BinCao,MDChina-JapanFriendshipHospital

Ins4tuteofRespiratoryMedicine,ChineseAcademyofMedicalScienceNa4onalClinicalResearchCenterforRespiratoryDiseases

Caobin_ben@163.com18,March2020

ChineseGuidelineofDiagnosisandtreatmentofCOVID-19(7thVersion)

2

n  Belongtotheβgenus;Haveenvelopes;Roundoroval;diameterbeing60to140nm

n  showed 79.0% nucleo4de iden4ty with the sequence of SARS-CoV and51.8%iden4tywiththesequenceofMERS-CoV.

SevereAcuteRespiratorySyndromeCoronavirus-2

n  Sensi4ve to ultraviolet and heat. 75% ethanol,chlorine-containing disinfectant, perace4c acid,and chloroform can effec4vely inac4vate thevirus.

n  Chlorhexidinewasnoteffec4ve

3

EpidemiologyofCOVID-19globally n  COVID-19hasspreadtotheworldrapidly.—— Athreatoftheword

h"ps://www.who.int/docs/default-source/coronaviruse/situa7on-reports/20200317-sitrep-57-covid-19.pdf?sfvrsn=a26922f2_4

4

PathogenicchangesofsevereCOVID-19inlung

XiaohongYaoetal.ChineseJournalofPathology.2020,49(2020-03-15).

n  The pathological features in lungs greatly resemble those seen inSARSandMERSinfec4on

n  bilateraldiffusealveolardamagewithcellularfibromyxoidexudates

hyalinemembraneforma4on（bluearrow)

Hyalinemembraneforma4on（bluearrow)

Inters44almononuclearinflammatoryinfiltrates Inters44almononuclearinflammatoryinfiltrates

Inters44almononuclearinflammatoryinfiltrates

Thrombusinpulmonaryarterioles(blackarrow)

5

SevereAcuteRespiratorySyndromeCoronavirus-2

n  Viralpar4cleinAlveolartypeIIcells(Electronmicroscopy)

ZheXuetal.LancetRespirMed.2020.DOI:10.1016/S2213-2600(20)30076-X

6

PathogenicchangesofsevereCOVID-19inotherorgans n  Degenera4onandnecrosisofparenchymalcells,forma4onofhyaline

thrombusinsmallvessels,andpathologicalchangesofchronicdiseaseswereobservedinotherorgansand4ssues

n  Decreasednumbersoflymphocyte,celldegenera4onandnecrosiswereobservedinspleen

ZheXuetal.LancetRespirMed.2020.DOI:10.1016/S2213-2600(20)30076-X

7

DiagnosIccriteriaofCOVID-19——Suspectedcases Suspectedcases

Epidemiologicalhistory(≤14days) Clinicalsymptoms Ø  travel/residenceinWuhananditssurrounding

areas,orothercommuni4eswhereCOVID-19hasbeenfound

Ø  feverand/orrespiratorysymptoms

Ø  contactwithCOVID-19pa4ents Ø  imagingcharacteris4csofCOVID-19

Ø  Contactwithpa4entswithfeverorrespiratorysymptomsandfromWuhananditssurroundingareas,orfromcommuni4eswhereCOVID-19hasbeenfound

Ø  NormalordecreasedofWBC;NormalordecreasedofLymphocytes

Ø  Clusteredcases

n  AnyonecriteriaofEpidemiologicalhistory+AnytwoClinicalsymptomsn  Allthreeclinicalsymptoms

8

DiagnosIccriteriaofCOVID-19——Confirmedcases

Confirmedcases E4ologicalorserologicalevidences

Nucleicacidtes4ng

n  SARS-CoV-2RNAwasposi4vedetectedbyreal4meRT-PCR

n  Viralgenesequenceishighlyhomologoustoknownnewcoronaviruses

Seruman4bodytes4ng

n  SARS-CoV-2specificIgMandIgGareposi4veinserum

n  SARS-CoV-2specificIgGisdetectablefromnega4vetoposi4ve

n  SARS-CoV-2specificIgGan4body4tershowsa4-foldorhigherchangebetweenthetwosetsofserumsamplesfromacuteandrecoveryphase

Suspectcases+oneofeIologicalorserologicalevidences

9

IgG/IgMDynamicchangesofAdultswithCOVID-19

ZhongLiuetal.unpublisheddata

10

TransmissionandincubaIonofCOVID-19

MedianincubaIonperiod4-5.2daysThe95thpercenIleofthedistribuIonwas12.5days

BasicreproducIvenumberR0=2.2-2.95

n  COVID-19paIentsincludingtheasymptoma4cinfectedpeoplearethemainsourceofinfec4on

n  Routeoftransmissionn  Respiratorydropletsandclosecontactn  Long-4meexposuretotheenvironmentwithahighconcentra4onsofaerosoln  Environmentcontaminatedbyfeces/urine→aerosolorcontacttransmission

n  Allthepopula4onaregenerallysuscep4ble

YWangetal.ZhonghuaLiuXingBingXueZaZhi.41(4),476-479;QunLietal.NEnglJMed.DOI:10.1056/NEJMoa2001316GuanWJetal.NEnglJMed.2020.doi:10.1056/NEJMoa2002032

11

DiseasespectrumofCOVID-19

81%

14%

5%

mild severe criIcaln  81%weremildstatusn  Nopneumoniaormildpneumonia

n  14%wereseverestatusn  DyspneaorRespiratoryRate≥30/minor

SpO2<93%orPaO2/FiO2<300mmHgn  Lunginfiltrates>50%within24to48

hoursn  5%werecriIcalillstatus

n  Needsmechanicalven4la4onn  Shockn  Complicatedwithotherorganfailure

requiredICUadmission ZunyouWuetal.JAMA.2020.DOI:10.1001/jama.2020.2648

12

ClinicalfeaturesofCOVID-19paIents SymptomsandcomplicaIons N%

Fever 98%

Cough 76%

Myalgiaorfa4gue 44%

Sputumproduc4on 28%

Diarrhea 3%

WBC≤10×109/L 70%

Lymphocytopnia 63%

ALT>40U/L 37%

Cr>133mmol/L 10%

LDH>243U/L 73%

Hypersensi4vetroponinI>28pg/ml 12%

Procalcitonin<0.1ng/ml 69%

Acuterespiratorydistresssyndrome 29%

SymptomsandcomplicaIons N%

Acutecardiacinjury 12%

Acutekidneyinjury 7%

Sep4cshock 7%

Secondaryinfec4on 10%

HuangCetal.Lancet.2020;395(10223):497-506.

13

ClinicalcourseofCOVID-19——SevereandcriIcalillness

FeiZhouetal.Lancet.2020.DOI:10.1016/S0140-6736(20)30566-3

n  Dura4onofdyspneawas13daysinsurvivorsn  45%survivorss4llhadcoughondischargen  Mediandura4onofviralsheddingwas20days,couldprolongas37daysn  lymphocytecountwaslowestonday7aoerillnessonsetandimprovedduringhospitalisa4onin

survivorsbutwhereasseverelymphopeniawasobservedun4ldeathinnon-survivors.

14

Healthycontrol

ICU care

No ICU care

0

10

20

30

4080

100

120

pg/m

l

IFN-γp < 0·01

p = 0·27p < 0·01

Healthycontrol

ICU care

No ICU care

0

5

10

15

20

25

pg/m

l

IL-2p = 0·26

p = 0·04p = 0·02

Healthycontrol

ICU care

No ICU care

0

5

10

15

20

pg/m

l

MIP-1a

p = 0·01

p = 0·02p < 0·01

Healthycontrol

ICU care

No ICU care

0

50

100

150

200

pg/m

l

TNF-α

p = 0·03

p = 0·01p < 0·01

InflammaIonofCOVID-19——SevereandcriIcalillness

All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint (which was not peer-reviewed) is the.https://doi.org/10.1101/2020.02.16.20023671doi: medRxiv preprint

All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint (which was not peer-reviewed) is the.https://doi.org/10.1101/2020.02.16.20023671doi: medRxiv preprint

n  IL-1β,IL-6,G-SCF,IP-10,andMCP1weresignificantlyelevated

n  Peripherallymphocytecounts,mainlyTcellsweresubstan4allyreducedinsevereCOVID-19pa4ents

Host-directedtherapiesmightbeanopIon

HuangC,etal.Lancet2020;395(10223):497-506; LiuJ,etal.BMJ2020;publishedonlineFeb19.

15

SARS-CoV-2Viralsepsis——FromBedsidetoBench

n  Pneumonia,Respiratoryfailure,Acuterespiratorydistresssyndrome

n  Metabolicacidosisandinternalenvironmentdisorders

n  Acutekidneyinjuryn  Acutecardiacinjuryn  ………

MulI-organdysfuncIon

RenL,etal.ChinMedJ2020;DOI:10.1097/CM9.0000000000000722；HuangC,etal.Lancet2020;395(10223):497-506HuiLi,etal.2020;unpublished,underrevision

——ViralSepsis

16

AbnormalcoagulaIoniscommoninsevereCOVID-19 1

5

10

15

20

25

30

35

40

45

50

55

Articles

8 www.thelancet.com Published online March 9, 2020 https://doi.org/10.1016/PII

might be directly caused by SARS-CoV-2 infection, but further research is needed to investigate the pathogenesis of sepsis in COVID-19 illness.

Cardiac complications, including new or worsening heart failure, new or worsening arrhythmia, or myocardial infarction are common in patients with pneumonia. Cardiac arrest occurs in about 3% of inpatients with pneumonia.21 Risk factors of cardiac events after pneumonia include older age, pre-existing cardiovascular diseases, and greater severity of pneumonia at presen-tation.22 Coronary heart disease has also been found to be associated with acute cardiac events and poor outcomes in influenza and other respiratory viral infections.22–24 In this study, increased high-sensitivity cardiac troponin I during hospitalisation was found in more than half of

those who died. The first autopsy of a 53-year-old woman with chronic renal failure in Jinyintan Hospital showed acute myocardial infarction (data not published [A: Can you provide information on where you obtained this information (eg, personal correspondence with some-one?)]). About 90% of inpatients with pneumonia had increased coagulation activity, marked by increased d-dimer concentrations.25 In this study, we found d-dimer greater than 1 µg/L is associated with fatal outcome of COVID-19. High levels of d-dimer have a reported asso-ciation with 28-day mortality in patients with infection or sepsis identified in the emergency department.26 Contri-butory mechanisms include systemic pro-inflammatory cytokine responses that are mediators of atherosclerosis directly contributing to plaque rupture through local inflammation, induction of procoagulant factors, and haemodynamic changes, which predispose to ischaemia and thrombosis.27–29 In addition, angiotensin converting enzyme 2, the receptor for SARS-CoV-2, is expressed on myocytes and vascular endothelial cells,30,31 so there is at least theoretical potential possibility of direct cardiac involvement by the virus. Of note, interstitial mononuclear inflammatory infiltrates in heart tissue has been document in fatal cases of COVID-19, although viral detection studies were not reported.32

The level and duration of infectious virus replication are important factors in assessing the risk of trans mission and guiding decisions regarding isolation of patients. Because coronavirus RNA detection is more sensitive than virus isolation, most studies have used qualitative or quantitative viral RNA tests as a potential marker for infectious coronavirus. For SARS-CoV, viral RNA was detected in respiratory specimens from about a third of patients as long as 4 weeks after disease onset.33 Similarly, the duration of MERS-CoV RNA detection in lower respiratory [A: specimens?] persisted for at least 3 weeks,34,35 whereas the duration of SARS-CoV-2 RNA detection has not been well characterised. In the current study, we found that the detectable SARS-CoV-2 RNA persisted for a median of 20 days in survivors and that it was sustained until death in fatal cases. This has important implications for both patient isolation decision making and guidance around the length of antiviral treatment. In severe influenza virus infection, prolonged viral shedding was associated with fatal outcome and delayed antiviral treatment was an independent risk factor for prolonged virus detection.36 Similarly, effective antiviral treatment might improve outcomes in COVID-19, although we did not observe shortening of viral shedding duration after lopinavir or ritonavir treatment in the current study. Randomised clinical trials for lopinavir–ritonavir (ChiCTR2000029308) and of intravenous remdesivir (NCT04257656, NCT04252664) in treatment of COVID-19 [A: Addition correct?] are currently in progress.

Our study has some limitations. First, due to the retrospective study design, not all laboratory tests were done in all patients, including lactate dehydrogenase,

Figure 2: Temporal changes in laboratory markers from illness onset in patients hospitalised with COVID-19Figure shows temporal changes in d-dimer (A), lymphocytes (B), IL-6 (C), serum ferritin (D), high-sensitivity cardiac troponin I (E), and lactate dehydrogenase (F). Differences between survivors and non-survivors were significant for all timepoints shown, except for day 4 after illness onset for d-dimer, IL-6, and high-sensitivity cardiac troponin I [A: Addition correct?]. COVID-19=coronavirus disease 2019. IL-6=interleukin-6.

4 7 10 13 16 19 22 4 7 10 13 16 19 25220Hi

gh-s

ensit

ivity

card

iac t

ropo

nin

I (ng

/mL)

Days from illness onset

0

50200

150

250100

300150350

200400

250 450

300500

550350 600

E F

Lact

ate d

ehyd

roge

nase

(U/L

)

4 7 10 13 16 19 4 7 10 13 16 190

IL-6

(pg/

mL)

0

6 500

12 1000

18

24

1500

30

2000

2500

C DSe

rum

ferri

tin (µ

g/L)

Days from illness onset

4 7 10 13 16 19 22 4 7 10 13 16 19 22 250

D-di

mer

(µg/

L)

0·0

60·40·2

0·612

0·818

1·0241·2301·4

361·6

42 1·848 2·0

A B

Lym

phoc

yte

coun

t (×1

09 per

L)

2·5

5·56·8 6·6 6·1

7·0

6·3

236

332

323

243

390

302

397 388

198

590

200

301

413

528

217240

8·8

9·5

1·50·5

2·6

14·416·7

0·6 0·7 1·0 0·5

0·600·67

0·520·54 0·49 0·54

0·420·44

1·080·91

0·971·18

1·201·41 1·42

1·43

42·2

35·6

23·8

0·60·3

12·010·7

11·7

17·2

26·4

1025

1646 1645 1698

2000 2000

432

635

447546531393

22·055·7

57·6

134·5

290·6

24·74·1 4·4 2·5 2·5 3·83·3

SurvivorsNon-survivors

20TL1767

n  SignificantlyincreasedD-dimerandFDPwereassociatedwithpoorprognosis

n  Vascularendotheliuminflamma4onExtensiveintravascularmicrothrombosisonautopsy

n  Vascular endothelial cells express high levelsofACE2

AnIcoagulaIontherapyshouldbeiniIatedforsevereCOVID-19paIentsifotherwisecontraindicated.

ZhouF,etal.Lancet2020;DOI:10.1016/S0140-6736(20)30566-3; HammingI,etal.JPathol2004;203(2):631-7.

D-Dimer＞ 1ug/mlwasindependentriskfactorofin-hospitaldeath

17

SARS-CoV-2RNAdetecIoninCOVID-19paIents n  SARS-CoV-2 RNA could be detected in nasopharyngeal swabs, sputum, lower

respiratorytractsecre4ons,blood,fecesusingRT-PCRand/orNGSmethodsn  Posi4veratewashigherinlowerrespiratorytractspecimenn  Thespecimensshouldbesubmiqedfortes4ngassoonaspossibleaoercollec4on

88,90%

73,30%

60,00%

82,20%

72,10%61,30%

0,0

0,2

0,4

0,6

0,8

1,0

Sputumsample Nasalswabs Throatswabs

milddisease severedisease

WeiZhangetal.EmergMicrobesInfect,9(1),386-389;YangYetal.medRxiv2020.

18

FeaturesofCTscanofCOVID-19

HeshuiShietal.LancetInfectDis.2020.DOI:10.1016/S1473-3099(20)30086-4

56-year-oldmanDay3aoersymptomonsetFocalground-glassopacity

74-year-oldwomanDay10aoerillnessonsetBilateral,peripheralground-glassopacity

61-year-oldwomanDay20aoersymptomonsetBilateralandperipheralpredominantconsolida4on

63-year-oldwomanDay17aoersymptomonsetBilateral,peripheralmixedpaqern；Airbronchogram；Pleuraleffusion

n  Common:bilaterallunginvolvement(79%);peripheraldistribu4on(54%);diffusedistribu4on(44%)

ground-glassopacity(65%);withoutseptalthickening(65%).

n  Lesscommon:nodules(6%),cys4cchanges(10%),bronchiolectasis(11%),pleuraleffusion(5%).

n  Notobserved:Tree-in-budsigns,masses,cavita4on,andcalcifica4ons

19

FeaturesofimaginechangeoverIme

Ctscanbeforeillnessonset ≤1weeka\er

symptomonset >1weekto2weeksa\ersymptomonset

>2weeksto3weeksa\ersymptomonset

HeshuiShietal.LancetInfectDis.2020.DOI:10.1016/S1473-3099(20)30086-4

20

RapiddeterioraIononCTscan-case1 Male,70yearsold

2020-1-28Day9a\erillnessonset

2020-2-1Day13a\erillnessonset. Died2weekslater.

21

Male,62yearsold

2020-2-7Day12a\erillnessonset

2020-2-7Day19a\erillnessonset.Died15dayslater

RapiddeterioraIononCTscan-case2

22

RenL,etal.ChinMedJ2020;DOI:10.1097/CM9.0000000000000722HuangC,etal.Lancet2020;395(10223):497-506.RenL,etal.ChinMedJ2020;DOI:10.1097/CM9.0000000000000722HuangC,etal.Lancet2020;395(10223):497-506.

IsolaIonandSupporttreatmentofCOVID-19 n  Allconfirmedpa4entsshouldbeisola4on.n  Suspectedcaseshouldbetreatedinisola4oninasingleroomn  HospitalandICUadmissiondecisionwasaccordingtodiseaseseverityn  Strengtheningsupporttreatment(mostpa4entscomplicatedwithhypoproteinemia)

n  sufficientcaloricn  waterandelectrolytebalance

n  Oxygentherapyn  Closelymonitoringvitalsignandlaboratory(progressrapidlyinseverepaIents)

n  WBC;Lymphocyten  Biochemicalindicators(liverenzyme,myocardialenzyme,renalfunc4on.etc)n  Markerofinflamma4on(serumferri4n,IL-6,cytokine)n  Chestimaging

23

TreatmentopIonsforsevereorcriIcalCOVID-19 Respiratorysupport

Circulatorysupport

Renalreplacementtherapy

Convalescentplasma

treatment

BloodpurificaIontreatment

Immunotherapy

OthertherapeuIcmeasures

AnIviralintervenIons

n  So far, no specific antiviral against SARS-CoV-2 has been proved

n  Clinically evaluated drugs：

n  Lopinavir/ritonavir monotherapy (LOTUS China, ChiCTR2000029308): completed, manuscript accepted, online tomorrow

n  Promising results

n  CAP China Remdesivir 1 (mild-moderate pneumonia, NCT04252664): ongoing

n  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

25

CAP-ChinaRemdesivirtrialsongoingforCOVID-19 Standardcare+Remdesivir

Standardcare+Placebo

Primaryoutcome：Clinicalimprovementonday28Secondaryoutcome：The4mefromrandomiza4ontoclinicalimprovement

Totalcourseoftreatment: 10days

2:1randomiza4on

Illnessonset

≤12days Screen enroll

hospitaliza4on 24 h

Followup

Day0

Remdesivir：Firstdosage：200mgivqd×1days；

Con4nuous100mgqd×9days

Placebo：50mlqd×10days

Day1 Day3 Day5 Day7 Day10 Day14 Day21 Day28

n  TheclinicaltrailofRemdesivirtreatmentforsevereCOVID-19isongoing

26

AnIviralforCOVID-19:otherpotenIalchoices

n  Alpha-interferon:5MU,atomiza4oninhala4ontwicedailyn  Ribavirin:usedtogetherwithinterferonorlopinavir/ritonavir,500mgtwiceor

three4mesofintravenousinjec4ondaily,nolongerthan10daysn  Chloroquinephosphate:500mgbidfor7daysforadultsaged18-65withbody

weightover50kg;500mgbidforDays1&2,and500mgdailyforDays3-7foradultswithbodyweightbelow50kg

n  Arbidol:200mgthree4medailyforadults,nolongerthan10daysn  Convalescentplasmatreatment: infusiondose200-500ml(4-5ml/kg)×2n  Favipiravir

27

UseofcorIcosteroidissIllcontroversial

n  Onlyforpa4entswithrapidprogressivedeteriora4onoxygena4on, radiology

imagingandexcessiveinflamma4on

n  Contraindica4ons:allergy;un-controlleddiabetes;uncontrolledhypertension;

glaucoma;GIbleeding;immunodepression;lymphocytelessthan300/ul;severe

bacterialand/orfungalinfec4ons

n  Shortterm,3-5days

n  Low-moderatedosagen  nomorethanmethylprednisolone1-2mg/kg/day

LianghanShangetal.Lancet.2020.h"ps://doi.org/10.1016/PIIZhaoJP,etal.ZhonghuaJieHeHeHuXiZaZhi2020;43:E007(inChinese).

28

DilemmaofARB/ACEi n  LeqerfromProf.GiovannideSimone,Chair,CouncilonHypertension,EuropeanSociety

ofCardiology

n  An4-RASmedsofcoursereduceangio-IIac4vity,whichisgoodforlung

inflammatoryresponse.

n  However,toomuchinhibi4onofangio-IImightincreaseACE2ac4vity,because

angio-IIincreaseACE2cleavagethroughAT1R-ac4vatedTNF-alfa-ACE,andthis

mightnotbegoodfortheCOVID-19ac4on.

n  BinCao’responsetoProf.GiovannideSimone

n  Inourcohort,48%(26/48)non-survivorshadhypertension,whereasthe

percentageofhypertensionwasonly23%(32/137)insurvivors.TheORfor

hypertensioninANOVAis3.05(1.57-5.92).

n  Nodefiniteanswertotheques4onofARB/ACEi ZhouF,etal.Lancet2020;DOI:10.1016/S0140-6736(20)30566-3

29

DischargecriteriaofCOVID-19

n  Bodytemperatureisbacktonormalformorethanthreedays

n  Respiratorysymptomsimprovedobviously

n  Pulmonaryimagingshowsobviousabsorp4on

n  Twoconsecu4venega4venucleicacidtestsforrespiratory

specimens(samplingintervalbeingatleast24hours)

30

Allhealth-careworkersinvolvedinthediagnosisandtreatmentofpaIentsinWuhan

China-Japan Friendship Hospital Chen Wang; Yeming Wang; Fei Zhou; Guohui Fan; Hui Li; Zhibo Liu; Yi Zhang

UniversityofVirginiaFrederickGHaydenOxfordUniversityPeterWHorby

HuaZhongUniversityLiangLiu

Wuhan Jinyintan Hospital Wuhan Tongji Hospital

Wuhan Lung Hospital The Central Hospital of Wuhan

Zhongnan Hospital of Wuhan University Renmin Hospital of Wuhan University

Union Hospital Wuhan First hospital

Wuhan Third hospital Wuhan Fourth hospital

Cooperators:

Acknowledgements