Pulmonary long-term consequences of COVID-19 infections after hospital discharge

Jou nal P e-p oo Pulmona y long- e m consequences o COVID-19 in ec ions a e hospi al discha ge J.R. Blanco, M.J. Cobos-Ceballos, F. Na a o, I. Sanjoaquin, F. A naiz de las Re illas, E. Be nal, L. Buzon-Ma in, M. Vi ibay, L. Rome o, S. Espejo-Pé ez, B. Valencia, D. Ibañez, D. Fe e -Pa gada, D. Malia, F.G. Gu ie ez-He e o, J. Olalla, B. Ju ado-Gamez, J. Ugedo PII: S1198-743X(21)00101-4 DOI: h ps://doi.o g/10.1016/j.cmi.2021.02.019 Re e ence: CMI 2434 To appea in: Clinical Mic obiology and In ec ion Recei ed Da e: 11 No embe 2020 Re ised Da e: 9 Feb ua y 2021 Accep ed Da e: 18 Feb ua y 2021 Please ci e his a icle as: Blanco J, Cobos-Ceballos M, Na a o F, Sanjoaquin I, A naiz de las Re illas F, Be nal E, Buzon-Ma in L, Vi ibay M, Rome o L, Espejo-Pé ez S, Valencia B, Ibañez D, Fe e - Pa gada D, Malia D, Gu ie ez-He e o F, Olalla J, Ju ado-Gamez B, Ugedo J, Pulmona y long- e m consequences o COVID-19 in ec ions a e hospi al discha ge, Clinical Mic obiology and In ec ion, h ps://doi.o g/10.1016/j.cmi.2021.02.019. This is a PDF ile o an a icle ha has unde gone enhancemen s a e accep ance, such as he addi ion o a co e page and me ada a, and o ma ing o eadabili y, bu i is no ye he de ini i e e sion o eco d. This e sion will unde go addi ional copyedi ing, ypese ing and e iew be o e i is published in i s inal o m, bu we a e p o iding his e sion o gi e ea ly isibili y o he a icle. Please no e ha , du ing he p oduc ion p ocess, e o s may be disco e ed which could a ec he con en , and all legal disclaime s ha apply o he jou nal pe ain. © 2021 Eu opean Socie y o Clinical Mic obiology and In ec ious Diseases. Published by Else ie L d. All igh s ese ed. Ti le: Pulmona y long- e m consequences o COVID-19 in ec ions a e hospi al discha ge AUTHORS: JR. Blanco 1,2 MJ. Cobos-Ceballos 3,4 F. Na a o 5 I. Sanjoaquin 6 F. A naiz de las Re illas 7 E. Be nal 8 L. Buzon-Ma in 9 M. Vi ibay 10 L. Rome o 2 S. Espejo-Pé ez 3,11 B. Valencia 12 D. Ibañez 13 D. Fe e -Pa gada 14 D. Malia 15 FG. Gu ie ez-He e o 16 J. Olalla 5 B. Ju ado-Gamez 3,4 J. Ugedo 17 Jou nal P e-p oo 1. Se icio de En e medades In ecciosas. Hospi al Uni e si a io San Ped o, Log oño, La Rioja, SPAIN. 2. Cen o de In es igación Biomédica de La Rioja, Log oño, La Rioja, SPAIN 3. Ins i u o Maimónides de In es igación Biomédica de Có doba. Uni e sidad de Có doba. SPAIN 4. Se icio de Neumología. Hospi al Uni e si a io Reina So ía, Có doba. SPAIN 5. Se icio de Medicina In e na. Hospi al Cos al de Sol, Ma bella. Málaga. SPAIN 6. Se icio de En e medades In ecciosas. HCU Lozano Blesa, Za agoza. SPAIN 7. Se icio de En e medades In ecciosas. H Uni e si a io Ma qués de Valdecilla, San ande . SPAIN 8. Sección de En e medades In ecciosas. Hospi al Gene al Uni e si a io Reina So ía de Mu cia. Uni e sidad de Mu cia. SPAIN 9. Se icio de Medicina In e na. Hospi al Uni e si a io de Bu gos. SPAIN 10. Vi o, Labo a 11. Se icio de Radiología. Hospi al Uni e si a io Reina So ía, Có doba. SPAIN 12. Se icio de Neumología. Hospi al Cos al de Sol, Ma bella. Málaga. SPAIN 13. Se icio de Radiología. HCU Lozano Blesa, Za agoza. SPAIN 14. Se icio de Neumología. H Uni e si a io Ma qués de Valdecilla, San ande . SPAIN 15. Se icio de Neumología. Hospi al Gene al Uni e si a io Reina So ía de Mu cia. SPAIN 16. Se icio de Neumología. Hospi al Uni e si a io de Bu gos. SPAIN 17. Se icio de Neumología. Hospi al Uni e si a io San Ped o, Log oño, La Rioja. SPAIN Keywo ds: COVID-19, In acellula adhesion molecule, Lung di usion capaci y, Os eop o ege in, Plasminogen ac i a o inhibi o , Tissue inhibi o o ma ix me allop o einases, Tomog aphy Co esponding au ho : D . José-Ramón Blanco Hospi al San Ped o – Cen o de In es igación Biomédica de La Rioja (CIBIR) Depa amen o de En e medades In ecciosas Pique as 98, 26006 Log oño, La Rioja, Spain Telephone: +34 941298993 Email: [email p o ec ed] ; j blanco [email protected] Jou nal P e-p oo ABSTRACT Objec i es: COVID-19 su i o s a e epo ing esidual abno mali ies a e discha ge om he hospi al. Limi ed in o ma ion is a ailable abou his s age o eco e y o he linge ing e ec s o he i us on pulmona y unc ion and in lamma ion. The aim o his s udy was o desc ibe lung unc ion and o iden i y bioma ke s in se um and induced spu um samples om pa ien s eco e ing om COVID-19 hospi alisa ion. Me hods: Pa ien s admi ed o Spanish hospi als wi h labo a o y-con i med COVID-19 in ec ion by a eal- ime PCR (RT-PCR) assay o se e e acu e espi a o y synd ome co ona i us 2 (SARS-CoV-2) we e ec ui ed o his s udy. Each hospi al sc eened hei lis s o discha ged pa ien s a leas 45 days a e symp om onse . SARS-CoV-2-in ec ed pa ien s we e di ided in o mild/mode a e and se e e disease g oups acco ding o he se e i y o hei symp oms du ing hospi alisa ion. Pa ien s’ epidemiological and medical his o ies, como bidi ies, ch onic ea men s, and labo a o y pa ame e s we e e alua ed. Pulmona y unc ion es s, he s anda dised 6-minu e walk es (6 MWT) and ches compu ed omog aphy (CT) we e also pe o med. The le els o p o eases, hei inhibi o s, and shed ecep o s we e measu ed in se um and induced spu um samples. Resul s: A o al o 100 pa ien s wi h espi a o y unc ion es s we e included in his s udy. The median numbe o days a e he onse o symp oms was 104 (IQR 89.25, 126.75). COVID-19 was se e e in 47% (47/100) o pa ien s. CT was no mal in 48% (48/100) o pa ien s. Lung unc ion was no mal (FEV1 ≥80%, FVC ≥80%, FEV1/FVC ≥0.7, and di using capaci y o ca bon monoxide [DLCO] ≥80%) in 92% (92/100), 94% (94/100), 100% (100/100) and 48% (48/100) o pa ien s, espec i ely. Mul i a ia e analysis showed ha a DLCO <80% (OR 5.92; 95%CI 2.28-15.37; p <0.0001) and a lowe se um LDH le el (OR 0.98; 95%CI 0.97-0.99) we e associa ed wi h he se e e disease g oup o SARS-CoV-2 du ing hospi al s ay. Conclusions: A di usion de ici (DLCO <80%) was s ill p esen a e hospi al discha ge and was associa ed wi h he mos se e e SARS-CoV-2 cases. Jou nal P e-p oo INTRODUCTION App oxima ely 104 million indi iduals wo ldwide ha e eco e ed om COVID-19 (h ps://co ona i us.jhu.edu/map.h ml). Howe e , some su i o s epo pe sis en se e e symp oms and o gan dys unc ion [1]. These symp oms migh be, in pa , a consequence o he cy okine s o m su e ed in he acu e phase o he in ec ion [2]. P e ious s udies ha e shown ha highe le els o p oin lamma o y cy okine esponses du ing he acu e phase o o he co ona i us in ec ions such as se e e acu e espi a o y synd ome (SARS) [3] and he Middle Eas Respi a o y Synd ome Co ona i us (MERS-CoV) [4], we e associa ed wi h se e e lung disease. Unlike p e ious co ona i uses, COVID-19 does no seem o be jus a espi a o y a lic ion; a he , i is a i al in ec ious p ocess in ol ing mul iple sys ems [5]. Residual lung abno mali ies ha e been ound in pa ien s wi h SARS-CoV-2 1-3 mon hs a e discha ge om he hospi al [6-9]. Howe e , limi ed in o ma ion is a ailable abou he se um in lamma o y s a e du ing eco e y om SARS-CoV- 2. The impac o esidual in lamma ion on he lungs is e en a e . Because he pe sis ence o his in lamma o y s a e in blood and spu um could ha e impo an p ognos ic implica ions, we pe o med his s udy. METHODS Pa icipan s This was a p ospec i e s udy o pa ien s olde han 18 yea s o age who we e admi ed o di e en Spanish hospi als wi h labo a o y-con i med COVID-19 in ec ion by eal- ime PCR (RT-PCR) assay o SARS-CoV-2. Each hospi al sc eened hei lis s o discha ged pa ien s. These pa ien s we e in e iewed by phone a leas 45 days a e symp om onse and asked o collabo a e i hey me inclusion c i e ia. Exclusion c i e ia included pa ien s wi h a need o p io in asi e mechanical en ila ion, ch onic in ec ious diseases, ch onic lung diseases, concu en au oimmune o cance diseases, ch onic use o co icos e oids o immunosupp essi e he apy, p egnancy, alcohol/d ug abuse, o pa ien s whose condi ions did no allow pa icipa ion in his s udy. The s udy was app o ed by he Ins i u ional Resea ch E hics Commi ees. All pa icipan s p o ided w i en in o med consen . Jou nal P e-p oo Pa ien s we e di ided in o mild (mild and mode a e) and se e e g oups acco ding o he se e i y o hei symp oms du ing hei hospi al s ays. The mild g oup did no ha e pneumonia imaging; he mode a e g oup showed pneumonia; and he se e e g oup had dyspnoea, espi a o y equency ≥ 30/minu e, blood oxygen sa u a ion ≤93%, PaO 2 /FiO 2 a io <300, and/o lung in il a es >50% o he lung ield wi hin 24-48 hou s [10]. Pa ien s equi ing in asi e mechanical en ila ion we e excluded because o i s impac on sys emic in lamma ion [11]. Epidemiological, medical his o y, como bidi ies, ch onic ea men s, and labo a o y pa ame e s we e e alua ed. Smoking s a us was de e mined om sel -adminis e ed su ey esponses. An h opome ic measu emen s included body mass index (BMI). A leas 45 days a e symp om onse , pulmona y unc ion es ing, s anda dised 6-minu e walk es s (6 MWT) [12], and ches compu ed omog aphy (CT) we e pe o med. Lung unc ion included o ced i al capaci y (FVC), o ced expi a o y olume in he i s second (FEV1), FEV1/FVC a io and di usion capaci y o he lung o ca bon monoxide (DLCO). Di usion de ici was conside ed a DLCO <80% o he p edic ed alue [13]. The 6 MWT, a p ac ical and simple es ha p o ides a global measu e o unc ional capaci y, was pe o med in acco dance wi h in e na ional ecommenda ions [12]. Pe iphe al oxygen sa u a ion (SpO 2 ) was moni o ed using a handheld oxime e . ∆SpO 2 -6 MWT was de ined as he di e ence be ween he es ing and nadi SpO 2 . The 6 MWT dis ance was also e alua ed [14]. CT was conside ed no mal in he absence o g ound-glass opaci ica ion, c azy-pa ing pa e ns, consolida ion, o linea opaci ies [15]. The le els o bioma ke s we e measu ed in se um and induced spu um samples. Se um samples we e ob ained om blood d awn a a da e close o he es s al eady desc ibed and s o ed a -80ºC. Spu um was induced as p e iously desc ibed [16] and s o ed a -80°C. I was ob ained, whene e possible, on he same day as he espi a o y unc ion es s. The concen a ions o mul iple p o eases and hei inhibi o s (plasminogen ac i a o inhibi o [PAI]-1, PAI-2, and issue inhibi o o ma ix me allop o einases [TIMP]-1). Shed ecep o (in acellula adhesion molecule [ICAM]-1, ICAM-3, os eop o ege in [OPG]) Jou nal P e-p oo we e e alua ed in se um and spu um samples. These pa ame e s we e analysed in duplica e employing comme cially a ailable ELISA ki s. The lowe de ec ion limi s a e shown (Supplemen a y Table 1). All samples we e es ed indi idually (one sample pe well), bu samples om all g oups we e measu ed on he same pla e. The hook e ec , a s a e o an igen excess ela i e o he an ibody p obes, esul ing in alsely lowe ed alues, was uled ou a e analysing undilu ed and dilu ed samples. Da a analysis Ca ego ical a iables we e epo ed as equencies and p opo ions. Con inuous a iables wi h a no mal dis ibu ion a e p esen ed as he mean (s anda d de ia ion [SD]), and hose wi h a non-no mal dis ibu ion a e p esen ed as he median (in e qua ile ange alues [IQR] p25, p75). To compa e he demog aphic and clinical a iables be ween g oups, he chi-squa e es o Fishe 's exac es was used o each ca ego ical a iable, as app op ia e. Fo quan i a i e a iables, he nonpa ame ic Mann-Whi ney U es was used. Mul i a ia e analysis was ca ied ou using bina y logis ic eg ession wi h he o wa d condi ional me hod, in oducing DLCO (<80 s. ≥80%) as he dependen a iable. Independen a iables we e all a iables ha we e s a is ically signi ican in he bi a ia e analysis, o clinical implica ions. The esul s o he mul i a ia e model we e adjus ed, and we p esen he odds a io and i s 95% con idence in e al (CI). S a is ical signi icance was se a p <0.05. Analyses we e pe o med using SPSS 24.0 so wa e (SPSS Inc., Chicago, IL, USA). RESULTS A o al o 108 pa ien s we e included in his s udy. O he sample, 100 had adequa e espi a o y unc ion es s. Mos (69%9 we e >50 yea s (69/100), 64% we e male (64/100), and 90% we e Caucasian (90/100). The median numbe o days a e he onse o symp oms was 104 (IQR 89.25, 126.75). Common como bidi ies included hype ension (25%; 25/100), diabe es melli us (10%; 10/100), ca dio ascula disease (4%; 4/100), and ch onic kidney disease (2%; 2/100). Obesi y (BMI ≥30%) was p esen in 37% (37/100), and 59% ne e had smoked (59/100). Ch onic he apy included angio ensin-con e ing enzyme Jou nal P e-p oo inhibi o s/angio ensin II ecep o blocke s use (17%, 17/100), s a in use (12%, 12/100), and aspi in use (3%, 3/100). COVID-19 was se e e in 47% o pa ien s (47/100). Lung unc ion was no mal (FVC ≥80%, FEV1 ≥80%, FVC/FEV1 ≥0.7, and DLCO ≥80%) in 92% (92/100), 94% (94/100), 100% (100/100), and 48% (48/100), espec i ely. Con ol CT was no mal in 48% (48/100). Gi en he high pe cen age o subjec s wi h DLCO <80% and i s in ol emen in lung damage, his lung pa ame e was e alua ed. Table 1 shows he pa ien cha ac e is ics acco ding o DLCO se e i y. Wi h he excep ion o signi ican da a e e ing o he se e i y o COVID-19 disease du ing hospi alisa ion and he leng h o hospi al, no o he signi ican di e ences we e obse ed. Table 2 shows he analy ical pa ame e s acco ding o DLCO se e i y. Finally, Table 3 p o ides in o ma ion abou he es s ca ied ou and he minimum ime elapsed un il es s we e pe o med. No di e ences we e obse ed a e analysing ∆SpO 2 -6 MWT (da a no shown). Mul i a ia e analysis showed ha a DLCO <80% was associa ed wi h se e e disease in he SARS-CoV-2 g oup du ing hei hospi al s ays (OR 5.92; 95% CI 2.28-15.37; p <0.0001) as we e lowe se um LDH le els (OR 0.98; 95% CI 0.97-0.99; p 0.002). DISCUSSION Since he SARS-CoV-2 ou b eak, he e has been inc easing conce n abou he po en ial isk o pa enchymal ib osis and lung unc ion impai men . The mos impo an ac o is lung di usion capaci y [17]. Zhao e al. [6] epo ed ha h ee mon hs a e COVID-19 discha ge, a high pe cen age o CT abno mali ies (70.9%) and DLCO anomalies (16.4%) we e s ill p esen in eco e ing pa ien s. O he au ho s, such as Mo e al. [7], epo ed ha nea ly a mon h a e hospi al discha ge ha , ega dless o he deg ee o SARS-CoV-2 se e i y, no signi ican di e ences in FEV1, FVC, o i s a io we e obse ed. Howe e , he DLCO alue was signi ican ly lowe as he se e i y o he clinical pic u e inc eased (47.2% in o al; 30.4% in mild illness and 84.2% in se e e pneumoniae). In his s udy, he au ho s included a small numbe o pa ien s wi h p e ious pulmona y pa hology, Jou nal P e-p oo one o he exclusion c i e ia o ou s udy. Likewise, F ija-Masson e al. [9] also obse ed ha mo e han hal o pa ien s wi h COVID-19 pneumonia, some o whom had espi a o y como bidi ies, exhibi ed abno mal lung unc ion one mon h a e symp om onse , wi hou a clea ela ionship wi h pneumonia ex en on ches CT. Huang e al. [18] obse ed ha 30 days a e discha ge om he hospi al, pa ien s exhibi ed nea ly signi ican di e ences in DLCO alues (<80%), 42.5% in non-se e e cases, and 75.6% in se e e cases (p < 0.053). In ha s udy, pa ien s wi h a p e ious his o y o pulmona y esec ion, neu ological disease, o men al illness we e excluded. In ou s udy, DLCO indings we e close o hose obse ed by Mo e al. [7] and Huang e al. [18], while he CT indings we e clea ly be e han hose epo ed by Zhao e al. [6]. A e he 2003 ou b eak o SARS, su i o s e alua ed wi hin h ee mon hs o discha ge showed ha lung ib o ic changes occu ed mos ly in se e ely sick pa ien s [19]. These same au ho s also obse ed ha when assessing lung ib o ic changes, DLCO sco es we e mo e sensi i e han ches adiog aphy and/o high- esolu ion CT. These esul s a e simila o hose obse ed by ou g oup. Du ing he ollow-up o SARS pa ien s, abno mal CT (30%) and impai ed DLCO unc ion (15.5%) [20] we e s ill p esen six mon hs la e . These au ho s also obse ed signi ican impai men in DLCO unc ion (23.7%) one yea a e illness onse [21]. All hese da a sugges ha some o he eco e ed COVID-19 pa ien s will ha e signi ican ly impai ed lung unc ion mon hs a e discha ge. Con a y o ou expec a ions, LDH le els we e signi ican ly lowe in pa ien s wi h DLCO abno mali ies (<80%). Howe e , se um LDH is a sensi i e, bu densome ma ke o cell inju y [22]. One o he easons could be ha i s le els a y in mul iple ci cums ances (cell damage ela ed o ischaemia, exposu e o bac e ial oxins, chemical poisoning, e c.), which is why se um LDH is di icul o use as a alid bioma ke o lung damage o in lamma ion [22]. Howe e , some au ho s ha e obse ed ha LDH (cu -o alue o 344.5 U/L) could be a p edic i e ac o o ea ly ecogni ion o lung inju y and se e e COVID-19 cases [23]. These le els a e clea ly highe han hose p esen ed by ou pa ien s. Jou nal P e-p oo [32] Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, e al. Endo heliopa hy in COVID-19-associa ed coagulopa hy: e idence om a single- cen e, c oss-sec ional s udy. Lance Haema ol. 2020;7(8):e575-e582. [33] Acke mann M, Ve leden SE, Kuehnel M, Ha e ich A, Wel e T, Laenge F, e al. Pulmona y ascula endo heliali is, h ombosis, and angiogenesis in Co id-19. N Engl J Med. 2020;383(2):120-128. [34] Tsou sou PG, Gou goulianis KI, Pe inaki E, Mpaka M, E emidou S, Mania is A, e al. ICAM-1, ICAM-2 and ICAM-3 in he se a o pa ien s wi h idiopa hic pulmona y ib osis. In lamma ion. 2004;28(6):359-364. [35] Taz TA, Ahmed K, Paul BK, Kawsa M, Ak a N, Mahmud SMH, e al. Ne wo k-based iden i ica ion gene ic e ec o SARS-CoV-2 in ec ions o Idiopa hic pulmona y ib osis (IPF) pa ien s. B ie Bioin o m. 2020. doi: 10.1093/bib/bbaa235. [36] Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM, e al. Vi al dynamics in mild and se e e cases o COVID-19. Lance In ec Dis. 2020;20(6):656-657. Jou nal P e-p oo Table 1. Pa ien cha ac e is ics among SARS-CoV-2 su i o s acco ding o DLCO se e i y. DLCO <80 (n = 52) DLCO ≥80 (n = 48) P alue Age in yea s, mean (± SD) Age >50 yea s, n (%) 54.98 ±10.72 34 (65.4) 54.75 ± 9.83 35 (72.9) 0.911 0.416 Male sex, n (%) 33 (63.5) 31 (64.6) 0.907 Caucasian, n (%) 47 (90.4) 43 (89.6) 0.894 Ne e smoke his o y, n (%) 32 (61.5) 27 (56.3) 0.591 Como bidi ies Ca dio ascula disease, n (%) 4 (7.7) 0 (0) 0.119 Hype ension, n (%) 15 (28.8) 10 (20.8) 0.355 Diabe es melli us, n (%) 7 (13.5) 3 (6.4) 0.324 Ch onic enal ailu e, n (%) 2 (3.8) 0 (0) 0.496 Ch onic aspi in use, n (%) 2 (3.8) 1 (2.1) 1.000 Ch onic s a in use, n (%) 8 (15.4) 4 (8.3) 0.362 Ch onic ACE/ARA-II use, n (%) 9 (17.3) 8 (16.7) 0.932 SARS - CoV - 2 da a du ing hospi al iza ion admission Se e i y disease du ing hospi al admission, n (%) 34 (65.4) 13 (27.1) <0.0001 Days o hospi aliza ion , median (p25, p75) 7.0 (5.0; 9.75) 8.0 (6.0; 11.0) 0.038 No e: ACE = angio ensin con e ing enzyme inhibi o s; ARA-II = angio ensin II ecep o blocke s; BMI = Body mass index; DLCO = di usion capaci y o he lung o ca bon monoxide; SD = S anda d de ia ion Jou nal P e-p oo Table 2. Analy ical cha ac e is ics among SARS-CoV-2 su i o s acco ding o DLCO se e i y. DLCO <80 (n = 52) DLCO ≥80 (n = 48) P alue Se um pa ame e s , median (p25, p75) WBC coun , cells/μL 6.10 (5.30; 6.59) 5.70 (5.0; 6.6) 0.383 Glucose, mg/dL 97.0 (93.25; 112.7) 32.4 (27.7; 39.9) 0.016 C ea inine, mg/dL 0.87 (0.74; 1.01) 0.87 (0.76; 0.98) 0.970 ALT, UI/L 21.0 (16-0; 32.0) 24.0 (18.0; 33.0) 0.224 AST, UI/L 22.0 (17.0; 25.0) 24.0 (20.0; 27.0) 0.034 LDH , UI/L 187.0 (164.0; 201.0) 196.0 (174.2; 256.7) 0.006 CRP g/dL 3.0 (1.0; 4.0) 4.0 (1.0; 4.0) 0.751 OPG pg/ml 62.6 (48.0; 81.0) 58.0 (48.4; 72.5) 0.410 TIMP-1 ng/ml 278.1 (249.8; 306.8) 281.3 (242.6; 312.3) 0.598 ICAM-1 ng/ml 169.9 (131.5; 245.9) 173.5 (122.5; 243.6) 0.738 ICAM-3 ng/ml 141.8 (115.8; 187.9) 136.6 (106-2; 163.0) 0.143 PAI-1 ng/ml 125.6 (98.2; 146.5) 119.2 (107.3; 142.4) 0.945 PAI-2 ng/ml 4.3 ±(2.8; 6.7) 3.7 (2.1; 5.2) 0.492 Induced spu um samples , median (p25, p75) OPG pg/ml 1.0 (1.0; 9.71) 1.0 (1.0; 11.1) 0.912 TIMP-1 ng/ml 68.9 (35.0; 120.4) 48.5 (35.0; 75.1) 0.112 ICAM-1 ng/ml 2.2 (0.9; 3.5) 2.21 (0.1; 2.38) 0.083 ICAM-3 ng/ml 34.2 (12.6; 86.1) 38.27 (16.2; 92.4) 0.812 No e: ALT = Alanine amino ans e ase; AST = Aspa a e amino ans e ase; CRP = C- eac i e p o ein; DLCO = di usion capaci y o he lung o ca bon monoxide; ICAM = In acellula adhesion molecule; LDH = Lac a e dehyd ogenase; OPG = Os eop o ege in; PAI = Plasminogen ac i a o inhibi o ; TIMP = Tissue inhibi o o ma ix me allop o einase; WBC = Whi e blood cell coun . Jou nal P e-p oo Table 3. Pulmona y unc ion es and compu ed omog aphy among SARS-CoV-2 su i o s acco ding o DLCO se e i y. DLCO <80 (n = 52) DLCO ≥80 (n = 48) P alue Days a e symp oms onse * Days a e symp oms onse >90, n (%) 100.0 (87.5; 108.7) 36 (69.2) 11 4 . 5 (94.2; 133.7) 38 (79.2) 0.012 0.258 Func iona l lung pa ame e and imaging CT FVC (%)* FVC >80%, n(%) 106.9 (91.0; 113.7) 48 (92.3%) 104.5 (94.7; 114.7) 46 (95.8%) 0.904 0.906 FEV1 (%)* FEV1 >80%, n (%) 102.5 (94.1; 113.0) 48 (91.7) 107.2 (98.0; 118.0) 44 (91.7) 0.214 0.458 FEV1/FVC a io* 1.0 (0.9; 1.0) 0.97 (0.92; 1.01) 0.066 6MWT dis ance, mean (± SD) 6MWT dis ance >550,n (%) 5 13 . 0 (450.0; 594.6) 20 (39.2) 577.0 (540.0; 645.0) 31 (66) 0.001 0.008 Pa hologic CT, n (%) 31 (59.6) 20 (42.6) 0.900 No e: Da a p esen ed as median (P25; P75)*; 6MWT = 6-minu e walk es ; CT = ches - compu ed omog aphy; DLCO = di usion capaci y o he lung o ca bon monoxide; FEV1 = o ced expi a o y olume in he i s second; FVC = o ced i al capaci y; SD = S anda d de ia ion Jou nal P e-p oo