cells were substantially reduced in severe COVID-19 patients
Host-directed therapies might be an option
Huang C, et al. Lancet 2020; 395(10223): 497-506; Liu J, et al. BMJ 2020;published online Feb 19.
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pg/ml
SARS-CoV-2 Viral sepsis——From Bedside to Bench
Multi-organ dysfunction

◼ Pneumonia, Respiratory failure, Acute respiratory distress syndrome
◼ Metabolic acidosis and internal environment disorders
◼ Acute kidney injury
◼ Acute cardiac injury
◼ ………
——Viral Sepsis
Ren L, et al. Chin Med J 2020; DOI: 10.1097/CM9.0000000000000722;Huang C, et al. Lancet 2020; 395(10223): 497-506 HuiLi,etal.2020;unpublished, underrevision 15
Abnormal coagulation is common in severe COVID-19
D-Dimer > 1ug/ml was independent risk factor of in-hospital death
◼ Significantly increased D-dimer and FDP were associated with poor prognosis
◼ Vascular endothelium inflammation Extensive intravascular microthrombosis on autopsy
◼ Vascular endothelial cells express high levels of ACE2
                                                                                                  
Anticoagulation therapy should be initiated for severe COVID-19 patients if otherwise contraindicated.
                                                                  
Zhou F, et al. Lancet 2020; DOI:10.1016/S0140-6736(20)30566-3; Hamming I, et al. J Pathol 2004; 203(2): 631-7.
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SARS-CoV-2 RNA detection in COVID-19 patients
◼ SARS-CoV-2 RNA could be detected in nasopharyngeal swabs, sputum, lower respiratory tract secretions, blood, feces using RT-PCR and/or NGS methods
◼ Positive rate was higher in lower respiratory tract specimen
◼ The specimens should be submitted for testing as soon as possible after collection
  
1.0 0.8 0.6 0.4 0.2 0.0
mild disease
severe disease 72.10%
 
88.90%
82.20%
Sputum sample
73.30%
                   
Wei Zhang et al.Emerg Microbes Infect, 9 (1), 386-389; Yang Y et al. medRxiv 2020.
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Nasal swabs
60.00% 61.30%
Throat swabs
Features of CT scan of COVID-19




56-year-old man
Day 3 after symptom onset Focal ground-glass opacity
74-year-old woman
Day 10 after illness onset Bilateral, peripheral ground- glass opacity
61-year-old woman
Day 20 after symptom onset Bilateral and peripheral predominant consolidation
63-year-old woman
Day 17 after symptom onset Bilateral, peripheral mixed pattern;Air bronchogram; Pleural effusion
◼ Common:bilateral lung involvement(79%); peripheral distribution (54%); diffuse distribution (44%) ground glass opacity (65%); without septal thickening(65%).
◼ Less common: nodules (6%), cystic changes (10%), bronchiolectasis (11%), pleural effusion (5%). ◼ Not observed: Tree in bud signs, masses, cavitation, and calcifications
Heshui Shi et al. Lancet Infect Dis.2020. DOI: 10.1016/S1473-3099(20)30086-4 18

Features of imagine change over time
     
Ct scan before illness onset
Heshui Shi et al. Lancet Infect Dis.2020. DOI: 10.1016/S1473-3099(20)30086-4 19
>2 weeks to 3 weeks after symptom onset
 
≤ 1 week after symptom onset
>1 week to 2 weeks after symptom onset
Rapid deterioration on CT scan-case 1
Male, 70 years old
2020-1-28 Day 9 after illness onset
     
2020-2-1 Day 13 after illness onset. Died 2 weeks later.
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Rapid deterioration on CT scan-case 2
Male, 62 years old
2020-2-7 Day 12 after illness onset
2020-2-7 Day 19 after illness onset. Died 15 days later
       
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Isolation and Support treatment of COVID-19
◼ All confirmed patients should be isolation.
◼ Suspected case should be treated in isolation in a single room
◼ Hospital and ICU admission decision was according to disease severity
◼ Strengthening support treatment (most patients complicated with hypoproteinemia)
◼ sufficientcaloric
◼ waterandelectrolytebalance ◼ Oxygen therapy
◼ Closely monitoring vital sign and laboratory (progress rapidly in severe patients)
◼ WBC;Lymphocyte
◼ Biochemicalindicators(liverenzyme,myocardialenzyme,renalfunction.etc) ◼ Markerofinflammation(serumferritin,IL-6,cytokine)
◼ Chestimaging
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Treatment options for severe or critical COVID-19
Respiratory support
    
Other therapeutic measures
Circulatory support
   
Immunotherapy
Renal replacement therapy
   
Blood purification treatment
Convalescent plasma treatment

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Antiviral interventions
◼ So far, no specific antiviral against SARS-CoV-2 has been proved ◼Clinically evaluated drugs:
◼ Lopinavir/ritonavir monotherapy (LOTUS China, ChiCTR2000029308): completed, manuscript accepted, online tomorrow
◼ Promising results
◼ CAP China Remdesivir 1 (mild-moderate pneumonia, NCT04252664):
ongoing
◼ CAP China Remdesivir 2 (severe-critical pneumonia, NCT04257656): ongoing
Emmie de Wit et al. Nature Reviews Microbiology 2016; 14, 523–534 Timothy P Sheahan; Nat Commun 2020; 11 (1), 222
Yeming wang, et al. Trial, 2020, under peer review
CAP-China Remdesivir trials on going for COVID-19
Standard care + Remdesivir
Standard care + Placebo
Remdesivir:
First dosage:200mg iv qd×1days; Continuous 100mg qd×9days
2:1 randomization
 
Placebo:50ml qd×10days
Illness
onset
hospitalization
Total course of treatment: 10 days

≤ 12 days
Screen
enroll
Follow up
                    
24h
Day 0
Day1 Day3 Day5 Day7 Day10 Day14 Day21
Day28
 
Primary outcome:Clinical improvement on day 28
Secondary outcome:The time from randomization to clinical improvement
◼ The clinical trail of Remdesivir treatment for severe COVID-19 is on going
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Antiviral for COVID-19: other potential choices
◼ Alpha-interferon:5MU,atomizationinhalationtwicedaily
◼ Ribavirin: used together with interferon or lopinavir/ritonavir, 500 mg twice or
three times of intravenous injection daily, no longer than 10 days
◼ Chloroquine phosphate: 500 mg bid for 7 days for adults aged 18-65 with body weight over 50 kg; 500 mg bid for Days 1&2, and 500 mg daily for Days 3-7 for
adults with body weight below 50 kg
◼ Arbidol: 200 mg three time daily for adults, no longer than 10 days
◼ Convalescent plasma treatment: infusion dose 200-500ml (4-5 ml/kg)×2
◼ Favipiravir
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Use of corticosteroid is still controversial
◼ Only for patients with rapid progressive deterioration oxygenation, radiology imaging and excessive inflammation
◼ Contraindications: allergy; un-controlled diabetes; uncontrolled hypertension; glaucoma; GI bleeding; immunodepression; lymphocyte less than 300/ul; severe bacterial and/or fungal infections
◼ Short term, 3-5 days ◼ Low-moderate dosage
◼ nomorethanmethylprednisolone1-2mg/kg/day
Lianghan Shang et al. Lancet.2020. https://doi.org/10.1016/PII
Zhao JP, et al. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43: E007 (in Chinese).

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Dilemma of ARB/ACEi
◼ Letter from Prof. Giovanni de Simone, Chair, Council on Hypertension, European Society of Cardiology
◼ Anti-RAS meds of course reduce angio-II activity, which is good for lung inflammatory response.
◼ However, too much inhibition of angio-II might increase ACE2 activity, because angio-II increase ACE2 cleavage through AT1R-activated TNF-alfa-ACE, and this might not be good for the COVID-19 action.
◼ Bin Cao’ response to Prof. Giovanni de Simone
◼ In our cohort, 48% (26/48) non-survivors had hypertension, whereas the
percentage of hypertension was only 23% (32/137) in survivors. The OR for
hypertension in ANOVA is 3.05 (1.57-5.92).
◼ No definite answer to the question of ARB/ACEi
Zhou F, et al. Lancet 2020; DOI:10.1016/S0140-6736(20)30566-3 28
Discharge criteria of COVID-19
◼ Body temperature is back to normal for more than three days ◼ Respiratory symptoms improved obviously
◼ Pulmonary imaging shows obvious absorption
◼ Two consecutive negative nucleic acid tests for respiratory
specimens (sampling interval being at least 24 hours)
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China-Japan Friendship Hospital
Chen Wang; Yeming Wang; Fei Zhou; Guohui Fan; Hui Li; Zhibo Liu; Yi Zhang
Cooperators:
Wuhan Jinyintan Hospital
Wuhan Lung Hospital
Zhongnan Hospital of Wuhan University
Union Hospital
Wuhan Third hospital
University of Virginia
Frederick G Hayden
Oxford University
Peter W Horby
HuaZhong University
Liang Liu
Acknowledgements

Wuhan Tongji Hospital
The Central Hospital of Wuhan
Renmin Hospital of Wuhan University
Wuhan First hospital
Wuhan Fourth hospital

All health-care workers involved in the diagnosis and treatment of patients in Wuhan
  
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