Impact of dexamethasone on persistent symptoms of COVID-19: an observational study

Dexa met ha sone h as b een shown to r ed uce m or tal i t y for pa t i en t s ho spit alis ed w it h a cute CO VI D-1 9 pneum onia . How ever , a signi fic ant pro portion of p ati ent s suf fe r pe rsi sten t sym pt om s fol lowing CO VI D -19 and li ttl e i s k nown a bo ut t he l onger- te rm impac t of thi s in t e r v en tion o n symptom b u r de n .

P a t i e n t s i n i t i a l l y h o s p i t a l i s e d w i t h C O V I D - 1 9 w e r e p r o s p e c t i v e l y r e c r u i t e d t o a n o b s e r v a t i o n a l s t u d y (April -Augu s t 20 20) with follow -up a t 8 month s ( Dec 2020- April 2021) p os t-a dm ission . A revie w o f ongo ing symptom s u sing a s tand ardi sed sys t e m s-ba sed p rof orma wa s per fo r m e d alongsid e he al th - relat ed qu ality o f li fe a sse ssment . I n th e U K, pati ent s wi th C O VI D -19 (re quiring ox ygen ) only r ec eive d dex ametha so ne foll owi ng t h e pr e -pri nt o f the RE C OVERY t rial (J une 2 020), o r as pa r t o f randomi sati on t o t ha t t ri al , allo wing for a compa r i son b e t w een p a ti ent s t rea ted a nd not tre ated w i th dex ametha so ne.

Betwe en April to Augu st 2020 , 198 pa t i e nts w e re r ecruit ed t o t hi s ob serva tio nal s t u dy. 87 r e qui red oxy gen and we r e follow e d up at 8 - mo nths, so we re elig ible for thi s anal y s i s . O f t hes e 39 rec eive d an inpa t i en t cour s e of d ex ametha so ne (c a s e s ) a nd 48 di d not (c ontr ol s). Th e g r ou p s w ere we ll matc he d at ba s el in e in te rms o f ag e , co mor bi dity and fra ilty sco re . Over tw o - t hird s o f pati e nts rep ort ed a t lea s t 1 o ngoing s y mpt o m at 8 -month foll o w-up. Pa t i e nts in the dexa me tha son e gr oup repo rte d few er s ym pt o m s ( n=7 3, 1.9 p er pa tien t) t han the non -d exa metha son e group (n=1 52, 3.2 per pa tien t) (p = 0.01 ). Conc lus ions In c oncl us i on , in thi s ca s e -c on tr ol ob se r v ational study, pati ent s who r ec eive d ora l dex ametha son e for ho spi tali se d CO VI D-1 9 were le ss lik el y t o experie nce p e rsi ste nt s y mpt o m s a t 8-month follow -up . The se a r e re a ssuring re sult s for phy sicia n s a dmini st er i ng dex ame tha son e to t hi s patie n t group. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint

SARS -C o V-2 caus e s a w ide spec trum of di s e a se with a pr o p ortion o f pati ent s re qui ring hospi tali sa tion for pr ogre s s i ve re spi rat ory failu r e with a 20% mo r t ali t y ra te (1 ). M any s urv ivor s of t h e ac ute pha s e of i n f e c tion suf fe r f r om prol onged s y mptom s w hich ha s be en te rme d L ong C ovid or Po st - a cu te S equ ela e of CO VI D -19 (P ASC ) (2). A la r g e r andomi sed pl a t f o r m t ri al r u n in UK hospit al s throughou t th e pa ndemic demo ns tr a t e d that the ste r oi d , dex ameth a sone , reduc e d mortality in hospi tali se d pa t i ent s r ec eivi ng oxy gen (3 ) . Thi s re s ul t was pr e -prin ted in Jun e 202 0 a nd rapidly bec ame stand ard o f c are for all pati ent s hospi tali se d wi t h r e s pir ato ry fa ilu re (4 ). De spit e it s wi des p rea d u se , lit tle i s k nown a bout t h e impac t of dex ame tha son e on pr ol onged symptom s a fte r CO VI D -19 . In thi s pro sp ectiv e ca s e -c on tr ol s tudy , w e a ss e ssed t h e s y mp tom burden a nd qua li t y of lif e of patie n ts 8 mo nt h s po st ini tial ho s p i t a li sa tion wi t h C O V ID -19, c ompa ring indivi dua ls pr e- and po st t he initia t i on of d ex ametha s one a s ro utin e tr eatmen t. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint

Pati e nts adm i t t ed t o a single U K ho s pi ta l with CO VI D-19 pn eum onia w e re pro s p e c tivel y recruit ed t o an observ ati onal study ( fr om March to Oc t o ber 2020 ). Pati e nts we re iden tifi ed from t he D I S COVE R study , a singl e -cen tre p ro spectiv e st udy (Br i s tol , UK) recruiti ng cons ec ut i ve pa t i en t s (≥1 8yo ) a dmi t ted with CO VI D-1 9, full d e ta ils pu bli she d prev iou sly (5) . Ethic s a pp roval via S outh York shi re REC : 20/ Y H /0121 . The i nclu sio n c rit e r i a we re a posi tive P CR re sult for SA RS- Co V -2 or a clini co -radiol o g ical diag nos i s o f C OV ID -19 di sea s e. F or t he purpo s e s o f thi s sub - s tudy, pa tien t s with a n oxy gen requi reme nt d uring thei r a dmi ssion w er e iden t ifi e d and group ed ac cording to whet her d e xametha s o ne was pr e scribed du ring thei r admi s sion ( eit her a s pa rt of sta ndar d ca r e po st- June 1 6 th 2020 or when ran domi s e d to dex ame tha son e in t he RECO VERY trial ). Dura tion o f dex amet ha sone cou r s e wa s r ecorde d al ong s i de r o u t in e d emog r a phic a nd cl inica l informa tion . Pa tien t s who ha d recei ve d a cours e o f s t e roi d s i n the 2 w eek s pri or to admi s s ion or we r e on long - te rm s ter oid s were e xclu de d. Ful l de fini t io n s o f c linic al v ariabl e s a r e avai lable with th e initia l pap e r (5 ). All pa tie nt s w er e follow ed up at 8 -month s po s t ini t i al admi ssion , ei t h e r by phone or in a f a c e- to -f ace cl inic (acc ording to pa t i en t choic e ). A t fol low up, pa t i en t s c omplet ed a ‘Sho rt F o rm 3 6’ (SF - 3 6) qual ity of li fe qu e st i onn aire (6) w ith r evi ew of ong oing symp toms u sing a s t anda rdi s e d s y st ems - bas ed pro forma . Cat eg or i cal varia ble s w ere p re sen ted as cou nts w it h perc entag es. All c on t i nuou s data we re non - parame t ric and th er efo re pr e sen ted w ith media ns a nd int erqua rtile ran ge ( I QR ), u nles s o t he r w ise speci fi ed . Di f fer ence s be tw een pa t ie n t g roup s were ev alu at ed using Mann Whi tn ey -U a nd Kru s k al Walli s te s ts fo r c ontinuo us d ata a nd Fis h er’ s exac t t e s t or Chi - squar ed t es ting fo r c ategoric al d ata . Stati s tica l s i gnific anc e was t ake n a s p ≤ 0 . 05. Da ta w er e ana ly sed u sing R ver s io n 4.0.0 with th e pac kag es “tidyv er se” and “gtsummary” . . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint

Betwe en April to Augu st 2020 , 198 w er e recruit ed t o t hi s ob serva tio nal s t u dy. F r o m t hi s t otal , 87 requir ed ox yge n and w ere f ollow ed up a t 8-mon th s , s o w ere eli gible fo r thi s an a l ysis . Of th es e 39 rece ived an inp a t i e nt cour s e of 6mg of o ral dex ameth a sone onc e da ily ( c a se s) an d 48 d id not (con t r ol s) . Pa tien t s rece ived d exame t h a sone fo r 10 day s o r the du r a ti on of thei r hospi tal stay, whi chev er was shor t e r (me di an of 7 day s , I QR 4-9 ). Th e grou ps we re simil ar a t ba s eline in t erm s of ag e, co mor bi di ty, fr ailty s c o r e , a nd requ i r e ment for ven tila t i on during a dmi s s ion (bo t h non -inva siv e and mecha nica l ven t il ation ). H owev er, t h ere wer e mor e men in t he no d ex ametha son e g r o up (69% vs 56% ), and a high e r r a te o f prior chr oni c lung dis e a s e (29% v s 15%) in t h e n o dex ametha so ne group. T a bl e 1 : De mog r aph i c s Charac t e r i stics No Dexamethasone Group (N = 48) Dexa methas one G roup (N= 39) Age 60 (5 1,68) 60 (53,72) Male 33 (6 9%) 22 (56%) Fe male 15 (3 1%) 17 (44%) Diabe te s Ty pe 1 1 (2.1 %) 1 (2.6%) Diabe te s Ty pe 2 5 (10 %) 10 (26%) Hear t Di s e a se 7 (15 %) 10 (26%) Chronic Lung Di s e a s e 14 (2 9%) 6 (15%) Se vere Kidn ey Impa i rmen t 3 (6.2 %) 3 (7.9%) Hyperte nsi on 15 (3 1%) 8 (27%) Roc kwood s c ore 3 (2-4) 3 (2-4) Bas eline PCR Po sitive 36 (7 5%) 36 (92%) Non-i nva s iv e ve n t i la tion 8 (17 %) 8 (21%) Requi rem ent for ITU 6 (12 %) 4 (10%) Le ngth of Ho spi tal St ay 5 (3- 8 ) 7 (4-9) Mean dura tion (day s) o f Inpa t i e nt D e xame tha s on e The r a py (S D) N/ A 7 (4-9) P C R - P ol y m e r as e C hai n R ea ct i on , I TU - I nte ns ive C a r e U n i t , N/ A- no t ap p l i cab l e. Sy mptoma tolo gy Acro s s the t w o group s (n =87), 68% of p a tient s (n= 59 ) rep ort ed at l ea s t 1 ongoing s y mptom a t 8- month foll ow-up . F atigu e (4 4%), b rea thl e ssn e s s (38% ) and i n s omni a (29% ) wer e t he mo st fr eque ntly repor ted . . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint Fi gure 1 de pict s th e preva l ence o f ongoi ng symptom s at 8 month s in e ach o f t he two group s. A t otal of 225 s y mpt oms wer e rep ort ed ac ro ss t he co hor t . P atie nt s in th e dex ameth a son e g r ou p rep orte d signific antly fe wer symptom s (n =73, 1 .9 per pati e nt) th a n th e non- dex ameth a son e g r oup (n =152, 3.2 per pa t i e nt), p =0.01 ( K W Ch i -Squar e 6 .2 ). The l arge st di ff er e nc e s we r e s e e n in fa ti g ue (52 v s 3 3%, p=0. 07) a nd i n s omni a (39 v s 1 5%, p= 0.01 ). P a t i e nts in t h e dex amet ha sone gro up w ere more l ikely t o be a s y mp tomatic a t foll ow-up, although t hi s di d not me et sta ti s tic al signi f i canc e . (41% vs 25% , p=0.11) . Fig ur e 1: Sy mpt oms at 8 - month follow - up comparing dexame t ha s one g r o up (or an ge) to no dex amethas one group (green) Ment al an d phy s ic al c ompo sit e score s The mental a nd phy sic al c ompo s i t e s c ore s (M CS and PC S ) a t 8 mon t h s w er e extrac t e d f r om an swer s giv en to the S F -36 qu e stionna i re by b ot h groups. There w a s no signif ic ant di ff er e nc e in MCS or PCS betwe e n the g r o up s w it h a medi an PCS o f 43 (36 - 5 7 ) ver su s 4 9 (I QR 37-56 ) and median MCS of 33 (I QR 28 -44) v ersu s 37 ( I QR 30-44 ) for de x ametha s o ne and no d exame t h a sone gro ups re s pec tivel y, p>0.1 f or all c ompari s ons. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint Dis c us sion Cor tico ste roid s have be en shown t o impr ove sho rt t erm outcom e s in ho s pi t a li se d patien t s with ac ute C O V I D -19 pn eumonia . There i s li ttl e evide nce o f t h e ir impac t on long e r te rm symptoms follow ing re solu tion o f t h e acu te inf ectio n. This pr ospe ctive ca s e-co n t rol s tudy d e monstra te s tha t symptom burd en at 8 -mon th s was r educ e d in pa t i e nts w ho were give n a sho rt co urse of d e xa m e t h as on e in h os pi t al . S A R S- CoV - 2 i n fe c t i o n c a us es a wi d e s pe ct r u m o f dis e a s e i n a cut e a n d pos t -a c ut e i n f e c t io n. F or patie n ts ho spit ali sed w ith ac u t e C OVI D-1 9 pn eumonia t h e REC OVERY t rial h a s de monstra ted th a t a co ur s e of the o r a l cort ic oste roid de xame tha s one can s ig ni fica nt l y r educ e 28 -day mortali ty i n modera te t o sev ere ca ses . Thi s l e d to a s ea-c h ange in th e ma nageme n t of acute C O V ID -19 a nd ha s saved ap proxima te ly 1 million lives w or l d wide ( h ttp s: / /ww w.eng land .nh s. uk/202 1 / 03/c ovid - trea tmen t-d eve lop ed-i n- the -nh s -sav e s-a -mi llion -liv e s/). Howe ve r, st e r oi d s ha ve a n exten ded sid e ef fec t p r of il e eve n whe n giv en short -te r m. A sub -grou p ana ly sis o f th e REC OVER Y trial s ugg e sted that the be ne fit wa s re s t ric te d to pa tien t s re quiring oxyg en or alre a dy on a ventil a tor with th o se le s s seve rely af fec t e d ac tua lly ha r me d by a cour se o f dex ameth a sone . G iv en the po te n t n atu r e o f ste r oi d s i n thi s c ondition t he r e ar e many out s ta nd ing que sti on s tha t sh ould be ad dre ssed w ith urgenc y in cludin g the optimum t i ming, d o se a nd c ourse (7) . Ano the r a r e a o f unc e rt a in ty that w e hav e att empt ed to a dd re ss i s thei r impa c t of po s t - a cute s equal a e. Fol lowing the ac ut e pha se o f th e di s e a se a propor tion o f pa t i e nt s d o not re cove r f ul ly w ith pers i sten t symptom s la sting for many month s . This syndrome h a s be en term ed L ong Cov id o r Po st-a cu te Se quela e of COVI D -19 ( PAS C) and a l thou gh more l ikely to occ ur in the mo r e s ev er ely aff ect ed i n the ac ute pha s e is al so c ommon in patie nt s who di d not requi re ho spi tali sa tion (8 ). T he syndr ome i s hete roge nou s i n s y mptoma tology , but th e ma jor i t y of ho spi tali s ed pa t i ent s r epor t fatigue , brea thle s sne ss, my algia and i n s omn i a. T w o-t h irds p ati e nts r epor t ongoi ng sympt oms at l ea st 6 month s af ter h o spitali s ation w ith COVI D - 19 (2). The re ar e s eve r a l hypo the s e s on t he pathophy s i ology o f Long Covid inclu ding pe rsi st e n ce o f v irus , d evel opmen t o f aut o-immu ne di se a se or a p r oduc t of o rgan damage duri ng the a cute ph a s e . All mig ht be theo re tica lly aff ecte d by steroid use in e ith er po s i t i ve o r neg a tive dir e c tio n. Re a ssuri ngly , this ca s e-c o nt r ol study sugg ests that dex ametha so ne g iven in the ac u te pha s e of C OV ID -19 i s a ssoc iat ed with red uc ed l ong - t erm symptom s. It i s worth ex plo ring p ot e n t i al r ea son s fo r t hi s. F ir stly, t h e se r e sul t s coul d rep r e s e nt c onfo unding by indi cation, with p ati e nts r ece iving s t eroi ds mor e li kely to recov e r r e gar dle s s of t h e ster oid . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint pre scripti on. How eve r, in nea rly a ll publ i s he d data , pa t i ent s w ith mor e sever e d isea s e have more prolong ed symptom s a fte r C O V ID -19, so we woul d expe ct the bi a s to f a vour more symptom s in tho se on d ex ametha so ne. S ec ondly, d ex ame t ha s o ne u s e incr ea s ed du r i ng the pa ndemic , af ter the RECO VERY trial r e s ult s , and t h e r e for e m o st of the pa t i en t s i n the d ex ametha s one g r oup were recruit ed la ter t han th os e not on de xame t ha s on e . The re for e, th e redu c ed sympt oma t ol ogy c ould be due t o gen eral improvem en ts in c ar e tha t oc curred du ring t h e p ande mic w hich r e duce l ong term symptom s. Howev e r , t h ere is li ttle ev ide nce to s up port a re duction in long te r m symp t oms o f CO VI D -19 du ring the p andemic . Thi r dl y, t he re sul ts c oul d be due to pa t i ent s w ith more s ever e dise a se dy ing a nd th ere fore being unabl e t o be ap p r oa ch ed f o r fol l ow up. This i s by na t ure, di f ficult to ac count for , but a s de xame t ha s on e is known t o improve m or t ali t y , we would e xpec t the bia s t o arti fici ally increa s e l onger term symptom s in th e de xameth a sone gro up (by v irt u e of grea te r su rviva l of a mor e fra il popul a tion, w ho ar e kn own to ha ve more symp t om s a ft er C OV ID - 1 9). Fina lly, thi s as s o cia tion might b e caus al. Dex ameth a s one i s k nown t o i mpact o n th e s e veri ty of i nitial d i sea s e whi ch is direc tly c or r el a ted wi t h f u t u re s ymptom bur d en (8 ) and ca se -con trol stu dies o f SA RS -C o V- 2 va cci nation ha ve shown t ha t r e d ucing s e verity of i ni tial in fe ctio n thro ugh v acc inat ion r e duce s symptom s beyon d 28 da y s (9 ). The r e i s c urr e ntly lit tle publi sh ed re se arc h on t h e impac t o f steroid u s e on long te r m s y mpt o m s . An obs ervati ona l s tudy remo tely fo llowed u p hospi tali sed p a t i e nt s f rom th e 1 st and 2 nd pa nd emic wav es in I t a ly w ith a f oc us o n ta s t e a nd smell di stu rbanc e . They fou nd tha t pa t i ent s w ho rece ived ste roid s we r e le s s li kely to r epor t ongoing chemo sen s ory dis turb ance at 3 mon th s (10) . A mul t i cent re obs ervati ona l s tudy in th e UK, rec rui ted patien t s foll ow ing ho s pi tal di scharg e wit h an ass es s m e nt o f symptom s and qu ali ty of l i fe a t 5 m ont h s pos t disch arge . F rom 10 77 patie nt s di sc ha r g ed f rom 53 ce ntres b etw e en March a nd Novem be r 2020, the y foun d “ no as soci atio n b etwe en r e ceiv ing sys t e mic st eroid s duri ng adm ission a nd r ecov ery”, howev er, th ey di d not limit the analy s i s f or oxy gen r eq uiremen t during admi s s ion . Not do ing s o wil l hea vily bias t he a s s e ssme nt ag ain st s t eroid s as, follow ing t h e r e l ea se o f th e de xame tha s o ne re sult s f rom the RE CO VERY a naly si s in Jun e 2020, the ma jorit y o f pat ien ts o n ox yge n recei ved s ter oid s , prio r t o thi s d a t e U K their u se was r es t ric ted t o the REC O VE RY t ria l whic h inc luded all h o spit ali sed pa tien t s r eg a rdle s s o f d isea s e sev erity. By limiting our s t u dy to pa tie n ts rece iving oxy gen during their a dmi ssio n we have reduc e d t he impa ct o f co nfounding by indi cati on. This study ha s w eakn e ss t hat r educ e the gen er a li sa bility of i t s fi nding s . Fir stly, it i s a r e lativel y small sampl e s iz e, bu t thi s ha s al lowed f o r d e t a iled da ta to be c oll ec ted wi t h minimal d a ta at tri tion. In addi t i on , the a na lysi s i s limit ed to pa t i en ts w ho r equir ed ox yge n during thei r in pa tient s tay a nd ar e ther ef ore qui te sev e r e ly c ompromi sed . The RECOVE RY dex ame tha son e trial show ed a tr end tow a rd s . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint harm in hosp it a li s ed pati en ts no t re quiri ng oxyg en and this analy s i s should no t b e use d to ju st i fy ste r oi d u se in outp atie n ts wi t h acut e C OVI D-19 o r tho s e with e s ta bl i s he d pe r s i ste nt sympt oms. In c oncl us i on , in thi s ca s e -c on tr ol ob se r v ational study patie nt s who rec eived oral dex ametha so ne f or hospi tali se d CO VI D -19 we r e l es s li kely t o expe r i ence p er s i st ent s y mptom s a t 8-mo nth foll ow -up . The se w ill b e rea s s uri ng r e sult s for phy si cia ns admini s tering d ex ametha so ne t o thi s pa t i en t group. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.17.21266392doi: medRxiv preprint

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