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Review
. 2019 Oct 3;10(10):CD007020.
doi: 10.1002/14651858.CD007020.pub4.

Antioxidant supplementation for lung disease in cystic fibrosis

Oana Ciofu  1 , Sherie Smith, Jens Lykkesfeldt
Affiliations
Review

Antioxidant supplementation for lung disease in cystic fibrosis

Oana Ciofu et al. Cochrane Database Syst Rev. .

Abstract

Background: Airway infection leads to progressive damage of the lungs in cystic fibrosis (CF) and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, beta-carotene and selenium) or N-acetylcysteine (NAC) as a source of glutathione, may therefore potentially help maintain an oxidant-antioxidant balance. Glutathione or NAC can also be inhaled and if administered in this way can also have a mucolytic effect besides the antioxidant effect. Current literature suggests a relationship between oxidative status and lung function. This is an update of a previously published review.

Objectives: To synthesise existing knowledge on the effect of antioxidants such as vitamin C, vitamin E, beta-carotene, selenium and glutathione (or NAC as precursor of glutathione) on lung function through inflammatory and oxidative stress markers in people with CF.

Search methods: The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies. We also searched online trials registries.Last search of Cystic Fibrosis Trials Register: 08 January 2019.

Selection criteria: Randomised and quasi-randomised controlled studies comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care in people with CF.

Data collection and analysis: Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted study investigators to obtain missing information. If meta-analysed, studies were subgrouped according to supplement, method of administration and the duration of supplementation. We assessed the quality of the evidence using GRADE.

Main results: One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias.Oral supplements versus controlThe change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants.Inhaled supplements versus controlTwo studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups.

Authors' conclusions: With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.

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Conflict of interest statement

Original review

All authors: none known.

Updates from 2014 onwards

All authors: none known.

Figures

1
1
Peroxide chain reaction characterized by initiation, propagation and termination. (RH: PUFA; R·: free radical; ROO·: peroxide; ROOH: hydroxyl peroxide; AH: vitamin E; A·: oxidized Vitamin E. Adapted from: Tappel AL. Vitamin E and free radical peroxidation of lipids. Annals of the New York Academy of Sciences. 1972; 203(1):12‐28.
2
2
Study flow diagram.
3
3
Risk of bias graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each methodological domain for each included study.
1.1
1.1. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 1 Lung function: FEV1 (% predicted) (mean change from baseline).
1.2
1.2. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 2 Lung function: FVC (% predicted) mean change from baseline.
1.3
1.3. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 3 QoL: Quality of Well Being Scale.
1.4
1.4. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 4 Oxidative stress: lipid peroxidation (H2O2) (μmol/L).
1.5
1.5. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 5 Oxidative stress: lipid peroxidation (F2‐isoprostanes) (ng/L).
1.6
1.6. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 6 Oxidative stress: lipid peroxidation (malondialdehyde) (μmol/L) mea difference to baseline).
1.7
1.7. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 7 Oxidative stress: urine 8‐iso‐PGF2α log 10 (pg/mL).
1.8
1.8. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 8 Oxidative stress: sputum 8‐iso‐PGF2α log10 (pg/mL).
1.9
1.9. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 9 Oxidative stress: sputum 8‐OHdG (log10) ng/ml.
1.10
1.10. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 10 Oxidative stress: enzyme function ‐ GPX (U/g Hb).
1.11
1.11. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 11 Oxidative stress: enzyme function ‐ SOD (U/mg Hb).
1.12
1.12. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 12 Oxidative stress: potency (TEAC) (mmol/L).
1.13
1.13. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 13 Plasma total antioxidant capacity (nmol) (change from baseline).
1.14
1.14. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 14 Plasma total antioxidant capacity (log10) (CRE).
1.15
1.15. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 15 Plasma antioxidant status: vitamin E (μmol/L).
1.16
1.16. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 16 Plasma antioxidant status: β‐carotene (μmol/L).
1.17
1.17. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 17 Plasma antioxidant status: selenium (μmol/L).
1.18
1.18. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 18 Plasma antioxidant status: vitamin C (μmol/L).
1.19
1.19. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 19 Plasma antioxidant status: whole blood GSH (μmol/L) (change from baseline).
1.20
1.20. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 20 Plasma antioxidant status: plasma fatty acid status (mg/L).
1.21
1.21. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 21 Plasma inflammation: IL‐6 (pg/mL) at 3 months (vitamin E).
1.22
1.22. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 22 Plasma inflammation: TNF‐α (pg/mL) at 3 months (vitamin E).
1.23
1.23. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 23 Plasma IL‐8 pg/mL (log 10) (change from baseline).
1.24
1.24. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 24 Sputum IL‐8 pg/ml (log 10) (per volume).
1.25
1.25. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 25 Sputum human neutrophil elastase (log 10) (mg/mg) per weight (change from baseline).
1.26
1.26. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 26 Sputum neutrophil count (logarithm).
1.27
1.27. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 27 Sputum myeloperoxidase (MPO) levels (log 10) (ng/mL).
1.28
1.28. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 28 Nutritional status: BMI (change from baseline).
1.29
1.29. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 29 Nutritional status: BMI percentile (change from baseline).
1.30
1.30. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 30 Nutritional status: weight (kg) (change from baseline).
1.31
1.31. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 31 Nutritional status: weight percentile (change from baseline).
1.32
1.32. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 32 Antibiotic days per participant.
1.33
1.33. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 33 Number of participants with at least one exacerbation.
1.34
1.34. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 34 Number of hospitalizations.
1.35
1.35. Analysis
Comparison 1 Oral antioxidants versus control, Outcome 35 Adverse effects.
2.1
2.1. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 1 Lung function: FEV1 (L) (change from baseline).
2.2
2.2. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 2 Lung function: FEV1 (% predicted) (change from baseline).
2.3
2.3. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 3 Lung function FVC (L) (change from baseline).
2.4
2.4. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 4 Lung function FVC (% predicted) (change from baseline).
2.5
2.5. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 5 QoL total score (change from baseline).
2.6
2.6. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 6 QoL respiratory score (change from baseline).
2.7
2.7. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 7 Oxidative stress markers in exhaled breath condensate: H2O2 (μM).
2.8
2.8. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 8 Sputum oxidative stress: lipid peroxidation (8‐isoprostan).
2.9
2.9. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 9 Sputum antioxidant status: free glutathione in sputum (pM).
2.10
2.10. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 10 Sputum antioxidant status: total glutathione in sputum (pM).
2.11
2.11. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 11 Sputum antioxidant status: glutathione in sputum neutrophils (MFI).
2.12
2.12. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 12 Plasma antioxidant status: free glutathione (pM).
2.13
2.13. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 13 Plasma antioxidant status: total glutathione (pM).
2.14
2.14. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 14 Plasma antioxidant status: glutathione in blood neutrophils (MFI).
2.15
2.15. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 15 Sputum oxidative stress: protein carbonyls (U).
2.16
2.16. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 16 Local inflammation: cytokines in sputum IL‐8 (pg/mL).
2.17
2.17. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 17 Local inflammation: cytokines in sputum IL‐10 (pg/mL).
2.18
2.18. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 18 Local inflammation: cytokines in sputum TNF‐α (pg/mL).
2.19
2.19. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 19 Nutritional status: BMI (change from baseline).
2.20
2.20. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 20 Nutritional status: weight (kg).
2.21
2.21. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 21 Number of pulmonary exacerbations during the study.
2.22
2.22. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 22 Time to first pulmonary exacerbation (days).
2.23
2.23. Analysis
Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 23 Adverse events.
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  • doi: 10.1002/14651858.CD007020.pub3

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References

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Conrad 2015 {published data only}
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Sagel 2018 {published and unpublished data}
    1. Jain R, Khan U, Baines A, Sagel SD. Biomarkers of inflammation and oxidative stress in CF: implications for antiinflammatory drug development. Pediatric Pulmonology 2016;51 Suppl 45:262. [CFGD Register: GN265b]
    1. NCT01859390. Effects of an antioxidant‐enriched multivitamin supplement on inflammation and oxidative stress in cystic fibrosis (AquADEKs‐2). clinicaltrials.gov/ct2/show/NCT01859390 (first posted 21 May 2013). [Clinicaltrials.gov: NCT01859390]
    1. Sagel SD, Baines A, Abdulhamid I, Borowitz D, Clancy JP, Daines C, et al. Effects of an antioxidant‐enriched multivitamin supplement on inflammation and oxidative stress in CF. Pediatric Pulmonology 2016;51 Suppl 45:283. [CFGD Register: GN265a]
    1. Sagel SD, Khan U, Jain R, Graff G, Daines C, Dunitz J, et al. Effects of an antioxidant‐enriched multivitamin in cystic fibrosis: randomized, controlled, multicenter trial. American Journal of Respiratory and Critical Care Medicine 2018;198(5):639‐47. [CFGD Register: GN265c; DOI: 10.1164/rccm.201801-0105OC; PUBMED: PMID 29688760] - DOI - PMC - PubMed
Stafanger 1988 {published data only}
    1. Stafanger G, Garne S, Howitz P, Koch C. Effect of peroral N‐acetylcysteine in patients with cystic fibrosis and primary cilia dyskinesia. 14th Annual Meeting of the European Working Group for Cystic Fibrosis; 1986 Sept 1‐2; Budapest, Hungary. 1986:129. [CFGD Register: BD29a]
    1. Stafanger G, Garne S, Howitz P, Morkassel E, Koch C. The clinical effect and effect on the ciliary motility of oral n‐acetylcysteine in patients with cystic fibrosis and primary ciliary dyskinesia. European Respiratory Journal 1988;1(2):161‐7. [CFGD Register: BD29b] - PubMed
Stafanger 1989 {published data only}
    1. Stafanger G, Garne S, Howitz P, Koch C. The effect of oral Nacteylcysteine on lung function CF patients. Excerpta Medica, Asia Pacific Congress Series 1988;74:R(c)29. [CFGD Register: BD30a]
    1. Stafanger G, Koch C. N‐acetylcysteine in cystic fibrosis and Pseudomonas aeruginosa infection: clinical score, spirometry and ciliary motility. European Respiratory Journal 1989;2(3):234‐7. [CFGD Register: BD30b] - PubMed
Visca 2015 {published data only}
    1. Data and Supplementary Materials, Visca et al 2012 Trial. uvicf.org/researchnewsite/glutathionenewsite/ViscaTrial_Data_and_Supplem... (accessed 29 November 2017). [CFGD Register: GN232d]
    1. Bishop CT, Visca A, Hudson V, Hilton S. Oral reduced L‐glutathione improves nutritional status and pulmonary function in pediatric cystic fibrosis patients. Pediatric Pulmonology 2013;48 Suppl 36:407. [Abstract no: 545; CFGD Register: GN232b]
    1. Visca A, Bishop CT, Hilton S, Hudson VM. Oral reduced L‐glutathione improves growth in pediatric cystic fibrosis patients. Journal of Pediatric Gastroenterology and Nutrition 2015;60(6):802‐10. [CENTRAL: 1105617; CFGD Register: GN232c ; CRS: 5500050000000307; EMBASE: 2015718545] - PubMed
    1. Visca A, Hilton SC, Hudson VM, Bishop CT. Oral reduced L‐glutathione improves weight and calprotectin in pediatric cystic fibrosis patients. Journal of Cystic Fibrosis 2013;12 Suppl 1:S64. [Abstract no: 62; CFGD Register: GN232a; ]
Wood 2003 {published data only}
    1. Wood LG, Fitzgerald DA, Lee AK, Garg ML. Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. American Journal of Clinical Nutrition 2003;77(1):150‐9. [CFGD Register: GN98; MEDLINE: ; REFWORKS: ID: 975] - PubMed

References to studies excluded from this review

Abdulhamid 2008 {published data only}
    1. Abdulhamid I, Beck FWJ, Millard S, Chen X, Prasad A. Effect of zinc supplementation on respiratory tract infections in children with cystic fibrosis. Pediatric Pulmonology 2008;43(3):281‐7. [CFGD Register: GN111b] - PubMed
    1. Abdulhamid I, Millard S, Beck F, Chen X, Wagnen C, Prasad A. Effect of zinc supplementation on respiratory tract infections in children with cystic fibrosis. Pediatric Pulmonology 2005;40 Suppl 28:348. [CFGD Register: GN111a; ] - PubMed
Anonymous 1975 {published data only}
    1. Anonymous. Vitamin E. Medical Letter on Drugs and Therapeutics 1975;17(17):69‐70. [MEDLINE: ; REFWORKS: ID: 677] - PubMed
Beddoes 1981 {published data only}
    1. Beddoes V, Laing S, Goodchild MC, Dodge JA. Dietary management of cystic fibrosis. Practitioner 1981;225(1354):557‐60. [MEDLINE: ; REFWORKS: ID: 697] - PubMed
Best 2004 {published data only}
    1. Best K, McCoy K, Gemma S, Disilvestro RA. Copper enzyme activities in cystic fibrosis before and after copper supplementation plus or minus zinc. Metabolism: Clinical and Experimental 2004;53(1):37‐41. [CFGD Register: GN105; ] - PubMed
Bines 2005 {published data only}
    1. Bines JE, Truby HD, Armstrong DS, Carzino R, Grimwood K. Vitamin A and E deficiency and lung disease in infants with cystic fibrosis. Journal of Paediatrics & Child Health 2005;41(12):663‐8. [MEDLINE: ; REFWORKS: ID: 703] - PubMed
Cobanoglu 2002 {published data only}
    1. Cobanoglu N, Ozcelik U, Gocmen A, Kiper N, Dogru D. Antioxidant effect of beta‐carotene in cystic fibrosis and bronchiectasis: clinical and laboratory parameters of a pilot study. Acta Paediatrica 2002;91(7):793‐8. [REFWORKS: ID: 348] - PubMed
Congden 1981 {published data only}
    1. Congden PJ, Bruce G, Rothburn MM, Clarke PC, Littlewood JM, Kelleher J, et al. Vitamin status in treated patients with cystic fibrosis. Archives of Disease in Childhood 1981;56(9):708‐14. [MEDLINE: ; REFWORKS: ID: 727] - PMC - PubMed
Ekvall 1978 {published data only}
    1. Ekvall S, Mitchell A. The effect of supplemental vitamin E on vitamin A serum levels in cystic fibrosis. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin‐ und Ernahrungsforschung. Journal international de vitaminologie et de nutrition 1978;48(4):324‐32. [MEDLINE: ; REFWORKS: ID: 746] - PubMed
Farrell 1977 {published data only}
    1. Farrell PM, Bieri JG, Fratantoni JF, Wood RE, Sant'Agnese PA. The occurrence and effects of human vitamin E deficiency. A study in patients with cystic fibrosis. Journal of Clinical Investigation 1977;60(1):233‐41. [MEDLINE: ; REFWORKS: ID: 751] - PMC - PubMed
Goodchild 1986 {published data only}
    1. Goodchild MC. Practical management of nutrition and gastrointestinal tract in cystic fibrosis. Journal of the Royal Society of Medicine 1986;79 Suppl 12:32‐5. [MEDLINE: ; REFWORKS: ID: 764] - PMC - PubMed
Homnick 1995a {published data only}
    1. Homnick DN, Spillers CR, Cox SR, Cox JH, Yelton LA, DeLoof MJ, et al. Single‐and multiple‐dose response relationship of beta‐carotene in cystic fibrosis. Journal of Pediatrics 1995;127(3):491‐4. [CFGD Register: GN68] - PubMed
Hoogenraad 1989 {published data only}
    1. Hoogenraad TU. Managing adults with cystic fibrosis. BMJ (Clinical Research Ed) 1989;298(6680):1098. [MEDLINE: ; REFWORKS: ID: 786] - PMC - PubMed
Hubbard 1980 {published data only}
    1. Hubbard VS, Barbero G, Chase HP. Selenium and cystic fibrosis. Journal of Pediatrics 1980;96(3 Pt 1):421‐2. [MEDLINE: ; REFWORKS: ID: 792] - PubMed
Jacquemin 2009 {published data only}
    1. Jacquemin E, Hermeziu B, Kibleur Y, Friteau I, Mathieu D, Coz F, et al. Bioavailability of oral vitamin E formulations in adult volunteers and children with chronic cholestasis or cystic fibrosis. Journal of Clinical Pharmacy and Therapeutics 2009;34(5):515‐22. [CFGD Register: GN216] - PubMed
Kauf 1995 {published data only}
    1. Kauf E, Janitzky E, Vogt L, Winnefeld K, Dawczynski H, Forberger M, et al. The value of selenotherapy in patients with mucoviscidosis. Medizinische Klinik (Munich, Germany : 1983) 1995;90(Suppl 1):41‐5. [MEDLINE: ; REFWORKS: ID: 811] - PubMed
Kawchak 1999 {published data only}
    1. Kawchak DA, Sowell AL, Hofley PM, Zemel BS, Scanlin TF, Stallings VA. Research and professional briefs. Longitudinal analysis shows serum carotenoid concentrations are low in children with cystic fibrosis. Journal of the American Dietetic Association 1999;99(12):1569‐72. [MEDLINE: ; REFWORKS: ID: 812] - PubMed
Kelleher 1987 {published data only}
    1. Kelleher J, Miller MG, Littlewood JM, McDonald AM, Losowsky. The clinical effect of corrections of vitamin E depletion in cystic fibrosis. International Journal for Vitamin and Nutrition Research (Internationale Zeitschrift für Vitamin und Ernährungsforschung. Journal International de Vitaminologie et de Nutrition) 1987; Vol. 57, issue 3:253‐9. [MEDLINE: ; REFWORKS: ID: 813] - PubMed
Khorasani 2009 {published data only}
    1. Khorasani EN, Mansouri F. Effect of zinc supplementation on respiratory infections in children with cystic fibrosis. European Respiratory Society Annual Congress; 2009; Sept 12‐16; Vienna, Austria. 2009:722s. [Abstract no: P4032; CENTRAL: 793188; CFGD Register: GN255 ; CRS: 5500050000000367]
Knopfle 1975 {published data only}
    1. Knopfle G, Rotthauwe HW, Odenthal A. Serum concentrations of vitamin A, carotene, retinol‐binding protein and prealbumin in patients with cystic fibrosis (author's transl). Zeitschrift fur Kinderheilkunde 1975;119(4):279‐91. [MEDLINE: ; REFWORKS: ID: 819] - PubMed
Lancellotti 1996 {published data only}
    1. Lancellotti L, D'Orazio C, Mastella G, Mazzi G, Lippi U. Deficiency of vitamins E and A in cystic fibrosis is independent of pancreatic function and current enzyme and vitamin supplementation. European Journal of Pediatrics 1996;155(4):281‐5. [MEDLINE: ; REFWORKS: ID: 825] - PubMed
Lepage 1996 {published data only}
    1. Lepage G, Champagne J, Ronco N, Lamarre A, Osberg I, Sokol RJ, et al. Supplementation with carotenoids corrects increased lipid peroxidation in children with cystic fibrosis [corrected] [published erratum appears in American Journal of Clinical Nutrition 1997 Feb; 65(2): 578]. American Journal of Clinical Nutrition 1996;64(1):87‐93. [MEDLINE: ; REFWORKS: ID: 829] - PubMed
Madarasi 2000 {published data only}
    1. Madarasi A, Lugassi A, Greiner E, Holics K, Biro L, Mozsary E. Antioxidant status in patients with cystic fibrosis. Annals of Nutrition & Metabolism 2000;44(5‐6):207‐11. [MEDLINE: ; REFWORKS: ID: 844] - PubMed
Mischler 1991 {published data only}
    1. Mischler EH, Marcus MS, Sondel SA, Laxova A, Carey P, Langhough R, et al. Nutritional assessment of infants with cystic fibrosis diagnosed through screening. Pediatric Pulmonology. Supplement 1991;7:56‐63. [MEDLINE: ; REFWORKS: ID: 850] - PubMed
Munck 2010 {published data only}
    1. Munck A, Ginies JL, Huet F, Wizla N, Gerardin M, Darviot E, et al. A new water‐soluble oral vitamin E formulation in cystic fibrosis (CF) children. Journal of Cystic Fibrosis 2010;9 Suppl 1:S91. [Abstract no.: 352; CFGD Register: GN219]
Nasr 1993 {published data only}
    1. Nasr SZ, O'Leary MH, Hillermeier C. Correction of vitamin E deficiency with fat‐soluble versus water‐miscible preparations of vitamin E in patients with cystic fibrosis. Journal of Pediatrics 1993;122(5 Pt 1):810‐2. [CFGD Register: GN42; REFWORKS: ID: 359] - PubMed
Oermann 2001 {published data only}
    1. Oermann CM. Anti‐inflammatory approaches to the treatment of cystic fibrosis lung disease: past, present and future. Current Opinion in Investigational Drugs 2001;2(7):900‐6. [MEDLINE: ; REFWORKS: ID: 861] - PubMed
Oudshoorn 2007 {published data only}
    1. Oudshoorn JH, Klijn PH, Hofman Z, Voorbij HA, Ent CK, Berger R, et al. Dietary supplementation with multiple micronutrients: no beneficial effects in pediatric cystic fibrosis patients. Journal of Cystic Fibrosis 2007;6(1):35‐40. [CFGD Register: GN113; MEDLINE: ; REFWORKS: ID: 370] - PubMed
Papas 2007 {published data only}
    1. Papas K, Kalbfleisch J, Mohon R. Bioavailability of a novel, water‐soluble vitamin E formulation in malabsorbing patients. Digestive Diseases and Sciences 2007;52(2):347‐52. [CFGD Register: GN114; MEDLINE: ; REFWORKS: ID: 369] - PubMed
Peters 1996 {published data only}
    1. Peters SA, Kelly FJ. Vitamin E supplementation in cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 1996;22(4):341‐5. [MEDLINE: ; REFWORKS: ID: 867] - PubMed
Portal 1995b {published data only}
    1. Portal BC, Richard M, Faure HS, Hadjian AJ, Favier AE. Altered antioxidant status and increased lipid peroxidation in children with cystic fibrosis. American Journal of Clinical Nutrition 1995;61(4):843‐7. - PubMed
Powell 2010 {published data only}
    1. Powell M, Kuitert L. Effect of vitamin K supplementation over one year on bone health in adolescents and adults with cystic fibrosis. Pediatric Pulmonology 2010;45(S33):421. [Abstract no.: 421; CFGD Register: CO47]
Rawal 1974 {published data only}
    1. Rawal BD, McKay G, Blackhall MI. Inhibition of Pseudomonas aeruginosa by ascorbic acid acting singly and in combination with antimicrobials: in‐vitro and in‐vivo studies. Medical Journal of Australia 1974;1(6):169‐74. [MEDLINE: ; REFWORKS: ID: 880] - PubMed
Rettammel 1995 {published data only}
    1. Rettammel AL, Marcus MS, Farrell PM, Sondel SA, Koscik RE, Mischler EH. Oral supplementation with a high‐fat, high‐energy product improves nutritional status and alters serum lipids in patients with cystic fibrosis. Journal of the American Dietetic Association 1995;95(4):454‐9. [MEDLINE: ; REFWORKS: ID: 884] - PubMed
Richard 1990 {published data only}
    1. Richard MJ, Aguilaniu B, Arnaud J, Gout JP, Favier A. Selenium and oxidant injury in patients with cystic fibrosis. Advances in Experimental Medicine and Biology 1990;264:175‐8. [MEDLINE: ; REFWORKS: ID: 886] - PubMed
Sharma 2016 {published data only}
    1. Sharma G, Lodha R, Shastri S, Saini S, Kapil A, Singla M, et al. Zinc supplementation for one year among children with cystic fibrosis does not decrease pulmonary infection. Respiratory Care 2016;61(1):78‐84. [CFGD Register: GN256 ; CRS: 5500135000001517; PUBMED: 26443019] - PubMed
Sokol 1989 {published data only}
    1. Sokol RJ, Butler‐Simon N, Heubi JE, Iannaccone ST, McClung HJ, Accurso F, et al. Vitamin E deficiency neuropathy in children with fat malabsorption. Studies in cystic fibrosis and chronic cholestasis. Annals of the New York Academy of Sciences 1989;570:156‐69. [MEDLINE: ; REFWORKS: ID: 919] - PubMed
Sung 1980 {published data only}
    1. Sung JH, Park SH, Mastri AR, Warwick WJ. Axonal dystrophy in the gracile nucleus in congenital biliary atresia and cystic fibrosis (mucoviscidosis): beneficial effect of vitamin E therapy. Journal of Neuropathology and Experimental Neurology 1980;39(5):584‐97. [MEDLINE: ; REFWORKS: ID: 933] - PubMed
Uden 1990 {published data only}
    1. Uden S, Bilton D, Guyan PM, Kay PM, Braganza JM. Rationale for antioxidant therapy in pancreatitis and cystic fibrosis. Advances in Experimental Medicine and Biology 1990;264:555‐72. [MEDLINE: ; REFWORKS: ID: 943] - PubMed
Underwood 1972a {published data only}
    1. Underwood BA, Denning CR, Navab M. Polyunsaturated fatty acids and tocopherol levels in patients with cystic fibrosis. Annals of the New York Academy of Sciences 1972;203:237‐47. [MEDLINE: ; REFWORKS: ID: 945] - PubMed
Underwood 1972b {published data only}
    1. Underwood BA, Denning CR. Blood and liver concentrations of vitamins A and E in children with cystic fibrosis of the pancreas. Pediatric Research 1972;6(1):26‐31. [MEDLINE: ; REFWORKS: ID: 944] - PubMed
van der Vliet 1997 {published data only}
    1. Vliet A, Eiserich JP, Marelich GP, Halliwell B, Cross CE. Oxidative stress in cystic fibrosis: does it occur and does it matter?. Advances in Pharmacology (San Diego, California) 1997;38:491‐513. [MEDLINE: ; REFWORKS: ID: 948] - PubMed
Winklhofer‐Roob 1995 {published data only}
    1. Winklhofer‐Roob BM, Ziouzenkova O, Puhl H, Ellemunter H, Greiner P, Muller G, et al. Impaired resistance to oxidation of low density lipoprotein in cystic fibrosis: improvement during vitamin E supplementation. Free Radical Biology & Medicine 1995;19(6):725‐33. [MEDLINE: ; REFWORKS: ID: 972] - PubMed
Winklhofer‐Roob 1996a {published data only}
    1. Winklhofer‐Roob BM. Beta‐carotene supplementation in cystic fibrosis. Journal of Pediatrics 1996;129(1):181‐2. [MEDLINE: ; REFWORKS: ID: 962] - PubMed
Winklhofer‐Roob 1996b {published data only}
    1. Winklhofer‐Roob BM, Shmerling DH, Schimek MG. Response of vitamin E deficient patients with cystic fibrosis (CF) to oral RRR‐alpha‐tocopherol or all‐rac‐alpha‐tocopheryl acetate. Clinical Nutrition 1992;11 Suppl:67. [REFWORKS: ID: 367] - PubMed
    1. Winklhofer‐Roob BM, van't Hof MA, Shmerling DH. Long‐term oral vitamin E supplementation in cystic fibrosis patients: RRR‐alpha‐tocopherol compared with all‐rac‐alpha‐tocopheryl acetate preparations. American Journal of Clinical Nutrition 1996;63(5):722‐8. [MEDLINE: ; REFWORKS: ID: 368] - PubMed
Winklhofer‐Roob 1996c {published data only}
    1. Winklhofer‐Roob BM, Puhl H, Khoschsorur G, van't Hof MA, Esterbauer H, Shmerling DH. Enhanced resistance to oxidation of low density lipoproteins and decreased lipid peroxide formation during beta‐carotene supplementation in cystic fibrosis. Free Radical Biology & Medicine 1995;18(5):849‐59. [MEDLINE: ; REFWORKS: ID: 964] - PubMed
    1. Winklhofer‐Roob BM, Schlegel‐Haueter SE, Khoschsorur G, van't Hof MA, Suter S, Shmerling DH. Neutrophil elastase/alpha 1‐proteinase inhibitor complex levels decrease in plasma of cystic fibrosis patients during long‐term oral beta‐carotene supplementation. Pediatric Research 1996;40(1):130‐4. [MEDLINE: ; REFWORKS: ID: 966] - PubMed
    1. Winklhofer‐Roob BM, van't Hof MA, Shmerling DH. Response to oral beta‐carotene supplementation in patients with cystic fibrosis: a 16‐month follow‐up study. Acta Paediatrica (Oslo, Norway : 1992) 1995;84(10):1132‐6. [MEDLINE: ; REFWORKS: ID: 971] - PubMed
Winklhofer‐Roob 1997a {published data only}
    1. Winklhofer‐Roob BM. Vitamin E supplementation in cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 1997;25(1):120‐2. [MEDLINE: ; REFWORKS: ID: 960] - PubMed
Winklhofer‐Roob 1997b {published data only}
    1. Winklhofer‐Roob BM. Beta‐carotene, malondialdehyde, and cystic fibrosis. American Journal of Clinical Nutrition 1997;65(2):575‐7. [MEDLINE: ; REFWORKS: ID: 961] - PubMed
Winklhofer‐Roob 1997c {published data only}
    1. Winklhofer‐Roob BM, Ellemunter H, Fruhwirth M, Schlegel‐Haueter SE, Khoschsorur G, van't Hof MA, et al. Plasma vitamin C concentrations in patients with cystic fibrosis: evidence of associations with lung inflammation. American Journal of Clinical Nutrition 1997;65(6):1858‐66. [MEDLINE: ; REFWORKS: ID: 963] - PubMed
Winklhofer‐Roob 2003 {published data only}
    1. Winklhofer‐Roob BM, Rock E, Ribalta J, Shmerling DH, Roob JM. Effects of vitamin E and carotenoid status on oxidative stress in health and disease. Evidence obtained from human intervention studies. Molecular Aspects of Medicine 2003;24(6):391‐402. [MEDLINE: ; REFWORKS: ID: 965] - PubMed
Wojewodka 2015 {published data only}
    1. Garic D, Wojewodka G, Sanctis JB, Hajduch M, Kopriva F, Pislariu R, et al. Fenretinide treatment increases long chain ceramide C24:0 and decreases short chain ceramide C16:0 levels in patients with cystic fibrosis (phase IB clinical trial). Pediatric Pulmonology 2015;50 Suppl 41:291. [Abstract no: 264; CENTRAL: 1092197; CFGD Register: GN253b; CRS: 5500135000001386]
    1. Radzioch D, Wojewodka G, Cupri S, Colin P, Pislariu R, Garic D, et al. A novel oral formulation of fenretinide demonstrates safety and tolerability in a phase 1B dose‐ascending trial involving adult cystic fibrosis patients. Pediatric Pulmonology 2015;50 Suppl 41:290. [Abstract no: 261; CENTRAL: 1092177; CFGD Register: GN253c ; CRS: 5500135000001373]
    1. Wojewodka G, Matouk E, Sanctis JB, Pislariu R, Colin P, Matin C, et al. The cystic fibrosis associated fatty acid imbalance is corrected by a novel formulation of fenretinide in a phase IB clinical trial. Pediatric Pulmonology 2015;50 Suppl 41:289. [Abstract no: 260; CENTRAL: 1092178; CFGD Register: GN253a ; CRS: 5500135000001374]
Wood 2002 {published data only}
    1. Wood LG, Fitzgerald DA, Gibson PG, Cooper DM, Garg ML. Increased plasma fatty acid concentrations after respiratory exacerbations are associated with elevated oxidative stress in cystic fibrosis patients. American Journal of Clinical Nutrition 2002;75(4):668‐75. [MEDLINE: ; REFWORKS: ID: 974] - PubMed
Zoirova 1983 {published data only}
    1. Zoirova RR. Use of the mucolytic agent, mucosolvin, in multiple modality treatment of cystic fibrosis in children. Pediatriia 1983;4(4):36‐7. [MEDLINE: ; REFWORKS: ID: 976] - PubMed

References to studies awaiting assessment

Tirouvanziam 2005 {published data only}
    1. Tirouvanziam R, Conrad CK, Dunn CE, Davies ZA, Aram B, Bottiglieri T, et al. High‐dose oral N‐Acetylcysteine as a systemic antioxidant and potent inhibitor of lung inflammation in CF: a pilot phase 1 trial. Pediatric Pulmonology 2005;40 Suppl 28:263. [Abstract no.: 214; CFGD Register: BD117]
Tirouvanziam 2006 {published data only}
    1. Tirouvanziam R, Conrad CK, Dunn CE, Davies ZA, Gernez Y, Aram B, et al. Phase 2 trial of high‐dose oral N‐Acetylcysteine as a systemic antioxidant and inhibitor of lung inflammation in CF. Pediatric Pulmonology 2006;41 Suppl 29:295. [Abstract no.: 253; CFGD Register: BD121a]
Wong 1988 {published data only}
    1. Wong LTK, Halstead C, Davidson AGF, Fang PM. Comparison of the efficacy of water‐miscible and fat soluble vitamin E in the therapy of vitamin E deficiency in cystic fibrosis patients. Pediatric Pulmonology 1988;5 Suppl 2:144. [CFGD Register: GN52; REFWORKS: ID: 352]

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