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W Arlt and others 183:1 G25–G32 Clinical Practice management during COVID-19 Guidance

ENDOCRINOLOGY IN THE TIME OF COVID-19 Management of adrenal insufficiency

Wiebke Arlt1,2, Stephanie E Baldeweg3,4, Simon H S Pearce5,6 and Helen L Simpson3,7

1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK, 2Department of , Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK, 3Department of Diabetes and Endocrinology, University College London Hospitals NHS Foundation Trust, London, UK, 4Department of Medicine, University College London, London, UK, 5Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK, 6Department of Endocrinology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, and 7Genetics and Genomic Medicine, University College London Great Ormond Street Institute for Child Health, London, UK

This manuscript is part of a commissioned series of urgent clinical guidance documents on the management of endocrine conditions in the time of COVID-19. This clinical guidance document underwent expedited open peer Correspondence review by Stefanie Hahner (Universitätsklinikum Würzburg, Würzburg, Germany), Ad R M M Hermus (University should be addressed Medical Centre, Nijmegen, The Netherlands), Andrea Isidori (Sapienza University of Rome, Rome, Italy), and Jeremy to W Arlt W Tomlinson (Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK) Email [email protected]

Abstract

We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high , we suggest oral stress dose cover with 20 mg every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency European Journal of Endocrinology showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.

European Journal of Endocrinology (2020) 183, G25–G32

Introductory remarks

This guidance has been drawn up to inform clinicians to autoimmune , that is, Addison’s disease and healthcare staff in their quest to provide guidance described by the eponymous Thomas Addison, or on the optimal management of patients with adrenal other causes including congenital adrenal hyperplasia, insufficiency under the circumstances of an acute global bilateral adrenalectomy and adrenoleukodystrophy. The healthcare capacity crisis due to COVID-19, the viral overwhelming majority of PAI patients suffer from both illness caused by the novel corona virus SARS-CoV-2. glucocorticoid and mineralocorticoid deficiency. Our For the purposes of this guidance, we define guidance similarly applies to patients with secondary primary adrenal insufficiency (PAI) as all patients with adrenal insufficiency (SAI) due to hypothalamic or loss of function of the adrenal itself, mostly either due pituitary disease; these patients typically suffer from

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-20-0361 European Journal of Endocrinology https://eje.bioscientifica.com • • COVID-19. severe courseofdiseaseinpatientswithAIfallingill evidence, however, suggestive of a higher likelihoodofa to betriggeredbytheinfection.Thereiscurrentlyno complications duetothepotentialforanadrenalcrisis catching thisinfectionandtheyhaveahigherriskof risk ofCOVID-19;theyareatanincreased Yes, patientswithadrenalinsufficiencyareatincreased an increasedriskofCOVID-19? Are patientswithadrenalinsufficiencyat than 4weeks. equivalent dosesofgreaterthan5mgdailyforlonger insufficiency arethosetreatedwithprednisolone- adrenal other conditions.Patientsatriskoftertiary exogenous glucocorticoidtherapyfortreatmentof adrenalinsufficiencyduetochronic with tertiary Similarly, rules apply to patients the same precautionary axes. with deficiencyofotherhypothalamic-pituitary glucocorticoid deficiency, inthemajoritycombination • • Clinical PracticeGuidance another conditionareateven higherriskofinfection. of exogenous for the treatment of receiving supraphysiologic, immunosuppressive doses an increasedriskofinfection withCOVID-19.Patients Therefore, patientswithPAI canbeassumed tobeat innate immunesysteminfightingviralinfections. cell cytotoxicity( shown to have significantly decreased natural killer PAI ( in patientswith to theincreasedmortalityobserved infectionshavebeenshowntocontribute respiratory disease( hypothalamic-pituitary has alsobeenshownforpatientswithSAIdueto be atanincreasedriskofinfections( congenital adrenalhyperplasiahavebeenshownto Patients withPAI includingAddison’s diseaseand Increased riskofinfectionsinadrenal insufficiency: patients. increasedmortalityinthese contribute totheobserved inpatientswithPAIobserved andSAI( the adrenal crisis ( replacement topreventand,ifalreadyinprogress,treat administration ofincreaseddosesglucocorticoid major stress,suchasanacuteillness.Thisrequires life-threatening adrenal crisis if experiencing adrenal insufficiencyareatrisktodevelopapotentially Risk ofadrenal crisisduringacuteillness: 12 , 13 ). Inaddition,patientswithPAI havebeen 14 1 , ), animportantfunctionofthe 2 , 3 ). Adrenal crises are regularly W Arltandothers 11 ). Furthermore, 8 4 Patientswith , , 5 9 , , 6 10 , 7 ); this ) and

• Educate Equip andEmpower). the 3Eframeworkforself-managementsupport(Educate, or videoconferencing, as appropriate.Thisshouldfollow communicated bymailshot,video,text,emailphonecall safely. Self-management support can be facilitated and enable themtomanagetheirconditionsadequatelyand be providedwithadequateself-managementsupportto All patientswithestablishedadrenalinsufficiencyshould A. Preventionmode adrenal insufficiency? established diagnosisof How shouldwemanagepatientswithan • management duringCOVID-19 Adrenal insufficiency • • that is,theneedtoincreasetheirusualglucocorticoid carers) areeducatedintheuseof‘thesickdayrules’, Ensure that all patients (and their families/partners/ adjust workingconditionsas appropriate. fact toensuretheiremployers areinformedandcan important toprovidepatients withlettersstatingthis workers, carers and supermarket cashier staff. It will be distance, asisthecase,for example,forhealthcare situations thatdonowallowthemtokeeptheirsafe that adrenalinsufficiencypatientsshouldnotworkin stringentsocialdistancingatalltimes. Thismeans very work fromhomeorunderconditionsthatallow distancing’. Iftheyareworking,shouldeither stringent social adrenal insufficiencyshould‘observe potent immunosuppressivedrugs.Allpatientswith undergoing cancertreatmentortakinghighdosesof risk ofCOVID-19,albeitnotashighinpatients Patients withadrenalinsufficiencyareatincreased section B). fever oversustainedperiodsoftime(see 19 infection,whichfrequentlypresentswithhigh rules, havinginmindpatientswithanacuteCOVID- of thisguidance,wehaverevisedthegenericsickday Endo-ERN-approved.pdf Stressinstructie-addisoncrisis-hydrocortison-ENG- endo-ern.eu/wp-content/uploads/2019/03/20190312- published clinicalguidelines( adrenal insufficiencyaredescribedindetailrecently trauma. Generalsickdayrulesforpatientswith and/or thepresenceofsevereandmajorillnessor be reliablyabsorbedduetovomitingordiarrhoea medical assistancewhentheoralmedicationcannot need toself-injecthydrocortisoneandcallforemergency replacement dose during intercurrent illness and the Downloaded fromBioscientifica.com at09/28/202112:14:12PM . However, forthepurposes 15 , 16 183 , 17 :1 ); seealso Table 1 https:// G26 and via freeaccess European Journal of Endocrinology • Equip Recovery; improvingrespiratoryfunction,reducingornormal On regularwardorintensivecareward,irrespectiveof At hospital Onset ofsignsandsymptoms‘clinicaldeterioration’ Onset of‘signsandsymptomssuggestiveCOVID-19’(fever At home Clinical scenario confirmed COVID-19infection. Table 1

Clinical PracticeGuidance example, byprescribingan extra4-weeksupplyof regular oralhydrocortisone foremergencyuse, have asufficientsupply ofimmediaterelease, take modifiedreleasehydrocortisone preparations prednisone). Ensurethatpatientswhousually but alsocortisoneacetate,prednisoloneor glucocorticoid preparations’(usuallyhydrocortisone, Ensure thatthepatienthas‘sufficientsuppliesoforal temperature ventilated positive airwaypressure(CPAP)respirationormechanically whether breathingunaidedorsupportedbycontinuous speaking shortness ofbreath,respiratoryrate confusion, lethargy;;severediarrhoea;increasing (dizziness; intensethirst;shakinguncontrollably;drowsiness, loss ofsensesmellortaste,achesandpains,fatigue) > 38 ° C ( Suggested managementandhydrocortisonestressdosecoverinpatientswithadrenalinsufficiencysuspectedor > 100 F),aneworcontinuousdrycough,sorethroat, W Arltandothers > 24/min, difficulty • • • • • • • • Suggested management • • • • • • • • • • • • • • • • • • • • • • • management duringCOVID-19 Adrenal insufficiency 50 mginschoolchildren) per i.m.injectioninadultsandadolescents(25mginfants, Immediately inject(patientorcarer)100mghydrocortisone Request medicaladviceonthesuspectedCOVID-19infection urine looksistoguidefurtherfluidintake Rest, drinkregularlyandmonitorhowconcentrated(dark) appropriately forinfantsandchildren) Take paracetamol1000mgevery6hforfever(adjustdose If onfludrocortisone,continueatusualdose equal dosesofatleast10mgeach mg shouldcontinuetheirusualdosebuttakeitsplitintotwo prednisolone every12h;patientsonoral Patients on5–15mgprednisolonedailyshouldtake10 every 6h to immediatereleasehydrocortisoneandtake20mgorally Patients onmodifiedreleasehydrocortisoneshouldswitch doses every6h) trebled (i.e.3-foldincrease)andadministeredinfourequal orally every6h(inchildren,theirusualdailydoseshouldbe Adults andadolescentsshouldtake20mghydrocortisone hydrocortisone dose Re-start usualfludrocortisonedoseinadultswhentotaldaily (endocrinologist toadvise) double regularreplacementdoseattimeofdischarge Gradual taperingofstressdosehydrocortisonedownto regularly checkureaandelectrolytes Continuous i.v.fluidresuscitationwithisotonicsaline; Pause fludrocortisoneinadults infants and100mg/24hinchildren infants and50mginchildren)followedbymg/24h injection of50mghydrocortisone/m Infants andchildrenshouldreceiveaninitialparenteral i.m. bolusinjection) hydrocortisone/24 h(alternatively50mgevery6peri.v.or adolescents, followedbycontinuousivinfusionof200mg Hydrocortisone 100mgperivinjectioninadultsand isotonic salineinfusionintheadmissionsunit if possible,theyshouldreceivei.v.hydrocortisoneandan should take50mghydrocortisoneevery6horallyathome; If patientscannotbetakenorkeptinhospital,thenthey hospital transfer tohospital,considermakingtheirownway Call foremergencymedicalattentiontreatmentand taking theirglucocorticoid replacementunderall Patients shouldunderstand thattheymustcontinue glucocorticoid dosesincase ofintercurrent illness. ensure thatthepatienthas accesstosufficientextra arrange forthemtobedispensedbymail;thiswill 2monthsand 3-month hydrocortisonesuppliesevery (fludrocortisone). Considerissuingprescriptionsof also ensuresufficientmineralocorticoidsupplies with PAI including congenital adrenal hyperplasia hydrocortisone 10mgthreetimesdaily. In patients < 50 mg Downloaded fromBioscientifica.com at09/28/202112:14:12PM https://eje.bioscientifica.com 2 (usually25mgin 183 :1 G27 > 15 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com (downloadable at Steroid emergencycardforpatients withadrenalinsufficiencyissuedbytheUKNational Health ServiceinMarch2020 Figure 1 • Empower • • • Clinical PracticeGuidance endocrinology.org/adrenal-crisis) a patient suffering from adrenal crisis ( website withdetailedinstructionsonhowtomanage includes a QR code that guides healthcare staff to a media/3563/new-nhs-emergency-steroid-card.pdf is downloadableat ( developed bytheEuropeanSocietyofEndocrinology proposed by a Swedishgroup ( card, developedfurtherfromaversionoriginally 1 stress situationthatpreventsself-management. healthcare staffonhowtotreatthepatientinamajor emergency card’orequivalentwritteninstructionsfor Ensure thatallpatientsareinpossessionofa‘steroid crisis the-emergency-injection-for-the-treatment-of-adrenal- training videos ( the procedure over the phone and providing links to Consider refreshingknowledge by talkingthrough is confidentinself-administrationoftheinjection. and thatthepatientarelative/partner/friend date hydrocortisoneemergencyself-injectionkit’ Ensure thatthepatientisinpossessionofan‘up-to- the doseunlesstheyfallill. circumstances and that there is no need to increase https://adrenals.eu/emergency-card/) showstherecentlyissuedUKversionofsteroid and https://www.adrenals.eu/animations/how) https://www.endocrinology.org/media/3563/new-nhs-emergency-steroid-card.pdf https://www.addisonsdisease.org.uk/ https://www.endocrinology.org/ W Arltandothers . 18 . TheUKversion ) and further https://www. Figure and . • 19 infection B. AcutesuspectedorconfirmedCOVID- management duringCOVID-19 Adrenal insufficiency • They shouldmonitorhowmuchurinetheypass;the night, ideally noting the amount of fluid they drink. well hydratedbydrinkingregularly, evenduringthe tokeep dose adjustmentinchildren).Theyshouldtry 6h(withappropriate mg dosesofparacetamolevery should restandcounteractthefeverbytaking1000 recommended forallaffectedbyCOVID-19,patients 19/ online coronavirusservice 19 infection,eitherovertheinternet(e.g.UK management oftheirsuspectedorconfirmedCOVID- like anyotherpatientmedicaladviceregardingthe and pains,and/orseverefatigue),theyshouldseek sore throat,lossofsensesmellortaste,aches > and symptomssuggestiveofCOVID-19’(e.g.fever ‘If apatientwithadrenalinsufficiencydevelopssigns daily doseshouldbetrebledandadministeredorally h, 1800hand2400( 6 h, for example, at 0600 h, 1200 hydrocortisone every replacement to20 mg four times daily’,thatis,20mg morning doseandthenincreasetheirhydrocortisone should also‘immediatelytakeadoublehydrocortisone an acutesuspectedorconfirmedCOVID-19infection prompt furtherincreasedoralfluidintake. urine indicatesinsufficienthydration,whichshould excretion ofonlylittleamountsdark,concentrated 38 Importantly, patientswithadrenalinsufficiencyand ) orbyaphonecalltotheirgeneralpractitioner. As ° C (or > 100 F), a new or continuous dry cough, 100 F), a new or continuous dry Downloaded fromBioscientifica.com at09/28/202112:14:12PM Table 1 ). https://111.nhs.uk/covid- ). Inchildren,theirusual 183 :1 G28 via freeaccess European Journal of Endocrinology • • Clinical PracticeGuidance indicating clinical deterioration in patients affected by 6h.‘Signsandsymptoms mg hydrocortisoneevery their ownwaytohospital and continuetotake50 patients and their carers should consider making toarrive.Ifneedbe, for medicalemergencyservices mg hydrocortisoneorally, ifpossible,while waiting the injection,theyshouldimmediatelytake50–100 (100 mg i.m.)’.If for any reason they cannot administer administer theirhydrocortisoneemergencyinjection withoutdelayandimmediately emergency services Patients (ortheircarers)should‘contactmedical and symptomsofCOVID-19significantlyworsen’. ‘iftheclinical signs contact medical emergencyservices, Under nocircumstances shouldpatientshesitateto COVID-19 ( infectionsuchas an acuteandhighlyinflammatory prolonged periodsofglucocorticoiddeficiencyduring regular glucocorticoiddosecouldleavepatientswith modelling indicates that the meredoubling of the on oralhydrocortisonepharmacokinetics( Crisis inStress(PACS) study( experimental datafromthePreventionofAdrenal ( hydrocortisone delivery suggested dosesonathree-compartmentmodeloforal cover throughoutdayandnight.We havebasedour in ourviewrequiresamoreevenlyspacedglucocorticoid inflammation andoftencontinuoushighfever, which is associatedwithsignificantandpersistentacute of theauthorsisthatanacuteCOVID-19infection intercurrent illness ( the regular glucocorticoid replacement dose during not needtoincreasetheirroutinereplacementdose. 19 positive,forexample,duetofamilyscreening,do recovered. AsymptomaticpatientswhotestedCOVID- regimen andthennormalroutinedosesoncefully tapered backtodoubledoseoftheroutinereplacement oral administrationof20mghydrocortisonecanbe to showsignificantclinicalimprovement,the6-honce time. Oncethepatientnolongerhasfeverandstarts morning andlateafternoondoseofatleast10mgeach their usualdailyprednisolonedosebutsplititintoa prednisolone doses 12h;patientsondaily 10 mgprednisoloneevery doses of5–15mgdailyshouldimmediatelytake 6h.Patientsonprednisolone hydrocortisone every should switchtotaking20mgimmediaterelease take modifiedreleasehydrocortisonepreparations 6h.Patientswhonormally in fourequaldosesevery While guidelinesusuallyrecommenddoublingof Fig. 2 ). 15 > 15 mgshouldcontinuetotake , 16 , 19 17 ) ( ), the personal experience 20 W Arltandothers Fig. 2 ) andapreviousstudy ), drawing from 21 ). This approach see( hydrocortisone cover.Fordetailsontheemployedmodelling results inalongstretchoftimewithoutappropriate increasing hydrocortisoneattheusualadministrationtimes administration ensuressteadydeliveryofcortisol,while evenly spaced,6-hintervals.Thisillustratesthattheonce respectively) and(B)oraladministrationoffourequaldosesin hydrocortisone regimens(twoandthreedailydoses, doses administeredattheusualtimesoftwotypicalroutine model after(A)doublingofimmediatereleasehydrocortisone of circulatingcortisolconcentrationsinathree-compartment timing anddosing.Predictionbasedonparameterestimates Prediction of24-horalhydrocortisonedeliverydependenton Figure 2 management duringCOVID-19 Adrenal insufficiency of thefirstCOVID-associatedsymptoms,include: COVID-19’, whichtypicallyoccur7–10daysafteronset ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ becoming drowsy, confused ordifficulttowakeup shaking uncontrollably cold feeling very thirsty despitedrinkingregularly feeling very dizzy onsittingorstanding feeling very 19 ); figurereproducedwithpermission. Downloaded fromBioscientifica.com at09/28/202112:14:12PM https://eje.bioscientifica.com 183 :1 G29 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com • • • • • • Clinical PracticeGuidance clinical improvementcanbe undertaken( further replacement doseinlinewith theobserved occurred. Then,gradualtapering oftheglucocorticoid required andsignificant clinical improvementhas (200 mg/24h)untilmechanical ventilationisnolonger be interrupted,butcontinuedatamajorstressdose ARDS, their glucocorticoid replacement should never insufficiency patientsdevelopCOVID-19-related doses tocovermajorstress.Therefore,ifadrenal but asalife-saving replacement therapy in adequate glucocorticoids notasapharmacologicaltreatment, However, patients withadrenalinsufficiencyreceive an effectivetherapyforCOVID-19relatedARDS. whether highdoseglucocorticoid treatment is the ongoing RECOVERY trial in the United Kingdom) unit ( 19 infectionrequiringtreatmentinanintensivecare inpatientswithCOVID- (ARDS) isfrequentlyobserved distresssyndrome ventilation: Acuterespiratory Patients withCOVID-19requiringmechanical treated withadultdoses. 6h.Adolescentsshouldbe administered dosesevery infusion, alternatively, splitinfourequalparenterally h forschoolchildren,preferablybycontinuousi.v. administration of 50 mg/24 h for infants and 100 mg/24 children) ( (usually 25mgforinfants,50school parenteral injection of 50–100mg/m adrenal insufficiency should receive an immediate 19 infectionwithclinicaldeterioration,children by COVID-19.However, incaseofanacuteCOVID- ‘Children’ are much less frequently severely affected patients withadrenalinsufficiency. and fluidresuscitationarecruciallyimportantfor administration ofhydrocortisoneinmajorstressdose resuscitation withi.v. isotonicsaline.Bothcontinuous 6h.Patientsshouldreceivegenerousfluid every could beadministeredviai.v. ori.m.bolusinjection ( intermittent troughsincortisollevelsareavoided via continuousi.v. infusion’,whichensuresthat 24 h,preferably in thehospitalsetting administered ‘major stressdosehydrocortisone,thatis,200mgover personnel, thepatientsshouldbemaintainedon hydrocortisone by self-injectionormedicalemergency Following emergencyinjectionof100mg ⚬ ⚬ Fig. 3 ⚬ ⚬ in completesentences. rate (respiratory increasing shortnessofbreathwithfastbreathing developing vomitingorseverediarrhoea 22 ) ( , 23 20 16 ). Itisamatterofdebate(andsubject ). Alternatively, 50mghydrocortisone ). Thisshould be followedbyparenteral > 24/min) ordifficulty speaking W Arltandothers 2 hydrocortisone Table 1 ). with permission. hydrocortisone/24 h.Figuremodifiedafter( injection, eachfollowedbyCIVinfusionof200mg concentrations after50mg(E)and100(F)i.v.bolus administration, topredictexpectedserumcortisol mass spectrometryafteri.v.IVIandCIVhydrocortisone modelling, basedonserumcortisolmeasurementsbytandem (shaded greyarea).(PanelsEandF)Linearpharmacokinetic (CIV). Dataarepresentedasmedian(blackline)andrange via continuousi.v.hydrocortisoneinfusionof200mg/24h injection every6h(IM),50mgperi.v.bolus(IVI)and modes: 50mgorallyevery6h(ORAL),peri.m.bolus 200 mghydrocortisone/24hinfourdifferentadministration underwent frequentserumsamplingafteradministrationof insufficiency whopausedtheirregularreplacementand otherwise healthy,unstressedadultpatientswithadrenal (Panels A,B,CandD)Serumtotalcortisol(nmol/L)inten Figure 3 • management duringCOVID-19 Adrenal insufficiency • guidance onmanaging‘type 1andtype2diabetes are morepronetodiabetic ketoacidosis.Arecent significantly increasedinsulin requirements,and quickly struggletomaintain glycaemiccontrol,with is that diabeticpatients affected by COVID-19 patients withPAI ( Co-incident type1diabetesisfoundinaround10%of 24 Downloaded fromBioscientifica.com at09/28/202112:14:12PM , 25 , 26 ). Theclinicalexperience 183 20 :1 ); reproduced G30 via freeaccess European Journal of Endocrinology • • • insufficiency duringtheCOVID-19crisis C. Regularmonitoringofpatientswithadrenal • • • Clinical PracticeGuidance teleconferencing. taking anddiscussionscan easilytakeplacevia evaluation( require laboratory and abilitytocopewithdaily stressanddoesnot monitored basedonthepatient’s clinicalperformance Routine glucocorticoidreplacement therapy is blood testisconsideredurgent. locations awayfromhospitalsthatcanbeusedifa have establishedbloodlettingcentresinconvenient contacting medicalstaff).Manyhealthcarecentres and wellpatientstoremeasureafter1hbefore blood pressure (such as resting heart rate contact theirspecialistcareteamforfurtheradvice rate andbeadvisedwhichreadingsshouldpromptto patients shouldalsobetaughthowtotaketheirheart standing upforaminute,shouldbeencouraged; after sittingforatleast5minandthenagain up. Bloodpressureself-measurement,forexample, of ,suchasdizzinesswhenstanding forpatientswithclinicalsigns should bereserved but duringtheCOVID-19crisisbloodchecks ensure adequacyof mineralocorticoid replacement, annual checksofelectrolytesandplasmareninto Patients onstablereplacementusuallyundergo undertaken bytelephoneorvideoconferencing. during theCOVID-19crisis,thesereviewscouldbe of6–12months;undergo follow-upreviewinintervals healthcare facilities.Thesepatientswouldnormally periods, whichmaycomewithrestrictedaccessto monitored duringprolongedCOVID-19lock-down steroid replacementshouldcontinuetoberegularly with established adrenal insufficiency on routine We healthypatients recommendthatotherwise COVID-19 ( impacts adverselyontype2diabetespatientswith evidence tojudgewhetheruseofDPP4inhibitors inhibitors, thereiscurrentlyinsufficientscientific entry, similartoACE2( acts asareceptorforsubsetsetofcoronavirusescell 2 diabeteswithanacuteCOVID-19infection.DPP4 peptidase-4 (DPP4)inhibitorsinpatientswithtype front-door-guidance) concise-advice-inpatient-diabetes-during-covid19- in COVID-19patients’( 28 ). < 100 mmHg; otherwise healthy 100 mmHg;otherwise , advisesstoppingDipeptidyl 27 ); however, justlikeforACE https://abcd.care/resource/ W Arltandothers > 100/min and systolic 29 ), thus history ), thushistory

the public,commercialornot-for-profitsector. This guidance did not receive any specific grant from any funding agency in Funding which sheislistedasanauthor.Theotherauthorshavenothingdisclose. on paper, this for process editorial or review the in involved not was A W Wiebke Arlt is the Editor-in-Chief of the European Journal of Endocrinology. Declaration ofinterest specific patient. circumstances whendevisingthemanagementplanfora medical care.Healthcarestaffneedtoconsiderindividual is notintendedtodetermineanabsolutestandardof document shouldbeconsideredasguidanceonly;it or meta-analysis,butonrapidexpertconsensus.The document isnotbasedonextensivesystematicreview Due totheemergingnatureofCOVID-19crisis,this Disclaimer References review andhighlyusefulcomments. informal their for UK, Group Self-Help Disease Addison’s Smith, Vick and UK, Birmingham, Trust, Foundation NHS Birmingham Hospitals University Shepherd, Lisa and Feliciano Chona Criseno, Sherwin Asia, Miriam nurses specialist endocrine UK, Birmingham, of University Prete, Alessandro Dr and Karavitaki Niki Dr UK, Sheffield, of University Ross, J Richard Prof to in doses replacement glucocorticoid patients with adrenal insufficiency and COVID-19. The authors are grateful oral suggested on decisions our informing modelling, mathematical of delivery rapid for UK, Birmingham, The authors thank Prof David J Smith, School of Mathematics, University of Acknowledgements management duringCOVID-19 Adrenal insufficiency 6 5 4 3 2 1 Reisch N, Willige M, Kohn D,Schwarz HP, Allolio B,Reincke M, White K &Arlt W. AdrenalcrisisintreatedAddison’s disease: Hahner S, Loeffler M,Bleicken B,Drechsler C,Milovanovic D, Wass JA &Arlt W. Howtoavoidprecipitating anacuteadrenalcrisis. Arlt W &SocietyforEndocrinologyClinicalCommittee. Allolio B. Extensiveexpertiseinendocrinology:adrenalcrisis. doi.org/10.1530/EJE-12-0161) deficiency. of adrenalcrisesoverlifetimeinpatients with21-hydroxylase Quinkler M, Hahner S&Beuschlein F. Frequencyandcauses 0559) Endocrinology a predictablebutunder-managedevent. 597–602. prevention strategies. adrenal crisisinchronicinsufficiency:theneedfornew Fassnacht M, Ventz M, Quinkler M&Allolio B.Epidemiologyof BMJ org/10.1530/EC-16-0054) adult patients. management ofacuteadrenalinsufficiency(adrenalcrisis)in for EndocrinologyEndocrineEmergencyGuidance:emergency org/10.1530/EJE-14-0824) ofEndocrinology European Journal 2012 (https://doi.org/10.1530/EJE-09-0884) 345 European Journal ofEndocrinology European Journal 2010 e6333. Endocrine Connections 162 (https://doi.org/10.1136/bmj.e6333) European Journal ofEndocrinology European Journal 115–120. Downloaded fromBioscientifica.com at09/28/202112:14:12PM 2015 (https://doi.org/10.1530/EJE-09- 2016 https://eje.bioscientifica.com 172 European Journal of European Journal R115–R124. 5 183 2012 G1–G3. :1 167 (https://doi. 35–42. 2010 (https://doi. 162 (https:// G31 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com

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Accepted 20April2020 Received 13April2020

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