Clinical impact of vitamin D treatment in cystic fibrosis: a pilot randomized, controlled trial

OPEN ORIGINAL ARTICLE Clinical impac o i amin D ea men in cys ic fib osis: a pilo andomized, con olled ial T Pinciko a 1,2,3,4 , D Paquin-P oulx 3 , JK Sandbe g 3 , M Flods öm-Tullbe g 3 and L Hjel e 1,2 BACKGROUND/OBJECTIVES: Vi amin D insu ficiency in cys ic fib osis is common. Vi amin D3 is cu en ly p e e ed o e D2. We aimed o s udy he e ficacy o i amin D2 and D3 a inc easing se um 25-hyd oxy i amin D (s25OHD) concen a ions and hei e ec on espi a o y heal h in cys ic fib osis. SUBJECTS/METHODS: Six een CF pa ien s we e andomized o ecei e i amin D2 o D3 o o se e as con ols. The s a ing dose o 5000 IU (o16 yea s old) o 7143 IU/day (⩾16 yea s old) was u he indi idually adjus ed. Th ee mon hs o in e en ion we e ollowed by wo o washou (ClinicalT ials.go NCT01321905). RESULTS: To inc ease s25OHD, he mean daily dose o i amin D2 and D3 had o be inc eased up o 15650 and 8184 IU, espec i ely. The combined g oup o i amin D2 and D3 ea ed pa ien s dec eased plasma IL-8 (Po0.05). Pa ien s p o ided i amin D3 imp o ed FVC a he end o he ial (Po0.05). Change in s25OHD was posi i ely co ela ed wi h changes in he adul Quali y-o -Li e espi a o y sco e a he end o supplemen a ion (P= 0.006, = 0.90), and wi h changes in FEV1 (P= 0.042, = 0.62) and FVC (P= 0.036, = 0.63) a one mon h o washou . CONCLUSIONS: Vi amin D supplemen a ion may con ibu e o educed inflamma ion and imp o ed lung unc ion in CF. Eu opean Jou nal o Clinical Nu i ion (2017) 71, 203–205; doi:10.1038/ejcn.2016.259; published online 14 Decembe 2016 INTRODUCTION In cys ic fib osis (CF), he majo cause o mo bidi y and mo ali y is p og essi e lung disease d i en by ecu ing acu e ai way in ec ions and ch onic bac e ial lung coloniza ion. 1 Vi amin D insu ficiency is common in CF despi e i amin D supplemen a ion. 2,3 In addi ion o i s impo ance o bone heal h, i amin D ac s as a po en immune modula o y agen wi h complex e ec s. 4,5 In CF, i amin D concen a ions ha e been associa ed wi h lung unc ion, 2,6 annual numbe o pulmona y exace ba ions 7 and wi h o al se um IgG le els. 2 The cu en ecommenda ions o i amin D supplemen a ion in CF we e designed wi h ocus on bone heal h. Because o i s highe e ficiency a inc easing se um 25-hyd oxy i amin D (s25OHD), i amin D3 (D3) is cu en ly p e e ed o e i amin D2 (D2). Mos Table 1. To -s25OHD concen a ion, FVC and FEF25% in pa ien s comple ing he s udy Pa ien s comple ing he s udy All pa ien s (n= 13) Con ol g oup (n= 4) D2 g oup (n= 4) D3 g oup (n=5) To -s25OHD a baseline (nmol/l; mean ±s.d.) 58.1 ±21.9 49.0 ±38.7 55.7 ±16.0 65.0 ±13.9 To -s25OHD a 1 week (nmol/l; mean ±s.d.) 61.3 ±23.8 57.3 ±40.9 53.0 ±15.8 70.4 ±18.7 To -s25OHD a 1 mon h (nmol/l; mean ±s.d.) 82.9 ±15.8 74.3 ±19.2 79.0 ±6.9 92.8 ±14.9 To -s25OHD a 2 mon hs (nmol/l; mean ±s.d.) 88.4 ±21.2 78.0 ±23.2 79.3 ±13.4 104.0 ±17.6* To -s25OHD a 3 mon hs (nmol/l; mean ±s.d.) 78.9 ±15.3 62.5 ±14.9 81.5 ±10.7 90.0 ±4.2* FVC a baseline (% p edic ed; mean ±s.d.) 86.3 ±20.6 89.3 ±15.0 87.8 ±24.9 83.2 ±23.8 FVC a 3 mon hs (% p edic ed; mean ±s.d.) 92.4 ±13.3 89.7 ±6.1 87.3 ±16.4 99.5 ±13.5 FVC a 5 mon hs (% p edic ed; mean ±s.d.) 87.9 ±20.8 92.8 ±7.3 84.0 ±27.9 87.0 ±25.1* FEF25% a baseline (% p edic ed; mean ±s.d.) 92.2 ±45.3 107.0 ±23.5 85.8 ±58.9 87.5 ±51.9 FEF25% a 1 mon h (% p edic ed; mean ±s.d.) 86.8 ±43.0 102.3 ±25.6 78.8 ±53.4 83.3 ±50.2 FEF25% a 2 mon hs (% p edic ed; mean ±s.d.) 86.3 ±40.0 89.3 ±14.2 (P=0.086) 80.0 ±55.7 89.4 ±43.8 FEF25% a 3 mon hs (% p edic ed; mean ±s.d.) 95.1 ±39.2 91.7 ±43.2 82.5 ±54.9 110.3 ±18.4 FEF25% a 5 mon hs (% p edic ed; mean ±s.d.) 84.7 ±42.7 76.7 ±20.0 (P=0.073) 90.5 ±61.9 84.8 ±43.0 Abb e ia ions: s.d., s anda d de ia ion; FVC, o ced i al capaci y; FEF25%, o ced expi a o y flow a e. Pai ed - es was used o compa ison wi h baseline alues wi hin he g oups; *Po0.05. 1 S ockholm CF Cen e , Ka olinska Uni e si y Hospi al Huddinge, S ockholm, Sweden; 2 Di ision o Pedia ics, Depa men o Clinical Science, In e en ion and Technology, Ka olinska Ins i u e , S ockholm, Sweden and 3 Cen e o In ec ious Medicine, Depa men o Medicine, Ka olinska Ins i u e , Ka olinska Uni e si y Hospi al, S ockholm, Sweden. Co espondence: D T Pinciko a, S ockholm CF Cen e , K56, Ka olinska Uni e si y Hospi al Huddinge, 141 86 S ockholm, Sweden. E-mail: [email p o ec ed] Da a om he manusc ip ha e been p esen ed a a mee ing: 36 h Eu opean Cys ic Fib osis Con e ence, Lisbon, Po ugal, 14 June 2013, Abs ac WS16.3. 4 Cu en add ess: Respi a o y, Alle gy and Sleep Resea ch, Uppsala Uni e si y, Uppsala, Sweden. Recei ed 7 Ap il 2016; e ised 24 Oc obe 2016; accep ed 26 Oc obe 2016; published online 14 Decembe 2016 Eu opean Jou nal o Clinical Nu i ion (2017) 71, 203–205 www.na u e.com/ejcn o he ecommenda ions a e consensus-based due o lack o knowledge on benefi –sa e y a io. 8,9 In he p esen pilo s udy, he p ima y goal was o es ablish an e ficien once-daily dosing s a egy and o in es iga e he e ficacy o D2 and D3 a inc easing s25OHD concen a ions. The seconda y goal was o explo e he e ec o he in e en ions on cy okine concen a ions and espi a o y heal h. SUBJECTS AND METHODS T ial design The s udy was app o ed by he Regional E hical Re iew Boa d in S ockholm, Sweden (2009/1723-31/1). Pa ien s we e en olled be ween 9 Ap il 9 2010 and 16 May 2011. The ial was conduc ed in acco dance wi h he Helsinki Decla a ion o 1975 as e ised in 1983. Six een CF pa ien s we e andomized o ecei e ei he D2 o D3 o o become a con ol (Supplemen a y Figu e E1). Pa ien s andomized o he in e en ion a ms ecei ed a s a ing dose o 35 000 Figu e 1. Immunological and clinical impac o i amin D supplemen a ion. (a) To -s25OHD le els in con ol g oup, D2 g oup and D3 g oup. The e was no change in o -s25OHD le els in con ol pa ien s h oughou he s udy, whe eas he e was a endency o inc ease in o -s25OHD in D2 g oup a he end o supplemen a ion (P=0.106). D3 g oup had inc eased o -s25OHD le els a 8 weeks o supplemen a ion and a he end o supplemen a ion (Po0.05). (b) F ee-s25OHD le els in con ol g oup, D2 g oup and D3 g oup. The e was no change in ee-s25OHD le els in con ol and D2 pa ien s h oughou he s udy, whe eas D3 g oup had inc eased ee-s25OHD le els a 8 weeks o supplemen a ion and a he end o supplemen a ion (Po0.05). (c) To al i amin D dose inges ed a he end o supplemen a ion e sus o -s25OHD in all pa ien s (P=0.03; =0.76). (d) The combined g oup o pa ien s ecei ing D2 and D3 had dec eased IL-8 concen a ion in ci cula ion a he end o supplemen a ion and a 1 mon h and 2 mon hs o washou (Po0.05). (e) Change om baseline in ee-s25OHD e sus change om baseline in IL-1βa he end o he s udy in all pa ien s (P=0.004; =−0.95). ( ) Change om baseline in ee-s25OHD e sus change om baseline in ci cula ing neu ophil coun a he end o supplemen a ion in all pa ien s (P=0.017; =−0.80). (g) Change om baseline in ee- s25OHD e sus change om baseline in QoL- espi a o y sco e a he end o supplemen a ion (P=0.006, =0.90). (h) Change om baseline in o -s25OHD e sus change om baseline in FEV1 a 1 mon h o washou (P=0.042, =0.62). (i) Change om baseline in o -s25OHD e sus change om baseline in FVC a 1 mon h o washou (P=0.036, =0.63). Vi amin D in cys ic fib osis: a pilo ial T Pinciko a e al 204 Eu opean Jou nal o Clinical Nu i ion (2017) 203 –205 IU (i o16 yea s old) o 50 000 IU (i ⩾16 yea s old) D2 o D3 pe week. The weekly dose was gi en as se en once-daily doses. The con ol g oup did no ecei e any ex a i amin D. All s udy pa ien s con inued hei o dina y i amin supplemen a ion unchanged. The s udy was open-label and consis ed o 3 mon hs o supplemen a ion ollowed by 2 mon hs o washou . Thi een pa ien s comple ed he ial and we e analyzed. The p ima y ou come o he ial was o al s25OHD ( o -s25OHD) a 3 mon hs isi . The goal o he supplemen a ion was o each o -s25OHD4100 nmol/l (ClinicalT ials.go Iden ifie : NCT01321905). Mo e in o ma ion is a ailable in he online Supplemen a y In o ma ion. RESULTS The e we e no significan di e ences in he baseline cha ac e is ics be ween he s udy a ms (Supplemen a y Table E1). One pa ien in each s udy a m le he ial sho ly a e comple ing he baseline isi . The 13 pa ien s comple ing he s udy we e included in he analyses (Supplemen a y Table E2). Fo some analyses, pa ien s andomized o ecei e D2 o D3 we e pooled in o one g oup (Supplemen a y Table E3). The adhe ence wi h i amin D ea men was o e all e y good (median sco e 7/7; lowes sco e 5/7). The e we e no di e ences in o -s25OHD o ee s25OHD ( ee- s25OHD) le els be ween he g oups a baseline. The con ol g oup did nei he change hei o -s25OHD no ee-s25OHD h oughou he s udy. A he end o supplemen a ion, he mean (s.d.) inges ed o al D2 and D3 dose was 771.173 (296.870) and 598.066 (132.126) IU, espec i ely. A his ime poin , he D3 g oup had highe o - s25OHD han he con ols had (P= 0.019), which was no he case o he D2 g oup (Table 1, Figu e 1a). In line wi h his, all pa ien s in bo h in e en ion a ms had o -s25OHD475 nmol/l a he end o supplemen a ion. None o he pa ien s alloca ed o he D2 g oup eached he goal o 100 nmol/l, whe eas wo ou o fi e D3 g oup pa ien s eached his goal. Pos hoc powe calcula ion showed ha fi e pa ien s a e needed o find a di e ence o 25 uni s in o - s25OHD (end o in e en ion compa ed wi h baseline) in 70% o cases. In he combined g oup o all pa ien s ecei ing i amin D, ee- s25OHD d opped du ing washou , and was significan ly lowe han ha a baseline (Figu e 1b). To -s25OHD a he end o supplemen a- ion co ela ed closely wi h o al i amin D dose (Figu e 1c). Pa ien s andomized o ecei e D2 o D3 showed dec eased le els o IL-8 in plasma a he end o supplemen a ion. Mo eo e , IL-8 emained dec eased a bo h 1 mon h and 2 mon hs o washou , as compa ed wi h baseline (Figu e 1d). A he end o he s udy, he change in IL-1β om baseline was nega i ely co ela ed wi h he change in ee-s25OHD (Figu e 1e). A he end o supplemen a ion, he change om baseline in ee-s25OHD was in e sely co ela ed wi h changes in neu ophil coun (Figu e 1 ). A 1 mon h o washou , he change in neu ophil coun s con inued o be in e sely co ela ed wi h he change in o - and ee-s25OHD. No ably, he changes in neu ophil coun s ollowed he changes in ee-s25OHD mo e closely han changes in o -s25OHD (Supplemen a y Figu es E2–E3). A baseline, o -s25OHD co ela ed posi i ely wi h he adul quali y-o -li e (QoL)- espi a o y sco e (Supplemen a y Figu e E4). Mo eo e , he change om baseline in ee-s25OHD a he end o supplemen a ion co ela ed posi i ely wi h change in he adul QoL- espi a o y sco e (Figu e 1g). A baseline, o -s25OHD co ela ed posi i ely wi h o ced expi a o y olume in 1 s (FEV1), FEV1 exp essed as pe cen age FVC (FEV%) and o ced expi a o y flow a 75% o FVC (FEF75%) (Supplemen a y Figu es E5–E7). Pa ien s alloca ed o se e as con ols had a endency o dec ease hei o ced expi a o y flow a 25% o FVC (FEF25%) a he 2- and 5-mon h isi s, compa ed wi h baseline (Table 1). Pa ien s alloca ed o he D3 a m imp o ed hei o ced i al capaci y (FVC) a he las s udy isi compa ed wi h baseline, whe eas hose ecei ing D2 did no change hei lung unc ion h oughou he s udy (Table 1). A 1 mon h o washou , he change in o -s25OHD om baseline was posi i ely co ela ed wi h changes in FEV1 and FVC (Figu es 1h–i). SUMMARY This pilo ial sugges s ha high doses a e needed o imp o e i amin D s a us in CF pa ien s. Vi amin D supplemen a ion may posi i ely a ec he immune sys em in pa ien s wi h CF, which migh e en ually lead o be e espi a o y unc ion. The esul s also sugges he possibili y ha ee-s25OHD may be a be e co ela e o he clinical impac o i amin D ea men , as compa ed wi h he cu en ly used o -s25OHD. La ge long- e m placebo-con olled s udies a e needed o es he new hypo heses gene a ed by his pilo ial. CONFLICT OF INTEREST The au ho s decla e no conflic o in e es . ACKNOWLEDGEMENTS This s udy was suppo ed by he Ka olinska Ins i u e , he S ockholm Coun y Council, S i elsen Sama i en, E ica Lede hausens Minness i else, he Swedish Cys ic Fib osis Associa ion, S i elsen F imu a e Ba nhuse i S ockholm, he Swedish Resea ch Council, he Hea and Lung Founda ion and he Swedish Cance Socie y. DPP is he ecipien o a pos doc o al ellowship om he Canadian Ins i u es o Heal h Resea ch. The s udy was egis e ed a ClinicalT ials.go as NCT01321905. AUTHOR CONTRIBUTIONS TP and LH designed he s udy and delinea ed hypo heses. TP collec ed he da a, analyzed and in e p e ed hem, wi h con ibu ion o LH, DPP, MFT and JS. TP w o e he a icle, wi h con ibu ions om he LH, JS, DPP and MFT; TP and LH had p ima y esponsibili y o final con en . All au ho s ead and app o ed he final manusc ip . REFERENCES 1 Bush A, Bil on D, Hodson M (eds). Hodson and Geddes' Cys ic Fib osis, 4 h edn. CRC P ess: London, UK, 2015. 2 Pinciko a T, Nilsson K, Moen IE, Ka pa i F, Fluge G, Hollsing A e al. In e se ela ion be ween i amin D and se um o al immunoglobulin G in he Scandina ian Cys ic Fib osis Nu i ional S udy. Eu J Clin Nu 2011; 65:102–109. 3 No on L, Page S, Sheehan M, Mazu ak V, B une -Wood K, La sen B. P e alence o inadequa e i amin d s a us and associa ed ac o s in child en wi h cys ic fib osis. 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An upda e on he sc eening, diagnosis, managemen , and ea men o i amin D deficiency in indi iduals wi h cys ic fib osis: e idence-based ecommenda ions om he Cys ic Fib osis Founda ion. J Clin Endoc inol Me ab 2012; 97:1082–1093. This wo k is licensed unde a C ea i e Commons A ibu ion- NonComme cial-NoDe i s 4.0 In e na ional License. The images o o he hi d pa y ma e ial in his a icle a e included in he a icle’s C ea i e Commons license, unless indica ed o he wise in he c edi line; i he ma e ial is no included unde he C ea i e Commons license, use s will need o ob ain pe mission om he license holde o ep oduce he ma e ial. To iew a copy o his license, isi h p:// c ea i ecommons.o g/licenses/by-nc-nd/4.0/ © The Au ho (s) 2017 Supplemen a y In o ma ion accompanies his pape on Eu opean Jou nal o Clinical Nu i ion websi e (h p://www.na u e.com/ejcn) Vi amin D in cys ic fib osis: a pilo ial T Pinciko a e al 205 Eu opean Jou nal o Clinical Nu i ion (2017) 203 –205