The effectiveness of glucocorticoid treatment in post-COVID-19 pulmonary involvement

Mize ae al. Pneumonia (2024) 16:2 h ps://doi.o g/10.1186/s41479-023-00123-7 RESEARCH The e ec i eness o glucoco icoid ea men inpos -COVID-19 pulmona y in ol emen Jan Mize a1† , Samuel Genzo 1,2*† , Milan So a1,3 , Ladisla S anke2 , Radim Bu ge 4 , Pe Jakubec1 , Ma in Vykopal1 , Pa ol Pobeha5 and Jana Zaple alo á6 Abs ac Ra ionale Pe sis en espi a o y symp oms ollowing Co ona i us Disease 2019 (COVID-19) a e associa ed wi h esid- ual adiological changes in lung pa enchyma, wi h a isk o de elopmen in o lung ib osis, and wi h impai ed pul- mona y unc ion. P e ious s udies hin ed a he possible e icacy o co icos e oids (CS) in acili a ing he esolu ion o pos -COVID esidual changes in he lungs, bu he a ailable da a is limi ed. Aim To e alua e he e ec s o CS ea men in pos -COVID espi a o y synd ome pa ien s. Pa ien s andme hods Pos -COVID pa ien s we e ec ui ed in o a p ospec i e single-cen e obse a ional s udy and scheduled o an ini ial (V1) and ollow-up isi (V2) a he Depa men o Respi a o y Medicine and Tube culosis, Uni e si y Hospi al Olomouc, comp ising o pulmona y unc ion es ing, ches x- ay, and complex clinical examina- ion. The decision o adminis e CS o main ain wa ch ul wai ing (WW) was in line wi h Czech na ional guidelines. Resul s The s udy in ol ed 2729 COVID-19 su i o s (45.7% male; mean age: 54.6). F om 2026 pa ien s wi h com- ple e V1 da a, 131 pa ien s we e indica ed o CS he apy. These pa ien s showed signi ican ly wo se adiological and unc ional impai men a V1. Mean ini ial dose was 27.6 mg (SD ± 10,64), and he mean du a ion o CS he apy was 13.3 weeks (SD ± 10,06). Following he apy, signi ican ly be e imp o emen o s a ic lung olumes and ans e ac o o ca bon monoxide (DLCO), and signi ican ly be e a es o good o comple e adiological and subjec i e imp o emen we e obse ed in he CS g oup compa ed o con ols wi h a ailable ollow-up da a (n = 894). Conclusion Be e imp o emen o pulmona y unc ion, adiological indings and subjec i e symp oms we e obse ed in pa ien s CS compa ed o wa ch ul wai ing. Ou indings sugges ha glucoco icoid he apy could ben- e i selec ed pa ien s wi h pe sis en dyspnea, signi ican adiological changes, and dec eased DLCO. Keywo ds Pos -co id synd ome, Pulmona y ib osis, Co icos e oids, Wa ch ul wai ing, Pulmona y unc ion Open Access © The Au ho (s) 2023. 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Pneumonia †Jan Mize a and Samuel Genzo con ibu ed equally o his wo k. *Co espondence: Samuel Genzo samuel.genzo @ nol.cz Full lis o au ho in o ma ion is a ailable a he end o he a icle Page 2 o 10 Mize ae al. Pneumonia (2024) 16:2 In oduc ion Pos -COVID-19 (Co ona i us Disease 2019) synd ome is a se o espi a o y and non- espi a o y symp oms ha pe sis o mo e han 3 mon hs a e he in ec ion wi h he Se e e acu e espi a o y synd ome co ona i us 2 (SARS-CoV-2). These symp oms should ha e a pa ho- physiological connec ion wi h he COVID-19 and should no be explicable by ano he cause [1, 2]. The e m meas- u able pos -COVID disabili y can be used o pa ien s p esen ing wi h abno mal indings on CXR, high- esolu- ion compu ed omog aphy (HRCT), o pulmona y unc- ion es ing, in he absence o subjec i e symp oms [3]. The epo ed p e alence o pos -COVID lung ib o- sis a ies g ea ly ac oss s udies, anging om 6% [3] o 44%, [4] likely due o me hodological and e minologi- cal disc epancies, such as he lack o dis inc ion be ween in e s i ial in lamma ion ( e e sible changes) and ib o- sis (pe manen changes). The mos equen ly desc ibed adiological and his ological indings in pa ien s wi h espi a o y o m o pos -COVID-19 synd ome a e con- sis en wi h o ganizing pneumonia (OP), ollowed by non-speci ic in e s i ial pneumonia (NSIP) [5]. O he adiological indings should aise suspicion o a di e en cause, o a p e-exis ing espi a o y disease. Mul iple pa hophysiological pa hways and mecha- nisms a e in ol ed in he ib o ic emodeling o lung issue, especially he down egula ion o ACE-2 ecep- o s a e he binding o SARS-CoV-2 i ions, esul ing in inc eased p o-in lamma o y and p o- ib o ic ac i i y. This leads o he up egula ion o a ious e ec o mol- ecules (ma ix me allop o einases 1 and 7, in e leukins: IL-1, 6 and 8, galec in-3 media ed pa hways, ans o m- ing g ow h ac o -β, TNF-α, ICAM, VCAM e c [6, 7]. Mo eo e , pulmona y asculopa hy and he esul an hypoxic emodeling may also be in ol ed [8, 9]. In he majo i y o pa ien s, he po en ially ib ogenic in lam- ma o y p ocess seems o be sel -limi ed and migh esol e wi hou any he apy in he pos -acu e s age o he COVID-19 [10, 11]. In he case o pe sis en lung in e s i ial in ol emen a e COVID-19 pneumonia, sys emic glucoco icoids (CS) a e equen ly used [5, 12]. The ea men wi h CS leads o down egula ion o a b oad spec um o p o- in lamma o y and p o- ib o ic molecules (IL-1, 2, 4, 5, 8, 13; ICAM, VCAM, e c.) and can hus help he esolu ion o in lamma o y and ib ogenic changes h ough mul i- ple pa hways [13–19]. Howe e , he CS seem o be mos e ec i e p io o he de elopmen o de ini i e ib o ic changes, he e o e app op ia e iming o he ea men is likely essen ial [5]. The exis ing li e a u e sugges s possi- ble bene i s o CS o selec ed indi iduals wi h espi a o y o m o pos -COVID-19 synd ome, especially in cases o pe sis en o ganizing pneumonia, bu hei gene al use is cu en ly no ecommended [20–26]. The nume ous and po en ially se ious sys emic and o gan speci ic side e ec s o CS a e well desc ibed in he li e a u e [27–29]. Se e al s udies o he use o CS in pos -COVID pa ien s ha e been published o da e, [5, 30, 31] hin ing a he possible e icacy o CS in he espi a o y pos -COVID-19 synd ome. These s udies ha e b ough impo an insigh s o he e icacy o CS, howe e , he coho size in hese s udies was usually small, [5, 30] and mos o he s ud- ies did no con ain a con ol g oup [5, 31]. Addi ionally, some s udies in ol ed only limi ed [31] o no [30] pul- mona y unc ion es s (PFT). The p esen s udy aims o expand on he cu en knowledge by p o iding a la ge , obus da ase , and mo e impo an ly, a con ol g oup wi h pa ien s managed by wa ch ul wai ing (WW). This s udy aims o answe wo ques ions: Fi s ly, how do he pa ien s ea ed by CS compa e o he pa ien s managed by WW wi h espec o he a e o imp o e- men o pa ame e s o pulmona y unc ion, adiological indings and subjec i e symp oms? And secondly, wha a e he cha ac e is ics o he pa ien s who a e ea ed wi h CS in eal-li e clinical p ac ice? Ma e ials andme hods Rec ui men F om May 13, 2020, o Janua y 11, 2022, mo e han h ee housand pa ien s we e e alua ed in he newly es ab- lished pos -COVID ambula o y cen e a he Depa men o Pulmona y Diseases and Tube culosis, Uni e si y Hos- pi al Olomouc, Czech Republic. The a ailabili y o he pos -COVID ambula o y was publicly announced on he websi e o he Uni e si y Hospi al Olomouc. The pa ien s we e in i ed o pa icipa e in a longi udinal obse a ional s udy o COVID-19 su i o s. Those who ag eed o pa - icipa e in he s udy signed an in o med consen o m. Fo he 12 adolescen pa ien s he consen o m was signed by a pa en . Non-pa icipan s ecei ed he same le el o medical ca e as s udy pa icipan s, bu hei clini- cal da a we e no included in he da ase . The inclusion c i e ia o he s udy we e: a minimum age o 15, and a p e ious COVID-19 in ec ion, de ined as: a his o y o a posi i e SARS-CoV-2 PCR es , a his- o y o a posi i e SARS-CoV-2 an igen es coupled wi h ypical symp oms, o posi i e le els o SARS-CoV-2 IgM an ibodies in non- accina ed indi iduals who expe i- enced ypical symp oms. No p ima y exclusion c i e ia we e de ined, howe e he pa ien s wi h a p obable e u- a ion o SARS-CoV-2 in ec ion we e excluded pos hoc (pa ien s ha had no e idence o ha ing had co id i.e., an absence o a posi i e PCR o an igen es o SARS-CoV-2 and unde ec able SARS-CoV-2 an ibody le els in se um). Addi ionally, he pa ien s wi h insu icien da a (such as missing baseline pulmona y unc ion es ing), and he Page 3 o 10 Mize ae al. Pneumonia (2024) 16:2 pa ien s on ch onic CS medica ion ( heuma oid a h i is, solid o gan ansplan ecipien s, e c.), o pa ien s wi h newly ini ia ed CS he apy o easons o he han pos - COVID espi a o y sequelae (b onchial as hma exace - ba ion, newly diagnosed sa coidosis, e c.) we e excluded pos -hoc om he s a is ical analysis o a oid bias. Cou se o  hes udy The s udy p o ocol manda ed wo p ima y isi s. The ini ial isi (V1) was scheduled o a mean o 12 weeks (1–68, SD ± 7.55) ollowing in ec ion. The second ollow- up isi (V2) was scheduled based on clinical necessi y, wi hin a mean in e al o 21 weeks (3–50, SD ± 7.96) be ween he wo isi s. In a limi ed numbe o subjec s, addi ional check-ups we e necessa y; howe e , he scope o hese addi ional examina ions was limi ed based on clinical equi emen s. Bo h V1 and V2 consis ed o an ex ensi e pa ien in e iew, documen ed in ee- o m by one o he in es iga ing pneumologis s (N = 14). The ocus o hese in e iews was on he symp oms o acu e COVID-19, pe sis ing o newly eme ging symp oms, como bidi ies, medica ions, occupa ional his o y, and o he de ails cus oma y o a comp ehensi e pneumo- logical examina ion. The esul s o a ca dio- espi a o y ocused physical examina ion we e eco ded in ee- o m acco ding o he s anda ds o he depa men . The ches X- ay (CXR) in pos e oan e io p ojec ion was ob ained and in e p e ed by a ained adiologis (N = 25). Ches HRCT was pe o med in selec ed indi iduals based on clinical necessi y. Pulmona y unc ion es ing (PFT) - including spi ome y, body-ple hysmog aphy, and lung di usion capaci y o ca bon monoxide (DLCO) - was conduc ed by expe ienced spi ome y echnicians using he Mas e Sc een by Jaege ®, wi h acco dance o he ecen Ame ican Tho acic Socie y (ATS) and Eu opean Respi a o y Socie y (ERS) guidelines [32]. Da a e ie al was accomplished h ough he Sen ySui eTM Ve sion 2.19 by Ca eFusion. Addi ionally, a se o blood es s was aken a V1 and V2, including ou ine biochemis y, di - e en ial blood coun and SARS-CoV-2 an ibodies. How- e e , om Oc obe 2021 onwa ds, he aking o blood es s was limi ed o cases wi h clinical necessi y due o limi ed inancial esou ces. The blood es s we e he e- o e no included in s a is ical analysis o a oid selec ion bias. The ea men wi h glucoco icoids (CS) was consid- e ed in pa ien s wi h pe sis en pa hological indings on CXR and/o HRCT and/o impai ed pulmona y unc ion pa ame e s, namely dec eased DLCO. The p esence o symp oms alone was no conside ed o be an indica ion o glucoco icoid he apy. In pa ien s conside ed o glu- coco icoid he apy, addi ional c i e ia such as age, ail y, como bidi ies, and o he indi idual isk ac o s we e e alua ed by he examining physician. Finally, selec ed pa ien s we e p esc ibed o al glucoco icoids (p edniso- lone o an equi alen dose o me hylp ednisolone). The ini ial dose and he ape ing egimen we e indi- idualized, wi h doses lowe han 0.5mg/kg o p edni- solone being u ilized in pa ien s wi h highe es ima ed isk o ad e se e ec s. The maximum ini ial dose o p ednisolone was 40 mg aken in a single daily dose. The mean p esc ibed ini ial dose o p ednisolone was 27.6mg (SD ± 10,64), and he mean du a ion o glucoco - icoid he apy was 13.3 weeks (SD ± 10,06). The dose was educed o 20mg a e 14 days. The dose o 20mg was aken o up o 14 days and was hen ape ed g adually by 5mg pe week. The dose ape ing egimen could be modi ied by he in es iga ing physician. This app oach was in line wi h he na ional posi ional documen on he ea men o pulmona y impai men in pa ien s eco e - ing om COVID-19 [12]. Cons uc ion andanalysis o  heda ase Fou main da a sou ces we e u ilized: he medical docu- men a ion, he da abase o labo a o y es esul s, he da abase o adiological s udies and he Czech na ional egis y o SARS-CoV-2 accina ion and es s. The da a we e ex ac ed, encoded, and s o ed in a Mic oso Excel sp eadshee and alida ed by he main au ho p io o s a is ical analysis. The medical documen a ion was sea ched manually, including he epo s om he wo main isi s (V1 and V2) and all in e im check-ups. Biome ic da a we e ga h- e ed (sex, age, weigh , heigh , BMI). The da e o he i s posi i e SARS-CoV-2 es (o onse o symp oms) was ex ac ed om he medical documen a ion and alida ed agains he Czech na ional egis y o SARS-CoV-2 acci- na ion and es s. The easons o missing ollow-up we e eco ded. Selec ed como bidi ies in he pa ien ’s medical his o y we e eco ded, including a e ial hype ension (AHT), diabe es melli us (DM), ischemic hea disease (IHD), pulmona y embolism (PE), dyslipidemia (DLD), hypo hy oidism (HT), b onchial as hma (BA), ch onic obs uc i e pulmona y disease (COPD), sa coidosis, in e s i ial lung disease (ILD). The como bidi y sco e (ComS) was es ablished by adding one poin o each o he en selec ed como bidi ies. The se e i y o acu e COVID-19 was classi ied in o one o h ee ca ego ies: mild, de ined as a mild ambu- la o y cou se wi hou pneumonia; mode a e, in ol - ing pneumonia bu no equi ing oxygen he apy; and se e e, in ol ing pneumonia ha equi ed oxygen he apy, en ila o y suppo , in ensi e ca e, o c i ical ca e. The da a ega ding espi a o y and ex apulmo- na y symp oms du ing acu e COVID-19 and du - ing pos -COVID phase we e eco ded. The a e o Page 4 o 10 Mize ae al. Pneumonia (2024) 16:2 subjec i e imp o emen was es ima ed based on he e bal desc ip ions in he medical documen a ion and eco ded on a scale anging om 0 o 10 (0 o 100% imp o emen wi h 10% s ep size). SIS sco es 9–10 we e conside ed comple e imp o emen , SIS sco es 5–8 we e conside ed good imp o emen , while SIS sco e o 0 was conside ed as no imp o emen . Pos -co id adio- logical sco e (PRS) was es ablished based on he ex en o pos -COVID changes as desc ibed by he adiolo- gis . The sco e anged om 0 (no changes), h ough 1 (changes on HRCT only), 2 (minimum e icula o linea opaci ies), 3 (se e al g ound glass opaci ies, pa chy o e icula opaci ies), 4 (ex ensi e opaci ies o di use e icula opaci ies in less han 3/6 lung ields) o 5 (changes desc ibed in 4 bu in ol ing mo e han 3/6 lung ields). The a e o adiological imp o emen be ween he wo main isi s was e alua ed by side- o- side compa ison o he adiological s udies by a sin- gle pneumologis expe ienced in eading adiological s udies and eco ded as a scale anging om 0 o 10 (0 o 100% imp o emen wi h 10% s ep size). RIS sco es 9–10 we e conside ed comple e imp o emen , RIS sco es 5–8 we e conside ed good imp o emen , while RIS sco e o 0 was conside ed as no imp o emen . The PFT da a encompassed p edic ed alues, ac ual meas- u ed alues, and ela i e alues (exp essed as a pe cen - age o p edic ed) whe e applicable. The da a ega ding he use o CS we e ex ac ed by a pneumologis blinded o he subjec i e and adiological imp o emen sco es, PFT and labo a o y es esul s. The da a included he delay om in ec ion o ini ia ion o he apy, he gluco- co icoid molecule used, ini ial dosage exp essed as an equi alen dose o p ednisolone, and he du a ion o he adminis a ion in weeks. The da a ega ding biome ic pa ame e s, subjec i e symp oms and hei imp o emen , adiological indings, and hei imp o emen , selec ed PFT pa ame e s and hei dynamics, he se e i y o COVID-19, and he da a desc ibing he indica ion, ini ial dosage and du a ion o CS he apy we e s a is ically desc ibed and hypo heses we e es ed by means o uni a ia e analysis. Pa ame ic and non-pa ame ic es s we e used as applicable (S u- den ’s - es , Mann-Whi ney U es , Chi-squa e es ). All es s we e conduc ed a he alpha le el o 0.05. Logis ic eg ession was employed o in es iga e po en ial p edic- o s o a lack o subjec i e and adiological imp o emen , de ined as a SIS o 0 and a RIS o 0, espec i ely. The p edic o s e alua ed in he logis ic eg ession included age, sex, COVID-19 se e i y, he use o glucoco icoids, como bidi y sco e, and obesi y (de ined as BMI > = 30). All s a is ical es s we e pe o med by an expe ienced s a is ician using he IBM SPSS S a is ics e sion 29 (IBM Co p., A monk, NY, USA). Resul s F om May 13, 2020, o Janua y 11, 2022, a o al o 2729 su i o s o COVID-19 we e ec ui ed o he p ospec i e obse a ional s udy (1247 male, 45.7%). A e applying he pos -hoc exclusion c i e ia, 2026 pa ien s (919 male, 45,36%) we e included in he s a is ical analysis, wi h 131 pa ien s (6.47%) in he CS g oup and 1895 pa ien s in he WW g oup. The mean age in he coho was 54.37 yea s (SD ± 14.67), wi h he pa ien s in he CS g oup being signi ican ly olde (mean age 63.44 ± 11.42) han he pa ien s in he WW g oup (mean age 53.74 ± 14.66; p < 0.0001). The BMI was compa able be ween he s udy g oups (mean 29.52, SD ± 5.87 in he o al sample). The pa ien s in he CS g oup had signi ican ly highe num- be o como bidi ies han he pa ien s in he WW g oup wi h he mean como bidi y sco es o 1.63 (SD ± 1.25) and 1.02 (SD ± 1.13), espec i ely (p = 0.0004). The pa ien s in he CS g oup we e signi ican ly mo e likely o be he su i o s o se e e COVID-19 han he pa ien s in he WW g oup (70.99% s. 22.16%, espec i ely; p < 0.0001). The pa ien s in he CS g oup we e signi ican ly mo e likely o epo dyspnea han he pa ien s in he WW g oup (80.15% s. 50.18%, espec i ely; p < 0.0001), while he incidence o pe sis en cough was compa able be ween he s udy g oups (36.64% s. 29.97%, espec- i ely; p = 0.1384). The alues o s a ic lung olumes and pa ame e s o pulmona y di usion capaci y obse ed a he baseline (V1) we e s a is ically signi ican ly lowe in he CS g oup compa ed o he WW g oup (p < 0.0001). The pos -COVID adiological sco e was signi ican ly highe in he CS g oup compa ed o he WW g oup wi h a PRS o 3.75 (SD ± 1.43) and 0.82 ± 1.37, espec i ely (p < 0.0001). See Table1 o he epidemiological and base- line cha ac e is ics o he sample and he subg oups. The ollow-up da a we e a ailable in 131 pa ien s in he CS g oup and 894 pa ien s in he WW g oup. The pul- mona y unc ion es (PFT) esul s a baseline (V1) and ollow-up (V2) isi s a e p esen ed in he Table2. Vi al capaci y (VC) has imp o ed signi ican ly in bo h he CS g oup (mean inc ease by 403.7ml, SD ± 510.05, o 10.29% o p edic ed alue, SD ± 13.33, p = 0.0003 and < 0.0001, espec i ely) and he WW g oup (mean inc ease by 95.1 ml, SD ± 353.23, o 2.68% o p edic ed alue, SD ± 9.94, p = 0.0336 and 0.0006, espec i ely). FEV1/ VC ( he Ti eneau index) has signi ican ly dec eased in he WW g oup (-0.73%, SD ± 4.71; p = 0.0212), bu no signi ican change was obse ed in he CS g oup. To al lung capaci y (TLC) has imp o ed signi ican ly in he CS g oup (mean inc ease by 649.84ml, SD ± 756.45, o 9.95% o p edic ed alue, SD ± 12.16, p = 0.0001 and < 0.0001, espec i ely), bu no in he WW g oup (mean inc ease by 92.72 ml, SD ± 758.67, o 1.27% o p edic ed alue, SD ± 12.84, p = 0.2036 and 0.1159, espec i ely). Residual Page 5 o 10 Mize ae al. Pneumonia (2024) 16:2 Table 1 Epidemiological and baseline cha ac e is ics o he sample a S uden ’s - es o wo samples; bComo bidi y sco e: calcula ed by adding 1 poin o each o he ollowing selec ed como bidi ies: a e ial hype ension, diabe es melli us, ischemic hea disease, pulmona y embolism, dyslipidemia, hypo hy oidism, b onchial as hma, ch onic obs uc i e pulmona y disease, sa coidosis, in e s i ial lung disease. The sco e was a ailable in 652 subjec s (46 in he CS g oup and 606 in he WW g oup); cMann-Whi ney U es ; eChi-squa e es ; mild: no pneumonia, no oxygen he apy, mode a e: pneumonia no equi ing oxygen he apy, se e e: pneumonia equi ing oxygen he apy o al sample (N = 2026) CS g oup (N = 131) WW g oup (N=1895) p- alue (mean ± SD) (mean ± SD) (mean ± SD) Age 54.37 ± 14.67 63.44 ± 11.42 53.74 ± 14.66 <0.0001a BMI 29.52 ± 5.87 29.82 ± 5.37 29.49 ± 5.90 0.5407a ComSb1.06 ± 1.15 1.63 ± 1.25 1.02 ± 1.13 0.0004c PRSd1.01 ± 1.55 3.75 ± 1.43 0.82 ± 1.37 <0.0001c VC [%p edic ed] 100.52 ± 16.30 86.93 ± 17.25 101.48 ± 15.80 <0.0001c FEV1/VC [%] 79.61 ± 6.80 79.96 ± 7.75 79.58 ± 6.73 0.2795c TLC [%p edic ed] 105.37 ± 15.70 90.78 ± 16.36 106.40 ± 15.14 <0.0001c RV [%p edic ed] 126.04 ± 30.42 108.24 ± 28.88 127.29 ± 30.14 <0.0001c DLCOc [%p edic ed] 79.62 ± 16.53 57.69 ± 15.94 81.13 ± 15.46 <0.0001c KCOc [%p edic ed] 89.00 ± 14.78 79.31 ± 16.00 89.67 ± 14.46 <0.0001c n (%) n (%) n (%) p- aluee Male sex 919 (45.36%) 85 (64.89%) 834 (44.01%) <0.0001 Acu e COVID-19 se e i y mild 1046 (51.63%) 7 (5.34%) 1039 (54.83%) <0.0001 mode a e 433 (21.37%) 27 (20.61%) 406 (21.42%) 0.9812 se e e 513 (25.32%) 93 (70.99%) 420 (22.16%) <0.0001 Pe sis en espi a o y symp oms dyspnea 1056 (52.12%) 105 (80.15%) 951 (50.18%) <0.0001 cough 616 (30.40%) 48 (36.64%) 568 (29.97%) 0.1384 Table 2 Compa ison o pulmona y unc ion es esul s be ween he wo main isi s a Mann-Whi ney U es ; bPa ien s wi h a ailable ollow-up da a Baseline isi (V1) Follow-up isi (V2) Mean di e ence p- aluea (mean ± SD) (mean ± SD) MD ± SD CS g oup (N = 131) VC [L, ml] 3.25 ± 0.86 3.65 ± 0.89 403.7 ± 510.05 0,0003 VC [%p edic ed] 86.93 ± 17.25 97.22 ± 14.96 10.29 ± 13.33 <0.0001 FEV1/VC [%] 79.96 ± 7.75 79.04 ± 7.69 -0.92 ± 5.23 0,3299 TLC [L, ml] 5.68 ± 1.21 6.30 ± 1.25 649.84 ± 756.45 0,0001 TLC [%p edic ed] 90.78 ± 16.36 100.09 ± 14.86 9.95 ± 12.16 <0.0001 RV [L, ml] 2.48 ± 0.72 2.67 ± 0.71 204.69 ± 700.12 0,0366 RV [%p edic ed] 108.24 ± 28.88 115.32 ± 27.35 8.37 ± 29.19 0,0299 DLCOc [%p edic ed] 57.69 ± 15.94 66.90 ± 14.93 10.18 ± 12.55 <0.0001 KCOc [%p edic ed] 79.31 ± 16.00 83.13 ± 16.51 4.43 ± 11.85 0,0969 WW g oup (N = 894b)VC [L, ml] 3.56 ± 0.98 3.65 ± 0.99 95.1 ± 353.23 0,0336 VC [%p edic ed] 99.23 ± 16.18 101.91 ± 15.65 2.68 ± 9.94 0,0006 FEV1/VC [%] 79.29 ± 7.00 78.56 ± 6.84 -0.73 ± 4.71 0,0212 TLC [L, ml] 6.11 ± 1.30 6.20 ± 1.34 92.72 ± 758.67 0,2036 TLC [%p edic ed] 105.16 ± 15.72 106.31 ± 14.65 1.27 ± 12.84 0,1159 RV [L, ml] 2.61 ± 0.71 2.63 ± 0.71 22.18 ± 611.47 0,6972 RV [%p edic ed] 126.57 ± 30.38 126.59 ± 28.51 0.18 ± 29.61 0,8244 DLCOc [%p edic ed] 77.79 ± 15.96 80.11 ± 14.71 2.79 ± 12.82 0,0101 KCOc [%p edic ed] 88.48 ± 15.43 89.10 ± 15.14 1.51 ± 10.01 0,5088 Page 6 o 10 Mize ae al. Pneumonia (2024) 16:2 olume (RV) has inc eased signi ican ly in he CS g oup (a mean inc ease by 204.69 ml, SD ± 700.12, o 8.37% o p edic ed alue, SD ± 29.19, p = 0.0366 and 0.0299, espec i ely). No signi ican change o RV was obse ed in he WW g oup. Signi ican inc ease o he ans e ac o o ca bon monoxide co ec ed o hemoglobin le el (DLCOc) was obse ed in bo h he CS g oup (a mean inc ease by 10.18% o p edic ed alue, SD ± 12.55, p < 0.0001) and he WW g oup (a mean inc ease by 2.79% o p edic ed alue, SD ± 12.82, p < 0.0101). Nei he g oup has shown a s a is ically signi ican inc ease o he ans- e coe icien o ca bon monoxide co ec ed o hemo- globin le el (KCOc), wi h a mean inc ease by 4.43% o p edic ed alue (SD ± 11.85; p = 0.0969) in he CS g oup, and 1.51% o p edic ed alue (SD ± 10.01; p = 0.5088) in he WW g oup. Table3 compa es bo h s udy g oups wi h espec o he a e o change o he PFT esul s be ween he wo main isi s. The inc ease o s a ic lung olumes (VC, TLC, RV) was signi ican ly highe in he CS g oup compa ed o he WW g oup (p < 0.0001 o VC and TLC, p = 0.0013 and 0.003 o absolu e and %p edic ed alues o RV, espec i ely). Simila ly, he inc ease o DLCOc was signi ican ly highe in he CS g oup (p < 0.0001). The di - e ences be ween he a es o change o FEV1/VC and KCOc we e no s a is ically signi ican (p = 0.1594 and 0.0564, espec i ely). A he ollow-up isi (V2), he mean Radiologi- cal Imp o emen Sco e (RIS) was 5.9 (SD ± 3.11) and 5.7 (SD ± 3.67) o he CS and WW g oup, espec- i ely (p = 0.7966). Comple e adiological imp o emen (de ined as RIS 9 o 10) was obse ed mo e equen ly in he CS g oup han he WW g oup wi h 21 (16.03%) s. 94 (10.51%), espec i ely, bu he di e ence was bo de line non-signi ican (OR 1.62, 95%CI 0.97–2.71). Good adio- logical imp o emen (de ined as RIS 5 o 8) was obse ed signi ican ly mo e equen ly in he CS g oup han he WW g oup wi h 64 (48.85%) s. 98 (10.96%), espec i ely (OR 7.76, 95%CI 5.19–11.59). The equency o no adio- logical imp o emen (de ined as RIS o 0) was compa a- ble be ween he s udy g oups wi h 12 (9.16%) cases in he CS g oup and 55 (6.15%) cases in he WW g oup, espec- i ely (OR 1.54, 95%CI 0.80–2.96). Finally, he mean Subjec i e Imp o emen Sco e (SIS) a he ollow-up isi (V2) was 7.1 (SD ± 2.71) and 6.7 (SD ± 3.27) o he CS and WW g oup, espec i ely (p = 0.7). Comple e subjec i e imp o emen (de ined as SIS 9 o 10) was obse ed signi ican ly mo e equen ly in he CS g oup han he WW g oup wi h 45 (34.35%) s. 189 (21.14%), espec i ely (OR 1.95, 95%CI 1.32–2.90). Good subjec i e imp o emen (de ined as SIS 5 o 8) was seen signi ican ly mo e equen ly in he CS g oup han he WW g oup wi h 66 (50.38%) s. 196 (21.92%), espec- i ely (OR 3.62, 95%CI 2.48–5.27). The equency o he subjec s epo ing no subjec i e imp o emen (de ined as SIS o 0) was compa able be ween he s udy g oups wi h 8 (6.11%) cases in he CS g oup and 57 (6.38%) cases in he WW g oup, espec i ely (OR 0.96, 95%CI 0.44–2.05) (Table4). Logis ic eg ession analysis was conduc ed o e alua e he likely p edic o s o lack o subjec i e and adiological imp o emen , de ined as SIS = 0 and RIS = 0, espec i ely. Age, sex, COVID-19 se e i y, he use o CS, Como - bidi y sco e (ComS), and obesi y we e selec ed as inde- penden a iables. The only independen a iable ha signi ican ly p edic ed he lack o subjec i e imp o e- men was he Como bidi y sco e, whe e a uni inc ease in he sco e inc eased he odds o he pa ien epo ing no subjec i e imp o emen 1.307 imes (95% CI 1.031– 1.658; p = 0.027). The only independen a iable ha sig- ni ican ly p edic ed he lack o adiological imp o emen was he inc easing se e i y o acu e COVID-19, wi h OR 0.271 (95% CI 0.119–0.618) and 0.323 (95% CI 0.156– 0.671) o a mode a e and se e e cou se o COVID-19, espec i ely (p = 0.002). Table 3 Compa ison o CS and WW g oups wi h espec o he changes o pulmona y unc ion a Pa ien s wi h a ailable ollow-up da a; bMann-Whi ney U es CS g oup (N = 131) WW g oup (N=894a) Mean di e ence p- alueb (mean ± SD) (mean ± SD) (MD ± SD) ΔVC [ml] 403.7 ± 510.05 95.1 ± 353.23 308.59 ± 46.10 <0.0001 ΔVC [%p edic ed] 10.3 ± 13.33 2.7 ± 9.94 7.62 ± 1.21 <0.0001 ΔFEV1/VC [%] -0.9 ± 5.23 -0.7 ± 4.71 -0.19 ± 0.48 0,1594 ΔTLC [ml] 649.8 ± 756.45 92.7 ± 758.67 557.13 ± 70.79 <0.0001 ΔTLC [%p edic ed] 9.9 ± 12.16 1.3 ± 12.84 8.68 ± 1.15 <0.0001 ΔRV [ml] 204.7 ± 700.12 22.2 ± 611.47 182.51 ± 64.50 0,0013 ΔRV [%p edic ed] 8.4 ± 29.19 0.2 ± 29.61 8.19 ± 2.74 0,003 ΔDLCOc [%p edic ed) 10.2 ± 12.55 2.8 ± 12.82 7.39 ± 1.18 <0.0001 ΔKCOc [%p edic ed] 4.4 ± 11.85 1.5 ± 10.01 2.92 ± 1.09 0,0564 Page 7 o 10 Mize ae al. Pneumonia (2024) 16:2 Discussion Bo h he pa ien s ecei ing o al CS and he pa ien s in he wa ch ul wai ing g oup ha e seen s a is ically signi i- can inc eases in s a ic lung olumes and DLCO. Mos o he baseline cha ac e is ics (Age, BMI, VC, FEV1/VC, DLCO, KCO) in ou s udy we e e y close o he cha ac- e is ics o he smalle coho (n = 35) desc ibed by Myall e al. [5] o e ing a good oppo uni y o compa ison. The a e o imp o emen o i al capaci y (9.6% o p edic ed alue, SD ± 13.6) epo ed in he a o emen ioned s udy was compa able o ou esul s, howe e , he epo ed imp o emen o DLCO (31.49% o p edic ed alue, SD ± 27.7) was much highe han in ou s udy, albei wi h highe a iance p obably due o smalle sample size. In e es ingly, he s udy epo ed a signi ican imp o e- men in KCO by a mean o 19.9% o p edic ed (95% CI 9.72–30.1), wi h no signi ican imp o emen being obse ed in ou coho . The au ho s b ie ly s a e ha he unc ional imp o emen in hei coho was mi o ed by good esolu ion o adiological changes and clinical imp o emen , which seems o be in line wi h ou coho , whe e comple e and good adiological and subjec i e imp o emen was equen ly obse ed in he CS g oup. Myall e  al. sugges CS he apy only o symp oma ic pa ien s wi h in ol emen o mo e han 15% o lung pa enchyma on ches CT, wi h he lack o spon aneous imp o emen . The ini ial dosage was simila o ou s udy (a mean dose o 26.6 s. 27.6mg o p ednisolone, espec- i ely). We specula e ha one o he easons o be e imp o emen o DLCO and KCO epo ed by Myal e al. may be he ea lie ini ia ion o he apy (6 weeks s. a mean o 12 weeks, SD 7.55), and pe haps e en he leng h o he apy (3 weeks s. a mean o 21 weeks, SD ± 7.96). Fu he mo e, he mo e es ic i e indica ion o VC he - apy based on 6-minu e walk es (6MWT), o he p es- ence o desa u a ion > = 4% may ha e been a mo e p ecise selec ion ool o he conside a ion o CS he apy, indi- ca ing possible o e p esc ip ion in ou coho , whe e he c i e ia we e less s ic (dec eased DLCOc, pe sis- en adiological abno mali ies and pe sis en espi a o y symp oms). We acknowledge he lack o 6MWT as one o he weaknesses o ou s udy. Impo an ly, ou s udy shows ha pa ien s in he CS medica ing g oup displayed signi ican ly be e a es o imp o emen o s a ic lung olumes and DLCO compa ed o he wa ch ul wai ing g oup, and ha he di e ence seems o be la ge enough o be clinically ele an . Dhoo ia e  al. [31] conduc ed an in es iga o -ini- ia ed, single-cen e , open-label, pa allel-g oup, an- domized, supe io i y ial ( he COLDSTER ial) compa ing wo p ednisolone dosage egimens in 130 pa ien s wi h pos -COVID di use lung abno mali- ies (PC-DPLAS). The CS he apy was ini ia ed 3–8 weeks pos -COVID - ea lie han in ou s udy. The sub- jec s we e andomized in o wo equally sized g oups o ecei e ei he he high-dose egimen (ini ial dose o 40 mg o p ednisolone ape ed o e 6 weeks) o he low-dose egimen (10mg o p ednisolone o e 6 weeks). The inclusion c i e ia we e di use lung abno - mali ies a ec ing a leas 20% o he lung pa enchyma on semiquan i a i e assessmen on hin sec ion CT, and a leas one o he ollowing: mMRC sco e o 2 o highe , es ing SpO2 94% o below, o desa u a ion by a leas 4% du ing 6MWT. No signi ican di e ence was obse ed be ween he wo CS egimens wi h ega ds o he a e o comple e adiological esponse (de ined as 90% o g ea e imp o emen on he ollow-up ches CT scan), which was seen in 24.6% and 18.5% in high and low-dose CS g oups, espec i ely. Simila ly, no signi i- can di e ence be ween he s udy g oups was obse ed wi h espec o he a e o “good o comple e adiologi- cal esponse” (de ined as 50% o g ea e imp o emen ), Table 4 Compa ison o CS and WW g oups wi h espec o he adiological and subjec i e imp o emen a Pa ien s wi h a ailable ollow-up da a; bRadiological imp o emen sco e (0–10); cMann-Whi ney U es ; dSubjec i e imp o emen sco e (0–10); eRIS 9–10; RIS 5–8; gRIS = 0; hSIS 9–10; iSIS 5–8; iSIS = 0 CS g oup (N = 131) WW g oup (N = 894a) Mean di e ence p- aluec (mean ± SD) (mean ± SD) (MD ± SD) RISb5.9 ± 3.11 5.7 ± 3.67 0.17 ± 0.30 0.7966 SISd7.1 ± 2.71 6.7 ± 3.27 0.40 ± 0.26 0.7 n (%N) n (%N) OR (95% CI) Comple e adiological imp o emen :e21 (16.03%) 94 (10.51%) 1.62 (0.97 - 2.71) Good adiological imp o emen : 64 (48.85%) 98 (10.96%) 7.76 (5.19 - 11.59) No adiological imp o emen :g12 (9.16%) 55 (6.15%) 1.54 (0.80 - 2.96) Comple e subjec i e imp o emen :h45 (34.35%) 189 (21.14%) 1.95 (1.32 - 2.90) Good subjec i e imp o emen :i66 (50.38%) 196 (21.92%) 3.62 (2.48 - 5.27) No subjec i e imp o emen :j8 (6.11%) 57 (6.38%) 0.96 (0.44 - 2.05) Page 8 o 10 Mize ae al. Pneumonia (2024) 16:2 which was seen in 84.6% and 80.0% in he high and low dose egimen, espec i ely. The epo ed a es o adio- logical esponse we e highe han in ou coho , whe e he comple e esponse in he CS g oup was obse ed in 16.03% and “comple e o good” esponse in 48.85%. Howe e , he compa ison is no di ec as he adio- logical imp o emen in ou coho was sco ed semi- quan i a i ely using pai ed ches X- ays a he han he quan i a i e assessmen o he CT scans used in he COLDSTER ial. Despi e his majo me hodological di e ence, he esul s consis en ly show ha he majo - i y o pa ien s p esc ibed CS ha e expe ienced signi i- can adiological imp o emen . Impo an ly, ou da a show ha he a es o “good o comple e” adiological imp o emen we e signi ican ly highe in he CS e sus wa ch ul wai ing g oup. Un o una ely, he PFT in he COLDSTER ial only encompassed s anda d spi om- e y and only he alue o FVC a week 6 was epo ed, wi hou p o iding he baseline alue. The epo ed mean FVC a week 6 is signi ican ly lowe e en in com- pa ison wi h he mean baseline alue obse ed in ou coho , e en mo e so when compa ed o he alue a V2. Addi ionally, he e we e signi ican di e ences be ween he s udy popula ion and ou coho wi h espec o sex, age and COVID-19 se e i y. Goel e  al. [30] epo ed on 49 pa ien s wi h long COVID, abno mal indings on ches CT, and es ing o exe ion hypoxemia. 24 o he pa ien s we e ea ed wi h de lazaco o 8 o 10 weeks, ini ia ed 4 weeks a e he in ec ion - ea lie han in ou coho . A he ini ia ion o he apy, 58% o he pa ien s epo ed Modi ied Medical Resea ch Council (mMRC) sco e o 4, which dec eased o a sco e 2 o less in 86% o he pa ien s ollowing CS ea men . The occu ence o b ea hlessness has hal ed, he incidence o cough has dec eased by almos 70%. The majo i y o he pa ien s (71%) epo ed subjec- i e imp o emen , which is in line wi h pa ien s in ou coho , whe e 50.38% and 34.35% o pa ien s ea ed wi h CS ha e epo ed good and comple e subjec i e imp o emen , espec i ely. Comple e adiological eso- lu ion o pos -COVID esidual changes was seen in 25% o he pa ien s, which is close o he 16.03% o pa ien s wi h comple e adiological esponse in he CS g oup o ou coho . Addi ionally, Goel e al. epo he 6-min- u e walk es dis ance (6MWD) inc ease by an a e age o 75m. Indica ion c i e ia o CS he apy we e abno - mali ies on HRCT o he lungs ( e icula ions, g ound glass opaci ies o pa enchymal bands) and oxygen sa u a- ion (SpO2) below 90%, o desa u a ion by mo e han 4% du ing 6MWT. De lazaco was adminis e ed in a dose equi alen o 0,25–0,5mg/kg o p ednisolone, which is compa able o ou s udy, and ape ed o e 6 o 10 weeks (usually 8 weeks) based on adiological eco e y. The weakness o he s udy was he lack o pulmona y unc- ion es ing and he small coho size. Acco ding o Bieksiene e al. [20] imely glucoco icoid he apy can be bene icial in p e en ing he de elopmen o de ini i e ib o ic changes in pa ien s wi h pos - COVID pulmona y impai men , ypically wi hin he i s 12 weeks om he acu e s age o he disease. In he case o mo e d ama ic la e-s age disease p esen a ions, such as acu e ib inous o ganizing pneumonia, se e al cases o good esponse o co icos e oid pulses (up o 1g me hyl- p ednisolone o 3 consecu i e days) ollowed by ape ing o lowe doses o CS ha e been epo ed in he li e a u e [23, 24, 33]. Limi a ions o  hes udy One o he majo limi a ions o he p esen s udy is he ac ha he da a ex ac ion p ocess is s ill ongoing. The esul s o he s udy should he e o e be iewed as in e im. This is pa ially ou weighed by he ela i ely la ge size and obus ness o he a ailable da a. Ano he weakness o his s udy is he lack o andomiza ion as his was a eal-li e s udy and he decision o CS he apy was d i en by pe cei ed clinical necessi y wi h a p ima y in en ion no o ha m. The dosage o CS used in he s udy was no s anda dized and was subjec o he decision o he in es iga ing physician. Finally, he cu en ly incomple e da a ega ding he cou se o acu e COVID-19 only pe - mi ed a ough di ision in o mild, mode a e and se e e ca ego ies, bu did no p o ide enough da a o accu a ely label he su i o s o c i ical COVID-19. This will likely change in he u u e as mo e da a a e being ex ac ed om he sou ce in o ma ion. Conclusion Despi e he ma ked di e ences be ween s udy popula- ions and me hodological di e ences, mos o he pub- lished s udies epo a o able adiological, subjec i e, and unc ional ou comes in mos pa ien s ea ed wi h glucoco icoids o pos -COVID pulmona y in ol e- men . Ou s udy con i ms hese p e ious obse a ions by p o iding a compa a i ely la ge da ase and a com- pa ison o an unma ched con ol g oup, showing be e unc ional, adiological, and subjec i e imp o emen in selec ed pa ien s ea ed wi h o al co icos e oids. Conside ing ou da a alongside p e iously published s udies, he sugges ed indica ion c i e ia should include signi ican pa enchymal in ol emen , dec eased alue o DLCO and pe sis en subjec i e symp oms. Res ing desa u a ion, o desa u a ion du ing he 6-minu e walk es may u he suppo he decision and lead o mo e p ecise indica ion o CS he apy. One possible app oach o imp o e clinical decision making may be he use o a i icial in elligence d i en Page 9 o 10 Mize ae al. Pneumonia (2024) 16:2 algo i hms, as demons a ed by an a ilia ed collec i e o Myska e al. [34], who ha e used he da a om Olomouc pos -COVID da ase o es he pe o mance o 9 di e - en machine lea ning algo i hms in p edic ing imp o e- men in he pa ien s indica ed o CS he apy. The bes esul s we e achie ed by he Decision T ee app oach, eaching 73.52% balanced accu acy on a alida ion po - ion o he da ase . The au ho s con inue wi h he wo ks on he Olomouc pos -COVID da ase , aiming a p o iding mo e de ailed da a on como bidi ies and o he clinical pa ame e s. The au ho s aim o make he da ase publicly a ailable and o p o ide da a om u he ollow-up o hope ully b ing new insigh s abou he mo e long- e m ou comes o hese pa ien s, as he e a e s ill ques ions o be answe ed. The opics o u u e esea ch include, among o he s, he op imum leng h o he apy, he c i e ia o cessa ion o he apy, he possible bene i s o an i ib o ics in combi- na ion wi h CS, o he incidence and cha ac e is ics o elapses ollowing CS cessa ion. Au ho s’ con ibu ions J.M. w o e manusc ip ex , collec ed and analyzed da a; S.G. coope a ed on w i ing he manusc ip ex , collec ed and analyzed da a; M.S. collec ed and analyzed da a; R.B. collec ed and analyzed da a; J.Z. analyzed da a and helped wi h manusc ip p epa a ion; P.J. helped wi h p epa a ion o manusc ip ex , collec ed and analyzed da a; M.V. helped wi h manusc ip p epa a ion; P.P. helped wi h manusc ip p epa a ion and da a analyzis; L.S. helped wi h manu- sc ip p epa a ion and da a analyzis. Funding The s udy was suppo ed by Czech Heal h Resea ch Council g an numbe NU22-A-105. A ailabili y o da a and ma e ials The da a ha suppo he indings o his s udy a e no openly a ailable due o easons o sensi i i y and a e a ailable om he co esponding au ho upon easonable eques . Da a a e loca ed in con olled access da a s o age a Palacky Uni e si y Olomouc, Czech epublic. Decla a ions E hics app o al and consen o pa icipa e All subjec s ag eed o join he s udy and signed in o med consen . The con- sen o mino s had o be signed by hei legal ep esen a i e (a pa en ). The local e hical commi ee app o ed he s udy (E hical Commi ee o Uni e si y Hospi al Olomouc and Facul y o Medicine and Den is y o Palacky Uni e si y Olomouc, Czech Republic), wi h decision numbe 98/21 (da e 7/JUN/2021). Compe ing in e es s The au ho s decla e no compe ing in e es s. Au ho de ails 1 Depa men o Respi a o y Medicine and Tube culosis, Facul y o Medicine and Den is y Palacky Uni e si y Olomouc, Uni e si y Hospi al Olomouc, Olomouc, Czech Republic. 2 Cen e o Digi al Heal h, Facul y o Medicine and Den is y, Palacky Uni e si y Olomouc, Hne o inska 976/3, Olomouc 779 00, Czech Republic. 3 Depa men o Respi a o y Medicine and Tube culosis, Facul y o Medicine and Den is y Masa yk, Uni e si y Hospi al B no, Uni e si y B no, B no, Czech Republic. 4 Dep . o Telecommunica ions, Facul y o Elec ical Enginee ing and Communica ion, B no Uni e si y o Technology, B no, Czech Republic. 5 Depa men o Respi a o y Medicine and Tube culosis, L.Pas eu Uni e si y Hospi al and Facul y o Medicine P.J. Sa a ik Uni e si y Kosice, Kosice, Slo akia. 6 Depa men o Medical Biophysics, Facul y o Medicine and Den is y Palacky Uni e si y Olomouc, Olomouc, Czech Republic. Recei ed: 3 Oc obe 2023 Accep ed: 2 Decembe 2023 Re e ences 1. Baig AM. Ch onic COVID synd ome: need o an app op ia e medi- cal e minology o long-COVID and COVID long-haule s. J Med Vi ol. 2021;93(5):2555–6. 2. Cen e s o Disease Con ol and P e en ion [h ps:// www. cdc. go /]. Long- e m e ec s o COVID-19; 2020. A ailable om: h ps:// s acks. cdc. go / iew/ cdc/ 97204. Accessed 15 May 2023. 3. Skala M, S oboda M, Kopecky M, e al. He e ogeni y o pos -COVID impai men : in e im analysis o p ospec i e s udy om Czechia. Vi ol J. 2021;18(1):73. 4. Hama Amin BJ, Kakamad FH, Ahmed GS, e al. Pos COVID-19 pulmona y ib osis; a me a-analysis s udy. Ann Med Su g (Lond). 2022;77:103590. 5. Myall KJ, Mukhe jee B, Cas anhei a AM, e al. Pe sis en pos -COVID-19 in e s i ial lung disease. An obse a ional s udy o co icos e oid ea - men . Ann Am Tho ac Soc. 2021;18(5):799–806. 6. Ba ah SS, Fab o AT. Pulmona y pa hology o ARDS in COVID-19: a pa ho- logical e iew o clinicians. Respi Med. 2020;176:106239. 7. Wigén J, Lö dahl A, Bje me L, e al. 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