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Appropriate
use
of
tocilizumab
in
COVID-19
infection
Şiran
Keske
a,
Süda
Tekin
b,
Bilgin
Sait
c,
Pelin _Irkören
b,
Mahir
Kapmaz
b,
Cansu
Çimen
a,
Semra
Ugur
d, _Irfan
Çelebi
h,
Veli
Oguzalp
Bak
ır
e,
Erhan
Palaoglu
f,
Evren
Şentürk
d,
Benan
Çaglayan
g,
Nahit
Çakar
d,
Levent
Tabak
g,
Önder
Ergönül
b,*
a
AmericanHospital,DepartmentofInfectiousDiseasesandClinicalMicrobiology,Istanbul,Turkey
b
KoçUniversity,SchoolofMedicine,DepartmentofInfectiousDiseasesandClinicalMicrobiology,Istanbul,Turkey
c
AmericanHospital,DepartmentofInternalMedicine,Istanbul,Turkey
dKoçUniversity,SchoolofMedicine,DepartmentAnesthesiology&IntensiveCareUnit,Istanbul,Turkey eKoçUniversity,CollegeofEngineering,DepartmentofIndustrialEngineering,Istanbul,Turkey f
AmericanHospital,ClinicalLaboratory,Istanbul,Turkey
g
KoçUniversity,SchoolofMedicine,DepartmentofChestDiseases,Istanbul,Turkey
h
AmericanHospital,DepartmentofRadiologyandBeykentUniversitySchoolofMedicine,Turkey
ARTICLE INFO
Articlehistory: Received17June2020
Receivedinrevisedform15July2020 Accepted21July2020 Keywords: Tocilizumab COVID-19 Cytokines Interleukin-6 Therapy ABSTRACT
Objective: This studyaimed todescribe the effectiveness and optimum use of tocilizumab (TCZ)
treatmentbythesupportofclinical,laboratoryandradiologicobservations.
Methods:Allpatientswerefollowedupinthehospitalwithdailyinterleukin-6(IL-6),C-reactiveprotein
(CRP),ferritin,D-dimer,fullbloodcount,andprocalcitonin.Thoraciccomputedtomography(CT)was
performedonadmission,whenoxygensupportwasnecessary,andsevendaysafterTCZstarted.Disease
courseofthepatientswasgroupedassevereorcritical,according totheirclinical,laboratoryand
radiologicevaluations.
Results:Forty-threepatientswereincluded:70%weremale;themedianagewas64years(minimum–
maximum:27–94);andsix(14%)patientsdied.Themediandurationofoxygensupportbeforetheonset
ofTCZwasshorteramongtheseverepatientgroupthanthecriticalpatientgroup(1vs.4days,p<0.001).
Threecasesof21(14%)whoreceivedTCZinthewardweretransferredtoICU,andnoneofthemdied.The
levelsofIL-6,CRP,ferritin,D-dimer,andprocalcitoninweresignificantlylowerintheseverecasesgroup
thanthecriticalcasesgroup(p= 0.025,p= 0.002,p= 0.008,p= 0.002,andp= 0.001,respectively).
RadiologicalimprovementwasobservedinseverecasesontheseventhdayofTCZ.Secondarybacterial
infectionwasdetectedin41%ofcriticalcases,butnoneofthesevereones.
Conclusion:EarlieruseofTCZinCOVID-19infectionwasbeneficialforsurvival,lengthofhospitalization
anddurationofoxygensupport.TherecommendationforadministrationofTCZwasbasedonanincrease
inrequirementofoxygensupport,progressioninthoracicCT,andelevationofinflammationmarkers,
includingIL-6,CRP,ferritin,andD-dimer,anddecreasein%lymphocytes.
©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.
ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(
http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Severeacuterespiratorysyndromecoronavirus2(SARS-CoV-2) isanovelcoronavirus,whichisthecauseofpneumoniathatwas firstseeninWuhan,China,inDecember2019(Wangetal.,2020a). SARS-CoV-2 pneumonia has been reported in many countries around the world, and the World Health Organization (WHO) declaredtheoutbreakasapandemicon11March2020.Patients diagnosedwithCOVID-19mayhaveawide rangeofsymptoms
frommildtosevere.Fever,coughandshortnessofbreatharethe mostcommonsymptomsthathave beenreported(Ciottiet al., 2020).Advancedage,underlyingcomorbiditiessuchas hyperten-sion,diabetes,cardiovasculardisease,andcerebrovasculardisease aretheriskfactorsthathavebeenreportedfor developinginto severetocriticalcases(Wangetal.,2020b;Huang etal.,2020). Acuterespiratorydistresssyndrome(ARDS)maydevelopinsome patients,whoaremorelikelytohavepooroutcomes(Ruanetal., 2020).Cytokinestormcauses ARDS and multipleorgan failure, whichoccursasaresultofthemacrophageactivatingsyndrome (MAS)bothinsepsisandCOVID-19(Choustermanetal.,2017;Ye et al.,2020).It hasbeen reportedthat theserum levelsof the cytokines, including interleukin-6 (IL-6), are higher in critical
*Correspondingauthor.
E-mailaddress:oergonul@ku.edu.tr(Ö.Ergönül).
https://doi.org/10.1016/j.ijid.2020.07.036
1201-9712/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
ContentslistsavailableatScienceDirect
International
Journal
of
Infectious
Diseases
patientswithCOVID-19(Chenetal.,2020;Hendersonetal.,2020). Hence,suppressingthecytokinestormseemstobeaneffective waytodecreasefatality(Liuetal.,2020).
Tocilizumab(TCZ)isananti-IL-6receptormonoclonalantibody thatinhibitssignaltransductionandisusedforthetreatmentof rheumatoidarthritis(Nishimotoetal.,2000;Tanakaetal.,2014). TCZ alsohas a significant effect onthetreatment of infection-inducedcytokinestorm,anditmightbeeffectiveinthetreatment ofcriticalpatientswithCOVID-19(Luoetal.,2020;Di Giambe-nedettoetal.,2020).However,correctuseandtimingofTCZinthe treatmentcourseisnecessary.
Thisstudyaimedtodetailthebenefitandappropriatetiming for TCZ treatment in severe to critical cases with COVID-19 pneumonia. It describesthe secondary bacterialinfections that couldbeassociatedwithTCZ.
Methods
Patientsandstudydesign
Inthisretrospectivestudy,thepatientswhowereinfectedwith SARS-CoV-2andreceivedTCZfrom10Marchto14April2020at theAmerican Hospitaland KocUniversity Hospitalin Istanbul, Turkey,wereincluded.Allpatientswerefollowedupforatleast 14daysatthehospitalafterTCZtreatment.ACOVID-19team– includinginfectious disease, internal medicine,chest medicine, andintensivecareunitphysicians–managedallthecaseswith weeklymeetingsanddailyon-calland/orbedsideconsultations. Definitions
TheWHO case definitionwas used in diagnosing COVID-19, includingprobableandconfirmedcases(WHO,2020).Con firma-tion was defined as a positive laboratory result of COVID-19 infection,whereasaprobablecasewasdefinedasinconclusiveora suspect case for whomtesting couldnot be confirmed for any reason.
Bloodoxygenlevels<93%wereacceptedasdecreasedoxygen saturation. If necessary, oxygen support was given by nasal cannula,aventurimask,andnon-invasiverespiratorysupportor invasivemechanicalventilation.
Patients werecategorized as severeor critical based onthe severityofinfection(Anon,2020).Thefeaturesoftheseverecases wererespiratorydistress(30breaths/minute)oroxygen satura-tion 93%or arterialpartial oxygenpressure(PaO2)/fractionof inspiredoxygen(FiO2)300mmHg.Thefeatures ofthecritical caseswererespiratoryfailurerequiringmechanicalventilationor shockororganfailurerequiringICU.
Primaryoutcomesweredurationofoxygenrequirement,being transferred to ICU and fatality. Secondary outcomes were the duration of oxygen support after using TCZ and length of hospitalization.
Treatmentalgorithmandfollow-up
AllsuspectedorconfirmedadultcaseswithCOVID-19received hydroxychloroquine(orplusazithromycin)onadmission, accord-ingtothenationalprotocolofMinistryofHealth(Figure1).By01 April2020,sinceitbecameavailable,favipiravirstartedtobeused asanalternativeincasesofprogressioninradiologicalimagingor requiringoxygensupport.TCZwasstartedwhencytokinestorm was suspected, byevaluating:radiological progression, require-mentofoxygensupport,C-reactiveprotein(CRP),IL-6, procalci-tonin, lactate dehydrogenase (LDH), ferritin, D-dimer level,
leucocyte, lymphocyte and platelet counts. The initial dose of TCZwas8mg/kg,basedonChineseguidelines(Anon,2020).Ifthe firstdosewasineffective,onemoredosewasgivenatleast12h later.Informedconsentwasobtainedfromthecasesifunavailable fromtheirrelatives.Thecaseswerefollowedupintermsofadverse eventswithbiosafetymonitoringdocument.
Laboratorystudies
Nasopharyngeal and oropharyngeal sampleswere tested for SARS-CoV-2 by real-time polymerase chain reaction in the laboratory of Koç University Hospital in Istanbul. Mediated amplification and detection of B-βCoV (target E gene) specific RNAandSARSCoV-2(targetSgene),QIAamp1ViralRNAMiniKit (Qiagen,Hilden,Germany)fornucleicacidextractionandthenthe RealStar1SARS-CoV-2RT-PCRKit 1.0(AltonaDiagnostics, Ham-burg, Germany) on Rotor-Gene1 Q5/6 plex Platform (Qiagen, Hilden, Germany)were used.IL-6, CRP, procalcitonin,aspartate
transaminase(AST),alaninetransaminase(ALT),ferritin,D-dimer,
LDH,leucocytes,neutrophil,lymphocyte,andplateletcountswere useddailyinfollow-up.Thoraciccomputedtomography(CT)was usedbeforetheinitiationofTCZ.
Statisticalanalysis
CategoricalvariableswerecomparedbyusingChi-squaretest. Forcontinuousvariables,thenon-parametricKruskal-Wallistest wasusedbecauseofthesmallsamplesize.STATA15vwasused forstatisticalanalysisandstatisticalsignificancewassetasp-value <0.05.TheInstitutionalReviewBoardofKoçUniversityapproved thestudywiththereferencenumber2020.143.IRB1.033. Results
Forty-threepatientswereincluded:70%weremale;themedian agewas64years(minimum–maximum:27–94);63%were>60 years (Table 1). Fever (91%) and cough (60%) were the most commonsymptoms.Allfatalcasesweremaleandaged>60years; themedianageoffatalcaseswasolderthanthosewhosurvived (75vs. 61 years,p=0.016, Table 1).Hypertensionand diabetes mellituswerethemostcommonly detected comorbiddiseases, andthecomorbiditiesweresimilarbetweentwogroups(Table1). The median duration of oxygensupport beforetheonset of TCZwas3.5daysinfatalcasesand2daysinthosewhosurvived (p=0.12).Thedurationfromtheonsetofsymptomstothestartof TCZwassimilaramongfatalandsurvivedcases.Noneofthesevere casesandthreecriticalcasesdied(p= 0.01,Table1).
The laboratory results of the patients on the day of TCZ administrationamongfatalandnon-fatalcasesaresummarizedin Table1.IL-6levelwas337pg/mLinfatalcases,whileitwas126pg/ mLin thosewho survived(p= 0.04).Ferritin,CRPandD-dimer
werefoundtobehigheramongthefatal casesthanthosewho survived,withnostatisticalsignificance(Table1).
Thesevereandcriticalcaseswerecompared(Table2).Thegroups weresimilar intermsof ageandcomorbiddiseases,whilemale gender was higher among critical cases (91% to 52%, p= 0.005).Favipiravir use among the severeand critical cases was similar(p= 0.23, Table 2).Themedian durationof oxygen supportbeforetheonsetofTCZwasshorteramongtheseverecases thancriticalcases(1vs.4days,p< 0.001).Themedianlengthof stay, duration of oxygen support and the total duration of hospitalization after administration of TCZ was shorter among the severe cases than critical cases (p< 0.001, p= 0.028 and p=0.001,respectively,Table2).Threeseverecasesof21(14%)were transferredtotheICU,andnoneofthemdied.Inlaboratoryanalysis, IL-6 was 115 in severe cases and 168 in critical cases (p= 0.025).CRP,ferritin,D-dimer,andprocalcitoninweresigni
fi-cantly lower in severe cases (p= 0.0029, p= 0.008, p=0.002,andp=0.001,respectively).Thelymphocytepercentage was 13.5% in severe casesand 11% in critical ones(p= 0.007). RadiologicalimagingwithCTwasalsoexaminedbeforetheonsetof TCZinmostofthecases,andradiologicalimprovementwasalso observedontheseventhdayofTCZinseverecases(Figure3).
AftertheuseofTCZ,theearliestchangeinlaboratorytestswas observedin%lymphocytes,whichincreasedwithinthefirstday. TheCRPsharplydeclinedonedayafterTCZ.TwodaysafterTCZ, IL-6 declinedsharply,but ferritinandD-Dimerslightly declined
(Table3,Figure2).
DuringICUstay,secondarybacterialinfectionsweredetectedin ninepatients(41%).Infivecases(22%),bloodstreaminfectionsof Gram-negative, Gram-positive bacteria and Candida spp. were detected.Amongsix(27.3%)caseswithpneumonia, Corynebacte-riumstriatumandCorynebacteriumjeikeumwereisolatedinfour cases(67%).
Table1
TheUnivariateAnalysisforthefatalityofCOVID-19patients.
TotalN=43(%) FatalN=6(%) SurvivedN=37(%) p Medianage 64(27–94) 75(64–82) 61(27–94) 0.016 >60years 27(62.8) 6(100) 18(56.8) 0.04 Malegender 31(72) 6(100) 25(67.6) 0.1 Comorbidities Hypertension 19(44) 3(50) 16(43) 0.75 Diabetesmellitus 13(30) 2(33) 11(29.7) 0.85 Obesity 5(11.6) – 5(13.5) 0.33
Chronicobstructivepulmonarydisease 3(7) – 3(8) 0.47 Coronaryarterydisease 8(19) 2(33) 6(16) 0.31 Laboratory(onthedayofTCZ)
CRP(mg/L) 188(1–380) 214(109–318) 182(1–380) 0.34 Ferritin(ng/mL) 1197(250–52,765) 1884(713–10,143) 844(250–52,765) 0.1 D-Dimer(mg/L) 993(360–100,000) 2645(790–56,200) 953(360–100,000) 0.13 IL-6(pg/mL) 133(18–50,000) 337(93–50,000) 126(18–3011) 0.04 ALT(U/L) 61(14–1578) 64(38–84) 78(14–1578) 0.97 AST(U/L) 60(24–2045) 101(62–180) 6624–2045) 0.18 LDH(U/L)) 373(197–5770) 381(366–783) 367(197–5770) 0.35 Procalcitonin(ng/mL) 0.23(0.04–100) 0.43(0.07–72.8) 0.22(0.04–100) 0.34 Leucocyte(K/mL) 7.0(1.7–19.1) 6.75(4.2–11.4) 7.0(1.7–19.1) 0.96 Lymphocyte(%) 12.5(3–47) 9(3–26) 13(3–47) 0.25 Platelet(K/mL) 242(62–582) 183(114–227) 254(62–582) 0.026 Clinical
Oxygensupportdurationbeforetocilizumab(days) 2(0–13) 3.5(2–6) 2(0–13) 0.12 Durationfromonsetofsymptomstotocilizumab(days) 10(5–26) 9(7–13) 10(5–26) 0.41
Severecase 21(48.8) 0 21(56) 0.01
Intensivecareunitadmission 25(58) 6(100) 19(51.4) 0.02 Secondarybacterialinfection 9(21) 4(67) 5(13.5) 0.03
Pneumonia 6(14) 2(33) 4(11) 0.14
Bacteremia 5(12) 2(33) 3(8) 0.074
Discussion
ClinicalpresentationofCOVID-19variesfrommildsymptomsto ARDSanddeath.ThisstudyanalyzedTCZtreatmentin43severeand criticalpatientswithCOVID-19pneumonia.EarlieruseofTCZhad significantlybetteroutcomeswithlowICUadmissions,lowerduration ofoxygenrequirementandnofatality.Theadaptiveimmuneresponse playsacrucialroleinthiswiderangeofoutcomes(Fungetal.,2020).A largeamount ofcytokinereleaseexplainsthepathogenesisofdyspnea andARDSinCOVID-19afterthevirusbindstoalveolarepithelialcells. Asaresultofover-inflammation,vascularpermeabilityincreasesand thisleadstothealveolifillingwithamassiveamountoffluid(Zhang etal.,2020).IL-6playsasignificantroleincytokinestorm(Hunterand Jones,2015).TCZisananti-inflammatorydrugthathasthe potentialto decrease MAS-induced cytokine storm, and was shown to be beneficialin COVID-19 insome caseseries (Luo et al., 2020; Xu etal., 2020;Sciasciaetal., 2020)anda recentsystematicreview (AlzghariandAcuna,2020).ThecurrentstudyobservedthatIL-6was higherinfatalthansurvivedcases.IntheearlydaysoftheCOVID-19 pandemic,becauseoftheoff-labeluseandinsufficientdataonefficacy andsafetyofTCZ,itcouldnotbeusedintheearlystagesofthedisease; however,itwascommonlyusedinICU,wherethecasescouldbe intubated.Lateron,accesstothedrugbecameeasier,thenitwas startedearlierontheward.Afterthisnofatalcasesandverylowlevels ofICUadmissionswereobserved(Table2).
The critical decision for TCZ usewas the onset of cytokine storm. After cytokine storm had started, oxygen saturation
decreasedwithinhourstodaysbytheincreaseinlung involve-ment.Inflammationparameterssuchas%lymphocytes,IL-6,CRP, ferritin,andD-dimerwerecomparedbeforeandafter administra-tionofTCZ.Amongseverecases,the%lymphocytesincreasedin oneday,CRPdeclinedafteroneday,IL-6sharplydeclinedaftertwo days, and ferritinand D-Dimer slightly declinedafter two days
(Fig. 2). However, among the critical cases, IL-6 levels did not declineand%lymphocytesdidnotincrease(Fig.2).
Amongnineof22(41%)patientswhowereadmittedtotheICU, secondarybacterialinfectionsweredetected.Secondarybacterial infections could not be solely related to TCZ use. However, secondarybacterialandfungalinfections,includingtuberculosis, should be kept in mind. Patients whose QuantiFERON test is positive shouldbe evaluated for isoniazid prophylaxis (Cantini etal.,2017).
Onelimitationofthisstudyisthatitwasanobservational pre-poststudy.Duringthestudyperiod,TCZstartedbeingusedearlier inthelaterphasecomparedwiththeearlyphase.However,patient distribution in severe and critical groups (Table 1) enabled comparison of starting TCZ in severeorcritical patient groups. Inclinicalpracticethepatientsweregroupedaccordingtoclinical, radiologicalandlaboratorycriteria,andthecategorizationwasin parallel with Chinese guidelines, although this was not yet validated.Thereisnodoubtabouttheneedofrandomizedclinical studies for definite conclusions. Adverseevents related toTCZ, including secondary infections, should be detailed in further studies.
Table2
Comparisonofthepatientswhoweregiventocilizumabbasedontheseverityofcases.
TocilizumabinseverecasesN=21(%) TocilizumabincriticalcasesN=22(%) p
Meanage 61(sd:15) 66(sd:11) 0.198 Malegender 11(52) 20(91) 0.005 ConfirmedCOVID-19 17(81) 18(82) 0.9 Hypertension 9(43) 10(45) 0.864 Diabetesmellitus 7(33) 6(27) 0.665 Obesity 3(14) 2(9) 0.595
Chronicobstructivepulmonarydisease 2(10) 1(5) 0.522
Coronaryarterydisease 6(29) 2(9) 0.101
Laboratory(onthedayofTCZ)(median,min–max)
CRP(mg/L) 88(1–299) 233(25–380) 0.0029 Ferritin(ng/mL) 575(273–1991) 1884(250–52,765) 0.008 D-Dimer(mg/L) 870(360–2300) 1710(620–100,000) 0.002 IL-6(pg/mL) 115(18–942) 168(27–50,000) 0.025 ALT(U/L) 78(14–428) 58(17–1578) 0.796 AST(U/L) 58(27–129) 64(24–2045) 0.354 LDH(U/L)) 358(205–544) 381(197–5770) 0.183 Procalcitonin(ng/mL) 0.15(0.04–0.44) 0.38(0.07–100) 0.001 Leucocyte(K/mL) 6.38(2.25–9.6) 7.98(1.74–19.1) 0.96 Lymphocyte(%) 13.5(7–47) 11(3–26) 0.007 Platelet(K/mL) 242(62–582) 227(97–473) 0.52 Clinicalsupport
Oxygensupportdurationbeforetocilizumab(days) 1(0–7) 4(1–13) <0.001 Durationfromonsetofsymptomstotocilizumab(days) 9.5(5–18) 10(5–26) 0.76
Favipiravir 15(71) 19(86) 0.23
Hydroxychloroquine 18(86) 20(91) 0.6
Azithromycin 14(67) 11(50) 0.27
Lopinavir/Ritonavir 0 7(32) 0.005
Outcomes
Durationofoxygensupportaftertocilizumab 5(0–16) 12(6–30) <0.001 Lengthofstayaftertocilizumab(days) 7.5(2–21) 12(4–30) 0.028
Lengthofstay 12.5(6–32) 20(8–43) 0.009
Secondarybacterialinfection – 9(41) 0.001
Pneumonia – 6(27.3) 0.01
Corynebacteriumspp. – 4
Bacteremia – 5(22.7) 0.02
Fatal 0(0) 6(27) 0.01
Figure3.A59-year-oldwomanwithCovid-19.Samelevelofmid-axial(A,CandE)andmid-coronal(B,DandF)chestCTscansonadmission(A–B),onthedayoftocilizumab givenbecauseofrequirementofoxygensupportandprogressivelungimaging(C–D)and7daysafteronsetoftocilizumab(E–F),retrospectively.
A–B:Focalperipheralground-glassopacities.Theleftupperlobelesionswereaccompaniedbyconsolidationwithbronchiectasis. Figure2. Laboratoryparameters3daysbeforeandaftertocilizumabamongsevereandcriticalcases.
In conclusion, earlier useof TCZ in COVID-19 infectionwas beneficialfor survival,lengthofhospitalization and durationof oxygensupport.Thisrecommendationfor theadministrationof TCZwasbasedontheincreaseinrequirementofoxygensupport, progressionofthoracicCT,andelevationofinflammationmarkers includingIL-6,CRP,ferritin,D-dimer,anddecreasein%
lympho-cytes.Secondarybacterialinfectionsshouldbeborneinmindafter TCZuse.
Authorcontributions
Conceptualization:ŞK,BS,CÇ,ÖE Datacuration:ŞK,VOB,CÇ,ÖE Formalanalysis:ŞK,VOB,ÖE Investigation:ŞK,ÖE
Methodology:ŞK,MK,ST,CÇ,P_I,ÖE Projectadministration:ÖE
Supervision:ÖE
Visualization:AliPekşen.
Writing-review&editing:ŞK,ÖE Fundingsource
Nofundingwasreceived. Ethicalapproval
IRBofKoçUniversitySchoolofMedicineapprovedthestudy. Conflictofinterest
Noconflictofinterestwasreportedbytheauthors. Acknowledgement
Wethanktheadministratorsof hospitalmanagement,Erhan Bulutçu,ÖmürErçelen, _IsmailBozkurt,ErdalAksoy,andlaboratory manager Erhan Palaoglu. Weare thankful toAliPekşenfor his drawing.
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