Differences in Disease Expression Between Primary Ciliary Dyskinesia and Cystic Fibrosis With and Without Pancreatic Insufficiency

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1 CHEST Originl Reserch GENETIC AND DEVELOPMENTAL DISORDERS Differences in Disese Expression Between Primry Ciliry Dyskinesi nd Cystic Fibrosis With nd Without Pncretic Insufficiency Mlen Cohen-Cymberknoh, MD ; Ntli Simnovsky, MD ; Nurith Hiller, MD ; Alex Gileles Hillel, MD ; Dvid Shoseyov, MD ; nd Eitn Kerem, MD Bckground: Impired mucociliry clernce cuses pulmonry disese in primry ciliry dyskinesi (PCD) nd contributes to cystic fibrosis (CF) lung disese. Although the sinopulmonry disese is similr, morbidity nd mortlity re different. Both ptients with PCD nd ptients with CF with pncretic sufficiency (CF-PS) show no nutrient mlbsorption nd re dignosed t lter ge compred with ptients with CF with pncretic insufficiency (CF-PI). Methods: Clinicl sttus, microbiology,, nd high-resolution CT (HRCT) scns presented s totl Brody score (CT-TBS) were compred for ptients with PCD, CF-PI, nd CF-PS, ll treted t the sme medicl center, by the sme tem, nd by similr routine follow-up. Results: One hundred sixty-four ptients, 34 with PCD, 88 with CF-PI, nd 42 with CF-PS were enrolled. PCD ws dignosed t similr ge s CF-PS but significntly lter thn CF-PI. Men % predicted ws similr for the three groups. The rte of chnge with ge in PCD ws similr to CF-PS but significntly lower thn in CF-PI. Severity of structurl lung disese (CT-TBS) ws similr for PCD nd CF-PS nd significntly higher in CF-PI. No correltion between TBS or Pseudomons eruginos infection nd in PCD ws seen, wheres negtive correltion with ws observed for both CF groups. Conclusions: Although in our study PCD ws similr to CF-PS, the lck of correltion between nd ge, CT-TBS, nd P eruginos infection in PCD suggests tht impired mucociliry clernce is not the only cuse for inducing pulmonry dmge in these diseses. Furthermore, comprison of disese chrcteristics for PCD nd CF should distinguish between CF-PI nd CF-PS s different entities. CHEST 2014; 145(4): Abbrevitions: CF 5 cystic fibrosis; CF-PI 5 cystic fibrosis with pncretic insufficiency; CF-PS 5 cystic fibrosis with pncretic sufficiency; CFTR 5 cystic fibrosis trnsmembrne conductnce regultor; HRCT 5 high-resolution CT; MCC 5 mucociliry clernce; PCD 5 primry ciliry dyskinesi; TBS 5 totl Brody score Effective mucociliry clernce (MCC) in the respirtory system requires proper mucus production nd functioning irwy surfce fluid lyer s well s competent nd coordinted ciliry beting. 1 The vitl role of these mechnisms is best demonstrted for primry ciliry dyskinesi (PCD) nd cystic fibrosis (CF), both chrcterized by impired MCC leding to cute nd chronic sinopulmonry infections. PCD is cused by defects in genes encoding the structure or function of the respirtory cili. 2,3 CF is cused by muttions in the CFTR gene cusing n bnorml irwy surfce fluid lyer, generting thickened nd viscous mucus, which impirs MCC. In both diseses, recurrent nd chronic respirtory infections nd persistent inflmmtion cuse progressive lung dmge. 4-6 Most ptients with CF suffer from pncretic insufficiency (CF with pncretic insufficiency [CF-PI]), lthough up to 15% hve sufficient pncretic enzyme For editoril comment see pge 674 production to mintin norml ft bsorption (CF with pncretic sufficiency [CF-PS]). CF-PS is cused by CF trnsmembrne conductnce regultor (CFTR) muttions of clss IV nd V, sso cited with reduction in the number or ctivity of functionl CFTR chloride 738 Originl Reserch

2 chnnels over the picl membrne of respirtory epithelil cells. 7 CF-PI is cused by CFTR muttions of clss I, II, nd III, resulting in severely reduced or bsent CFTR function Compred with CF-PI, ptients with CF-PS re dignosed t lter ge, hve better nutritionl sttus, re less colonized by Pseudomons eruginos, nd generlly live longer. 11,12 Pulmonry function ws shown to be highly vrible in both ptient groups. 13 Additionlly, we hve recently shown tht lung bnormlities on chest CT scns of ptients with CF-PI nd CF-PS show different ptterns.14 Ptients with PCD nd CF-PS do not suffer from pncretic insufficiency nd, therefore, usully do not show nutritionl deficiencies typiclly ssocited with more severe pulmonry disese in CF-PI. Additionlly, PCD nd CF-PS re often dignosed t lter ge, nd ptients hve longer survivl compred with ptients with CF-PI. 13,15,16 In this study, we compred pulmonry disese expression between PCD, CF-PS, nd CF-PI, s mesured by pulmonry function, high-resolution CT (HRCT) scn scores, nd sputum bcteriology, correlted with ge nd nutritionl sttus. Previous studies between PCD nd CF did not distinguish between CF-PS nd CF-PI s seprte groups. 16,17 Mterils nd Methods Ptients with confirmed dignosis of PCD or CF, who were treted t the Hdssh Medicl Center from 2007 to 2011 nd for whom spirometry, HRCT scn, sputum cultures, nd pncretic sufficiency test dt were vilble, were included in the study. The study ws pproved by the Hdssh Medicl Center Institutionl Review Bord, nd written informed consent ws wived (Committee on Reserch Involving Humn Subjects of the Hebrew University Hdssh Medicl School, HMO). The CF nd PCD Centers t the Hdssh Medicl Center mintin dtbses for their ptients from the time of dignosis. These ptients present t the clinic routinely every 1 to 3 months nd re seen by the sme specilist stff. However, ptients with PCD do not regulrly consult with our nutritionist, in contrst Mnuscript received My 16, 2013; revision ccepted September 4, Affilitions: From the Deprtment of Peditrics (Drs Cohen- Cymberknoh, Gileles Hillel, nd Shoseyov nd Prof Kerem), the Cystic Fibrosis nd Primry Ciliry Dyskinesi Center (Drs Cohen- Cymberknoh, nd Shoseyov nd Prof Kerem), nd the Deprtment of Rdiology (Drs Simnovsky nd Hiller), Hdssh Hebrew- University Medicl Center, Mount Scopus, Jeruslem, Isrel. Drs Cohen-Cymberknoh nd Simnovsky contributed eqully to this mnuscript. Funding/Support: This study ws funded by deprtmentl grnts from Hdssh Hebrew University Hospitl. Correspondence to: Eitn Kerem, MD, Peditric Division, Hdssh Hebrew-University Medicl Center, POB 12000, Jeruslem, Isrel; e-mil: kerem@hdssh.org.il 2014 Americn College of Chest Physicins. Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins. See online for more detils. DOI: /chest to ptients with CF. Besides this exception, similr routine follow-up is performed for the three ptient groups, nmely, frequent visits, pulmonry function nd sputum culture t ech visit, nd chest CT scns every 2 yers. PCD is dignosed ccording to typicl clinicl presenttion together with low nsl nitric oxide nd bnorml ciliry morphology on electron microscopy nd/or bnorml ciliry bet pttern nd/or two PCD known muttions 15 ( Tble 1 ), wheres CF is dignosed ccording to the consensus sttement of the Cystic Fibrosis Foundtion. 18 Pncretic function ws defined in ll ptients bsed on 3-dy stool ft collection, fecl elstse ssessment, or both. Pncretic insufficiency ws defined s stool elstse, 100 m g/g stool or coefficient of ft bsorption, 93%. Pulmonry function tests were performed ccording to Americn Thorcic Society/Europen Respirtory Society guidelines. 19 Ptients ble to complete spirometry tests, usully those. 5 yers of ge, were included. ws presented s % predicted vlue ccording to Wng et l 20 for children nd Hnkinson et l 21 for dults. Periodic HRCT scns were performed for ll ptients s prt of the routine ssessment, using dul-slice CT scnner (Twin Flsh; Mrconi Medicl Systems), four-slice multidetector spirl CT scnner (Light Speed Plus; Generl Electric), or 16-slice scnner (Light Speed; Generl Electric). Imges were cquired using stndrd scn prmeters, including mximum 120 kvp, uto-ma (mximl-350 ma), pitch-1, nd mtrix. Slice width ws 3.75 to 5 mm for conventionl scns nd 1 to 1.25 mm for high-resolution imges, reconstructed with bone lgorithm. HRCT scns were obtined in single breth-hold during suspended end-inspirtion, in supine position, without contrst mteril injection. HRCT scn studies were jointly reevluted on lung nd medistinl windows by n experienced peditric rdiologist (N. S.) nd n experienced chest rdiologist (N. H.), both blinded to the ptient group, using the institutionl PACS system (Centricity PACS; Generl Electric). Lung chnges were ssessed on high-resolution imges in the lung window. For ech lung lobe, including the lingul, counted s seprte lobe, the Brody score 22 ws clculted with slight modifiction, nmely, hyperertion of the lungs ws evluted insted of ir trpping, s expirtory imges were not obtined in ll ptients. Such modifiction of the Brody score hs been used previously.23 Briefly, subscores for the presence nd severity of bronchiectsis, mucous plugging, bronchil wll thickening, prenchym, nd focl hyperertion in ech lobe were clculted. Prenchyml findings of ground glss, consolidtion, nd cysts or bulle were ll considered in determining single prenchym subscore. 22 The sum of subscores constituted lung totl Brody scores (TBSs) for ech ptient. For the current nlysis, in ptients who hd more thn one HRCT scn during the study period, the most recent study ws considered nd correlted with clinicl prmeters tht were performed closest to the dte of HRCT scn. BMI ws clculted for ll ptients. For those, 20 yers of ge, BMI ws presented s percentile for ge, nd for those 20 yers, the corresponding BMI percentile ws clculted, fcilitting comprisons. 24 Sputum cultures were obtined routinely t every clinic visit, using the sme microbiologic culture methods for ptients with PCD nd CF. Chronic infection ws defined when ptients hd t lest three positive cultures within 1 yer. For this cross-sectionl study, ll prmeters were clculted using descriptive sttistics nd percentile methods. Groups were compred using the Student t test, one-wy nlysis of vrince, or nonprmetric Person x 2 test. Correltions between continuous vribles were evluted with Person correltion, wheres correltions between nonprmetric vribles were evluted with Spermn r correltion. Continuous dt re expressed s men SD unless otherwise specified. A two-tiled P,.05 ws journl.publictions.chestnet.org CHEST / 145 / 4 / APRIL

3 Tble 1 Dignostic Prmeters of Ptients With PCD Prmeter considered significnt. All sttisticl nlysis ws performed with SPSS softwre (IBM). Results Mesure No. of ptients 34 Men current ge (SD), y 15.9 (8.6) % predicted (SD) 85 (14) Dextrocrdi/situs inversus 10 TTN/recurrent AOM/bronchiectsis/chronic sinusitis 34 Nsl NO (rnge), ppb 39.7 (1-108) F eno (rnge), ppb 10.6 (1-37) Norml EM 9 Absent IDA or ODA 4 Short DA 4 Not done/technicl problem 11 PCD-relted 2 muttions 18 AOM 5 cute otitis medi; DA 5 dynein rms; EM 5 electron microscopy; F eno 5 frctionl exhled nitric oxide; IDA 5 inner dynein rm; NO 5 nitric oxide; ODA 5 outer dynein rm; PCD 5 primry ciliry dyskinesi; ppb 5 prts per billion; TTN 5 trnsient tchypne of the newborn. A totl of 164 ptients, 34 with PCD nd 130 with CF (88 with CF-PI [67.7% of ptients with CF, 53.7% of the study popultion] nd 42 with CF-PS [32.3% of CF nd 25.6% of ll ptients]), were enrolled. Tble 2 summrizes the clinicl presenttion of ll ptients. Ptients with PCD nd CF-PI were similr in ge nd younger thn the CF-PS group ( P nd 0.014, respectively). Additionlly, PCD ws dignosed t significntly lter ge compred with the totl CF group ( P 5.002) but t similr ge s CF-PS. Men ws similr in the three groups ( Tble 2 ). As shown in Figure 1, there ws strong negtive correltion between nd ge in CF-PI nd CF-PS ( r , P 5.018, nd r , P 5.022, respec- tively), wheres in PCD the correltion between ge nd did not rech sttisticl significnce ( r , P 5.061). However, the rte of chnge in with ge ws similr in PCD nd CF-PS (B , P 5.061, nd B , P 5.022, respectively) nd significntly lower thn in CF-PI (B , P 5.018), suggesting tht in PCD, the decrese in lung function with ge is similr to CF-PS nd slower thn in CF-PI. Ptients with PCD hd less severe lung disese, mesured by TBS, compred with CF ( P 5.019); however, different results were found when nlyzing the CF subgroups seprtely ( Tble 3 ). The severity of TBS ws similr for PCD nd CF-PS (TBS of 30.8 for PCD vs 31.4 for CF-PS) nd significntly higher in ptients with CF-PI (TBS of 57.3, P,.001), gin indicting similr lung disese severity in PCD nd CF-PS. For ll groups, the level of lung disese ws similr in both sides; however, the distribution of structurl chnges within the lung fields vried significntly: In PCD, 56% of TBS ws ssigned to the right middle lobe nd lingul nd 38% to the lower lobes, wheres only 6% ws ttributed to the upper lobes ( P,.001). In contrst, in CF-PI, the upper lobes represented 39% of TBS ( P for comprison between the upper, middle, nd lower lobes in CF-PI). In CF-PS, no prticulr distribution of pthology ws found in HRCT scn ( P 5.330). As shown in Figure 2, no correltion ws seen between nd TBS in PCD ( r , P 5.71), wheres there ws strong negtive correltion between TBS nd for both CF subgroups (CF-PS: r , P 5.005; CF-PI: r , P,.001). Ptients with PCD hd significntly lower BMI compred with the CF group ( P,.001) nd with the CF-PI nd CF-PS subgroups ( P nd P 5.001, respectively). As expected, strong positive correltion between BMI nd in CF-PI ( r , Tble 2 Prmeters of Ptients With PCD, CF-PI, nd CF-PS Prmeter PCD CF CF-PI CF-PS P vlue (PCD vs CF) P Vlue (PCD, CF-PI, CF-PS) No. of ptients Sex, No. (%) Mle 14 (41) 71 (54.7) 52 (59) 19 (45.2) Femle 20 (59) 59 (45.3) 36 (41) 23 (54.8) Age t dignosis, y Men (SD) 10.2 ( 5.9) 4.28 ( 7.9) 1 ( 1.5) 12.6 ( 11).002,.001 Medin (rnge) 10 (0.1-25) 0.7 (0.1-45) 0.6 (0.1-8) 10 (0.1-45) Current ge, y Men (SD) 15.9 ( 8.6) 17.7 ( 12.3) 15.6 ( 8.6) 22.1 ( 17) Medin (rnge) 14 (2-32) 15 (1-68) 15 (1-35) 16.5 (4-68) % predicted, 85 (14) 85.3 (23.5) 83.1 (22.3) 89.6 (25.5) Men (SD) BMI, percentile (SD) 21.3 (19.3) 44.2 (28) 42 (27.2) 49.3 (29.3), CF 5 cystic fibrosis; CF-PI 5 cystic fibrosis with pncretic insufficiency; CF-PS 5 cystic fibrosis with pncretic sufficiency. See Tble 1 legend for expnsion of other bbrevition. Comprison between the three groups. 740 Originl Reserch

4 Figure 1. The reltionship between ge nd pulmonry function ssessed by in ptients with PCD, CF-PI, nd CF-PS. CF-PI 5 cystic fibrosis with pncretic insufficiency; CF-PS 5 cystic fibrosis with pncretic sufficiency; PCD 5 primry ciliry dyskinesi. P 5.007) nd trend towrd significnt correltion for the PCD group ( r , P 5.06) ws observed. No correltion between BMI nd in CF-PS ws found ( r , P 5.77) ( Fig 3 ). The most common bcteril infection in PCD ws Hemophilus influenze, wheres for both CF subgroups P eruginos ws predominnt ( Tble 4 ). The rte of P eruginos infection in the PCD group ws reltively high nd similr to the CF-PS group. For both CF-PI nd CF-PS groups, chronic infection with P eruginos ws ssocited with reduced ( r , P,.001) nd with more severe TBS ( r , P,.001) ( Fig 4 ); however, mong ptients with PCD, there ws no correltion between P eruginos infection nd (r , P 5.29) or TBS ( r , P 5.26). Figure 2. The reltionship between pulmonry function ssessed by nd TBS in high-resolution CT imges of ptients with PCD, CF-PI, nd CF-PS. TBS 5 totl Brody score. See Figure 1 legend for expnsion of other bbrevitions. Discussion To our knowledge, this is the first study compring disese expression between PCD nd CF, nlyzing seprtely CF-PI nd CF-PS. Ptients with PCD, like those with CF-PS, do not suffer from pncretic insufficiency nd re generlly dignosed t lter ge compred with ptients with CF-PI. In PCD, in contrst to results seen for both CF groups, no correltion between nd TBS or between nd ge ws found. For PCD, these dt provide Tble 3 Chest HRCT Scn TBS of Ptients With PCD, CF-PI, nd CF-PS View PCD CF-PI CF-PS P Vlue Both lungs 30.8 (28.1) 57.3 (33.8) 31.4 (30.5),.001 Right lung 16.3 (16.1) 28.9 (17.7) 15.4 (16.4).001 Left lung 14.5 (13.7) 28.4 (17.6) 15.9 (15.9),.001 Upper 1.9 (3.5) 22 (13.1) 8.9 (11.4),.001 lobes 6% of TBS 39% of TBS 29% of TBS Middle 17.3 (16.6) 17.2 (11.9) 11 (10.3).095 lobes 56% of TBS 30% of TBS 35% of TBS Lower lobes 11.6 (11.7) 18 (14.1) 11.3 (12.8) % of TBS 31% of TBS 36% of TBS HRCT 5 high-resolution CT; TBS 5 totl Brody score. See Tble 1 nd 2 legends for expnsion of other bbrevitions. Comprison between the three groups. Figure 3. The reltionship between nd BMI of ptients with PCD, CF-PI, nd CF-PS. See Figure 1 legend for expnsion of bbrevitions. journl.publictions.chestnet.org CHEST / 145 / 4 / APRIL

5 Tble 4 Bcteril Sputum Cultures of Ptients With PCD, CF-PI, nd CF-PS Bcteri PCD (n 5 34) CF (n 5 130) CF-PI (n 5 88) CF-PS (n 5 42) P Vlue (PCD vs CF) P Vlue (PCD, CF-PI, CF-PS) Pseudomons eruginos Hemophilus influenz ,.001,.001 MSSA ,.001,.001 MRSA Dt presented s % of ptients. MRSA 5 methicillin-resistnt Stphylococcus ureus ; MSSA 5 methicillin-sensitive Stphylococcus ureus. See Tble 1 nd 2 legends for expnsion of other bbrevitions. further support tht is not strong predictor for lung disese severity. 17,25-27 Therefore, in the bsence of strong mrkers, follow-up by chest HRCT scns should be considered. To compre lung structurl bnormlities between the three groups, the Brody score system ws used, s described previously for ptients with PCD. 17 The risk of rdition must be considered; therefore, modifiction of the low-rdition protocol described by Loeve et l 28 should be used for the follow-up. Although imges re of lower qulity, they suffice for monitoring progression of lung disese. The disprity in the distribution of lung structurl chnges between the three groups ws not necessrily to be expected. It is uncler why structurl dmge of the lungs in PCD only scrcely involved the upper lobes; however, this could be due to grvittion ugmenting mucus clernce. In CF, mechnicl fctors my possibly fvor mucus stsis nd progressive dilttion of bronchi nd cysts in the upper lobes, 29 or erly or more severe gstroesophgel reflux in CF could led to the observed dmge. Differences in regionl blood flow distribution for both diseses my be considered s well. We hypothesized tht ptients with PCD would hve nutritionl sttus nd respirtory disese sim- ilr to tht of ptients with CF-PS, s both groups do not show pncretic insufficiency. Unexpectedly, we found tht ptients with PCD hd worse nutritionl sttus thn ptients with CF-PI. Mintining good nutrition is fundmentl component of medicl mngement for ptients with CF. However, in PCD, the focus on nutrition is not prt of the stndrd of cre. 30 The direct correltion between BMI nd in our ptients with PCD emphsizes the need to include routine nutritionl ssessment s prt of the routine PCD mngement. Assessment nd correction of nutritionl deficiencies my prevent or slow disese progression in PCD, s it does in CF. Rtes of bcteril infection detected by sputum cultures differed between the three groups. The most common bcterium observed in ptients with PCD ws H influenze, which ws significntly less common in ptients with CF. In ptients with CF s group, s in both subgroups s well, chronic infection with P eruginos ws ssocited with more severe lung disese, nd reduced ( Fig 4 ). However, no correltion between P eruginos infection nd or TBS ws observed in PCD, suggesting different role for this microorgnism in the pthogenesis of pulmonry disese. Figure 4. Correltion between P eruginos coloniztion nd TBS. P. eruginos 5 Pseudomons eruginos. See Figure 1 nd 2 legends for expnsion of other bbrevitions. 742 Originl Reserch

6 Although both PCD nd CF re ssocited with impired MCC, the type of impirment nd its reltive contribution to lung dmge is different for the two diseses. It ws shown tht in CF, MCC is preserved in young ptients nd those with mild lung disese, 31 wheres ptients with PCD hve no MCC from birth, which my explin their neontl respirtory distress nd middle er problems rrely seen in CF. Cough clernce is well preserved in PCD, wheres in CF it is drmticlly decresed (by tencity), gin rguing for immune dysregultion s being most importnt for the pthogenesis nd progress of CF. 32,33 The principl problem in CF is probbly hyperinflmmtory response. 34,35 CF sputum hs been shown to be nonviscous, but rther tencious. This is surfce property tht is influenced by polymeric DNA nd ctin. Bush et l 16 compred mucus properties in both diseses, showing tht inflmmtion, mesured by IL-8 concentrtion, ws greter in PCD sput. No significnt differences in the sputum biophysicl or trnsport properties were seen; however, survivl in ptients with PCD ws generlly better. Another study, by Sntmri et l, 17 compred pulmonry HRCT scn scores for ptients with PCD nd group of ge- nd sex-mtched ptients with CF. They showed tht ptients with PCD hd significntly less structurl lung dmge thn ptients with CF. In our study, ptients with CF-PI hd worse nd TBS compred with ptients with PCD, suggesting tht other cuses, in ddition to impired MCC, re responsible for the higher pulmonry morbidity in CF. Epithelil cell dysregultion, excessive irwy inflmmtion, nd innte immune deficiency in CF were recently described.4,34,35 It is importnt to note tht, in generl, ptients with PCD receive less intensive therpy, 30 nd in our experience, mny do not dhere to the scheduled visits nd to the routine tretments, lthough there is lso published evidence of suboptiml tretment dherence for ptients with CF. Stndrd cre for ptients with PCD in our center consists of tretment with rotting orl ntibiotics, dily inhltions with hypertonic sline, physiotherpy, nd monthly follow-up. Mny of these modlities re used in CF, lthough no evidence for their efficcy ws demonstrted in PCD. 36 Nevertheless, the results of this study show tht dults with PCD do hve better pulmonry functions, reffirming tht disese progression in most ptients is slower thn in CF. PCD nd CF re both chrcterized by impired MCC nd respirtory infections; nevertheless, ptients with PCD hve different disese expression compred with ptients with CF-PS nd CF-PI, s ssessed by, HRCT scn, BMI, nd bcteril infection detected by sputum cultures. Men ws comprble for the three groups. In PCD, ws close to norml even for ptients with severe structurl lung dmge with no substntil chnge with ge. This my suggest more involvement of the lrge irwys in PCD, wheres in CF smll irwys re more ffected. Furthermore, P eruginos infection ws less common in PCD thn in both CF groups nd ws not ssocited with worse lung disese. In conclusion, comprison of disese chrcteristics for PCD nd CF should distinguish between CF-PI nd CF-PS s different entities. Further studies re needed to understnd the implictions of these results nd the correltion between CT scn findings nd outcome in PCD. Acknowledgments Author contributions: Prof Kerem is gurntor of the mnuscript, tking responsibility for the integrity of the dt nd ccurcy of the dt nlysis. Dr Cohen-Cymberknoh: contributed to conception nd design of the study, cquisition of dt, nlysis of the results, nd revision of the mnuscript nd provided finl pprovl of the version to be published. Dr Simnovsky: contributed to performing the CT scns, nlysis, clcultions of TBS, nd revision of the mnuscript nd provided finl pprovl of the version to be published. Dr Hiller: contributed to performing the CT scns, nlysis, clcultions of TBS, nd revision of the mnuscript nd provided finl pprovl of the version to be published. Dr Gileles Hillel: contributed to cquisition of dt, nlysis of the results, nd revision of the mnuscript nd provided finl pprovl of the version to be published. Dr Shoseyov: contributed to cquisition of dt, nlysis of the results, nd revision of the mnuscript nd provided finl pprovl of the version to be published. Prof Kerem: contributed to conception nd design of the study, cquisition of dt, nlysis of the results, nd revision of the mnuscript nd provided finl pprovl of the version to be published. Finncil/nonfinncil disclosures: The uthors hve reported to CHEST tht no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my be discussed in this rticle. 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