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ClinicalReview&Education
JAMA | Review
Pathophysiology,Transmission,Diagnosis,andTreatment
ofCoronavirusDisease2019(COVID-19)
AReview
W.JoostWiersinga,MD,PhD;AndrewRhodes,MD,PhD;AllenC.Cheng,MD,PhD;
SharonJ.Peacock,PhD;HallieC.Prescott,MD,MSc
JAMAPatientPage
IMPORTANCE Thecoronavirusdisease2019(COVID-19)pandemic,duetothenovelsevere
acuterespiratorysyndromecoronavirus2(SARS-CoV-2),hascausedaworldwidesuddenand
substantialincreaseinhospitalizationsforpneumoniawithmultiorgandisease.Thisreview
discussescurrentevidenceregardingthepathophysiology,transmission,diagnosis,and
managementofCOVID-19.
OBSERVATIONSSARS-CoV-2isspreadprimarilyviarespiratorydropletsduringclose
face-to-facecontact.Infectioncanbespreadbyasymptomatic,presymptomatic,and
symptomaticcarriers.Theaveragetimefromexposuretosymptomonsetis5days,and
97.5%ofpeoplewhodevelopsymptomsdosowithin11.5days.Themostcommon
symptomsarefever,drycough,andshortnessofbreath.Radiographicandlaboratory
abnormalities,suchaslymphopeniaandelevatedlactatedehydrogenase,arecommon,but
nonspecific.DiagnosisismadebydetectionofSARS-CoV-2viareversetranscription
polymerasechainreactiontesting,althoughfalse-negativetestresultsmayoccurinupto
20%to67%ofpatients;however,thisisdependentonthequalityandtimingoftesting.
ManifestationsofCOVID-19includeasymptomaticcarriersandfulminantdisease
characterizedbysepsisandacuterespiratoryfailure.Approximately5%ofpatientswith
COVID-19,and20%ofthosehospitalized,experienceseveresymptomsnecessitating
intensivecare.Morethan75%ofpatientshospitalizedwithCOVID-19requiresupplemental
oxygen.TreatmentforindividualswithCOVID-19includesbestpracticesforsupportive
managementofacutehypoxicrespiratoryfailure.Emergingdataindicatethat
dexamethasonetherapyreduces28-daymortalityinpatientsrequiringsupplementaloxygen
comparedwithusualcare(21.6%vs24.6%;age-adjustedrateratio,0.83[95%CI,
0.74-0.92])andthatremdesivirimprovestimetorecovery(hospitaldischargeorno
supplementaloxygenrequirement)from15to11days.Inarandomizedtrialof103patients
withCOVID-19,convalescentplasmadidnotshortentimetorecovery.Ongoingtrialsare
testingantiviraltherapies,immunemodulators,andanticoagulants.Thecase-fatalityratefor
COVID-19variesmarkedlybyage,rangingfrom0.3deathsper1000casesamongpatients
aged5to17yearsto304.9deathsper1000casesamongpatientsaged85yearsorolderin
theUS.Amongpatientshospitalizedintheintensivecareunit,thecasefatalityisupto40%.
Atleast120SARS-CoV-2vaccinesareunderdevelopment.Untilaneffectivevaccineis
available, theprimarymethodstoreducespreadarefacemasks,socialdistancing,and
contacttracing.Monoclonalantibodiesandhyperimmuneglobulinmayprovideadditional
preventivestrategies.
CONCLUSIONSANDRELEVANCEAsofJuly1,2020,morethan10millionpeopleworldwidehad
beeninfectedwithSARS-CoV-2.Manyaspectsoftransmission,infection,andtreatment
remainunclear.AdvancesinpreventionandeffectivemanagementofCOVID-19willrequire AuthorAffiliations:Author
basicandclinicalinvestigationandpublichealthandclinicalinterventions. affiliations are listed at the end of this
article.
CorrespondingAuthor:W.Joost
Wiersinga,MD,PhD,Divisionof
InfectiousDiseases,Departmentof
Medicine,AmsterdamUMC,location
AMC,Meibergdreef9,1105AZ
Amsterdam,theNetherlands(w.j.
wiersinga@amsterdamumc.nl).
SectionEditors:EdwardLivingston,
JAMA.doi:10.1001/jama.2020.12839 MD,DeputyEditor,andMaryMcGrae
PublishedonlineJuly10,2020. McDermott,MD,DeputyEditor.
(Reprinted) E1
©2020AmericanMedicalAssociation.All rights reserved.
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Clinical Review&Education Review CoronavirusDisease2019(COVID-19)—Epidemiology,Diagnosis,andTreatment
hecoronavirus disease 2019 (COVID-19) pandemic has spike(S)proteinthatbindstotheangiotensin-convertingenzyme
7
causedasuddensignificantincreaseinhospitalizationsfor 2(ACE2)receptor (Figure2).Thetype2transmembraneserinepro-
Tpneumoniawithmultiorgandisease.COVID-19iscausedby tease(TMPRSS2),presentinthehostcell,promotesviraluptakeby
the novel severe acute respiratory syndrome coronavirus 2 (SARS- cleavingACE2andactivatingtheSARS-CoV-2Sprotein,whichme-
CoV-2).SARS-CoV-2infectionmaybeasymptomaticoritmaycause diatescoronavirusentryintohostcells.7ACE2andTMPRSS2areex-
awidespectrumofsymptoms,suchasmildsymptomsofupperre- pressed in host target cells, particularly alveolar epithelial type II
spiratory tract infection and life-threatening sepsis. COVID-19 first cells.8,9 Similar to other respiratory viral diseases, such as influ-
emergedinDecember2019,whenaclusterofpatientswithpneu- enza,profoundlymphopeniamayoccurinindividualswithCOVID-19
moniaofunknowncausewasrecognizedinWuhan,China.AsofJuly whenSARS-CoV-2infectsandkillsTlymphocytecells.Inaddition,
1, 2020, SARS-CoV-2hasaffectedmorethan200countries,result- theviralinflammatoryresponse,consistingofboththeinnateand
inginmorethan10millionidentifiedcaseswith508000confirmed the adaptive immune response (comprising humoral and cell-
deaths(Figure1).Thisreviewsummarizescurrentevidenceregard- mediatedimmunity),impairslymphopoiesisandincreaseslympho-
ing pathophysiology, transmission, diagnosis, and management of cyteapoptosis.AlthoughupregulationofACE2receptorsfromACE
COVID-19. inhibitorandangiotensinreceptorblockermedicationshasbeenhy-
pothesizedtoincreasesusceptibilitytoSARS-CoV-2infection,large
observationalcohortshavenotfoundanassociationbetweenthese
Methods medications and risk of infection or hospital mortality due to
10,11
COVID-19. Forexample,inastudy4480patientswithCOVID-19
WesearchedPubMed,LitCovid,andMedRxivusingthesearchterms fromDenmark,previoustreatmentwithACEinhibitorsorangioten-
coronavirus,severeacuterespiratorysyndromecoronavirus2,2019- sinreceptorblockerswasnotassociatedwithmortality.11
nCoV,SARS-CoV-2,SARS-CoV,MERS-CoV,andCOVID-19forstudies Inlaterstagesofinfection,whenviralreplicationaccelerates,epi-
published from January 1, 2002, to June 15, 2020, and manually thelial-endothelialbarrierintegrityiscompromised.Inadditiontoepi-
searchedthereferencesofselectarticlesforadditionalrelevantar- thelialcells,SARS-CoV-2infectspulmonarycapillaryendothelialcells,
ticles.Ongoingorcompletedclinicaltrialswereidentifiedusingthe accentuatingtheinflammatoryresponseandtriggeringaninfluxof
diseasesearchtermcoronavirusinfectiononClinicalTrials.gov,the monocytesandneutrophils.Autopsystudieshaveshowndiffusethick-
ChineseClinicalTrialRegistry,andtheInternationalClinicalTrialsReg- eningofthealveolarwallwithmononuclearcellsandmacrophages
istry Platform. We selected articles relevant to a general medicine infiltratingairspacesinadditiontoendothelialitis.12Interstitialmono-
readership, prioritizing randomized clinical trials, systematic re- nuclear inflammatory infiltrates and edema develop and appear as
views,andclinicalpracticeguidelines. ground-glass opacities on computed tomographic imaging. Pulmo-
naryedemafillingthealveolarspaceswithhyalinemembraneforma-
tion follows, compatible with early-phase acute respiratory distress
Observations syndrome(ARDS).12Bradykinin-dependentlungangioedemamay
13
contributetodisease. Collectively,endothelialbarrierdisruption,dys-
Pathophysiology functionalalveolar-capillaryoxygentransmission,andimpairedoxy-
Coronaviruses are large, enveloped, single-stranded RNA viruses gendiffusioncapacityarecharacteristicfeaturesofCOVID-19.
foundinhumansandothermammals,suchasdogs,cats,chicken, InsevereCOVID-19,fulminantactivationofcoagulationandcon-
cattle, pigs, and birds. Coronaviruses cause respiratory, gastroin- sumptionofclottingfactorsoccur.14,15AreportfromWuhan,China,
testinal, and neurological disease. The most common coronavi- indicatedthat71%of183individualswhodiedofCOVID-19metcri-
rusesinclinicalpracticeare229E,OC43,NL63,andHKU1,whichtypi- teriafordiffuseintravascularcoagulation.14Inflamedlungtissuesand
cally cause common cold symptoms in immunocompetent pulmonaryendothelialcellsmayresultinmicrothrombiformationand
individuals.SARS-CoV-2isthethirdcoronavirusthathascausedse- contribute to the high incidence of thrombotic complications, such
1
verediseaseinhumanstospreadgloballyinthepast2decades. The as deepvenousthrombosis,pulmonaryembolism,andthrombotic
first coronavirus that caused severe disease was severe acute re- arterial complications (eg, limb ischemia, ischemic stroke, myocar-
spiratory syndrome (SARS), which was thought to originate in dialinfarction)incriticallyillpatients.16Thedevelopmentofviralsep-
2
Foshan,China,andresultedinthe2002-2003SARS-CoVpandemic. sis, defined as life-threatening organ dysfunction caused by a dys-
Thesecondwasthecoronavirus-causedMiddleEastrespiratorysyn- regulated host response to infection, may further contribute to
3
drome(MERS),whichoriginatedfromtheArabianpeninsulain2012. multiorganfailure.
SARS-CoV-2hasadiameterof60nmto140nmanddistinc-
tive spikes, ranging from 9 nm to 12 nm, giving the virions the ap- TransmissionofSARS-CoV-2Infection
pearance of a solar corona (Figure 2).4 Through genetic recombi- Epidemiologic data suggest that droplets expelled during face-to-
nation and variation, coronaviruses can adapt to and infect new faceexposureduringtalking,coughing,orsneezingisthemostcom-
hosts.BatsarethoughttobeanaturalreservoirforSARS-CoV-2,but monmodeoftransmission(Box1).Prolongedexposuretoanin-
it has been suggested that humans became infected with SARS- fectedperson(beingwithin6feetforatleast15minutes)andbriefer
5,6
CoV-2viaanintermediatehost,suchasthepangolin. exposurestoindividualswhoaresymptomatic(eg,coughing)areas-
sociated with higher risk for transmission, while brief exposures to
TheHostDefenseAgainstSARS-CoV-2 asymptomaticcontactsarelesslikelytoresultintransmission.25Con-
Earlyininfection,SARS-CoV-2targetscells,suchasnasalandbron- tactsurfacespread(touchingasurfacewithvirusonit)isanotherpos-
chial epithelial cells and pneumocytes, throughtheviralstructural siblemodeoftransmission.Transmissionmayalsooccurviaaerosols
E2 JAMA PublishedonlineJuly 10,2020 (Reprinted) jama.com
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CoronavirusDisease2019(COVID-19)—Epidemiology,Diagnosis,andTreatment Review ClinicalReview&Education
Figure1.KeyEventsintheEarlyCoronavirusDisease2019(COVID-19)Pandemic
190 000 June 29: Global reported
180 000 WHO region COVID-19 cases exceeds
170 000 Africa 10 million
160 000 Americas
150 000 Eastern Mediterranean
140 000 Europe
130 000 Southeast Asia
120 000 Western Pacific
110 000 Other
100 000
Cases per day90 000
80 000
70 000
60 000
50 000
40 000
30 000
20 000
10 000
0
Dec Jan Jan Jan Jan Feb Feb Feb Feb Mar Mar Mar Mar Mar Apr Apr Apr May May Jun Jun Jun
30 6 13 20 27 3 10 17 24 2 9 16 23 30 6 13 20 4 18 1 15 29
2019 2020 2020 2020 2020 2020 2020 2020 20202020 2020 2020 2020 2020 2020 2020 2020 2020 2020 2020 2020 2020
Dec Jan Feb Mar Apr May June
Dec 31: China alerts WHO Jan 13: First confirmed Feb 2: First confirmed Mar 11: WHO declares Apr 1: No. of May 9: No. of global
on a cluster of cases of case outside of China death outside China the coronavirus confirmed cases of reported COVID-19 cases
pneumonia with unknown (Thailand) in a traveler (Philippines) of a Chinese outbreak a pandemic COVID-19 exceeds exceeds 4 million
cause in Wuhan who has visited Wuhan man from Wuhan 1 million
Jan 7: WHO officials Jan 30: WHO declares coronavirus a Feb 11: WHO announces March 16: More April 9: Italy has reached May 22: South America at
announce they have global emergency with cases reported that the new disease cases outside transmission peak with center of pandemic with more
identified a new in US, Japan, Nepal, France, Australia, caused by SARS-CoV-2 mainland China more than 132 000 cases than 330 000 cases in Brazil
coronavirus initially Malaysia, Singapore, South Korea, is named “COVID-19” than within alone
named 2019-nCoV Vietnam, and Taiwan
Feb 14: Egypt first country in Africa Mar 18: WHO launches International April 28: No. of cases in US June 29: No. of global
to report a case and France reports Solidarity Trial aiming to find the surpasses 1 million with 58 000 reported COVID-19 cases
Europes first death from the virus most effective treatments for confirmed deaths exceeds 10 million
COVID-19
BasedondatafromWorldHealthOrganization(WHO)COVID-19situationreports.TheCOVID-19outbreakwasfirstrecognizedinWuhan,China,inearly
December2019.ThenumberofconfirmedCOVID-19casesisdisplayedbydateofreportandWHOregion.SARS-CoV-2indicatessevereacuterespiratory
syndromecoronavirus2.
(smallerdropletsthatremainsuspendedinair),butitisunclearifthis upto3to4daysafterinoculation.32Widespreadviralcontamina-
28
is a significant source of infection in humans outside of a laboratory tion of hospital rooms has been documented. However, it is
setting.26,27 The existence of aerosols in physiological states thoughtthattheamountofvirusdetectedonsurfacesdecaysrap-
(eg,coughing)orthedetectionofnucleicacidintheairdoesnotmean idlywithin48to72hours.32Althoughthedetectionofvirusonsur-
thatsmallairborneparticlesareinfectious.28MaternalCOVID-19iscur- facesreinforcesthepotentialfortransmissionviafomites(objects
rently believed to be associated with low risk for vertical transmis- suchasadoorknob,cutlery,orclothingthatmaybecontaminated
sion. In most reported series, the mothers' infection with SARS- with SARS-CoV-2) and the need for adequate environmental hy-
CoV-2occurredinthethirdtrimesterofpregnancy,withnomaternal giene,dropletspreadviaface-to-facecontactremainstheprimary
29-31
deathsandafavorableclinicalcourseintheneonates. modeoftransmission.
Theclinical significance of SARS-CoV-2 transmission from in- Viralloadintheupperrespiratorytractappearstopeakaround
animatesurfacesisdifficulttointerpretwithoutknowingthemini- the time of symptom onset and viral shedding begins approxi-
mumdoseofvirusparticlesthatcaninitiateinfection.Viralloadap- mately 2 to 3 days prior to the onset of symptoms.33 Asymptom-
pearstopersistathigherlevelsonimpermeablesurfaces,suchas atic andpresymptomaticcarrierscantransmitSARS-CoV-2.34,35In
stainless steel and plastic, than permeable surfaces, such as Singapore,presymptomatictransmissionhasbeendescribedinclus-
32
cardboard. Virushasbeenidentifiedonimpermeablesurfacesfor tersofpatientswithclosecontact(eg,throughchurchgoingorsinging
jama.com (Reprinted) JAMA PublishedonlineJuly 10,2020 E3
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Clinical Review&Education Review CoronavirusDisease2019(COVID-19)—Epidemiology,Diagnosis,andTreatment
Figure2.ImmunopathogenesisofCoronavirusDisease2019(COVID-19)
A SARS-CoV-2 viral infection of host airway cells
SARS-CoV-2 virion
Viral RNA S protein ACE2
TMPRSS2 receptor
TMPRSS2 activates viral S protein and
cleaves ACE2 receptor to facilitate Virus enters host cell via endocytosis,
viral binding to host cell membrane. releases its RNA, and uses cell machinery One infected host cell can create
to replicate itself and assemble more virions. hundreds of new virions, rapidly
HOST AIRWAY CELL progressing infection.
B Early-stage COVID-19
Bronchial epithelial cells, type I and type II alveolar
pneumocytes, and capillary endothelial cells are ALVEOLAR LUMEN Neutrophil
infected, and an inflammatory response ensues. Monocyte
Infected
type II pneumocyte SARS-CoV-2 T lymphocyte Macrophage
virus release
T lymphocyte, monocyte,
Type I and neutrophil recruitment
pneumocyte TNF-α
IL-1
IL-6
Cytokine release enhances
inflammatory response
ALVEOLUS ALVEOLAR CAPILLARY
Capillary
endothelial cell
C Late-stage COVID-19
Continued inflammatory response results in
alveolar interstitial thickening, increased
vascular permeability, and edema.
Thickened Pulmonary edema Increased
interstitium T lymphocyte apoptosis
Hyaline membrane
formation
Influx of monocytes
Increased and neutrophils
vascular permeability
Activation of coagulation leads
to microthrombus formation
Pulmonary
Activation of the kinin-kallikrein system thrombus
can further contribute to local vascular
leakage leading to angioedema.
Currentunderstandingofthesevereacuterespiratorysyndromecoronavirus2 earlystage,viralcopynumberscanbehighinthelowerrespiratorytract.
(SARS-CoV-2)–inducedhostimmuneresponse.SARS-CoV-2targetscells Inflammatorysignalingmoleculesarereleasedbyinfectedcellsandalveolar
throughtheviralstructuralspike(S)proteinthatbindstotheangiotensin- macrophagesinadditiontorecruitedTlymphocytes,monocytes,and
convertingenzyme2(ACE2)receptor.Theserineproteasetype2 neutrophils.Inthelatestage,pulmonaryedemacanfillthealveolarspaceswith
transmembraneserineproteas(TMPRSS2)inthehostcellfurtherpromotes hyalinemembraneformation,compatiblewithearly-phaseacuterespiratory
viral uptakebycleavingACE2andactivatingtheSARS-CoV-2Sprotein.Inthe distresssyndrome.
E4 JAMA PublishedonlineJuly 10,2020 (Reprinted) jama.com
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