Supplemental Table 1:Characteristics of the Included Rcts

Supplemental Table 1:characteristics of the included RCTs

Study / Intervention / Control / Time of intervention / Number of patients / Inclusion / Age group / Outcomes as defined
Abdulhamid 2008 [6] / 30 mg/d elemental Zn. / placebo / 12 months / 26 / Mild to moderate lung disease. / Range: 7 - 18 years. / Rate of RTI, use of antibiotics, plasma cytokines
Panchaud 2006 [7] / EPA, DHA, GLA, STA supplements according to weight (570–1710 mg). / placebo / 6 months / 17 / No specific inclusion. / 18±9 years (mean±SD) / In vitro neutrophilic response, neutrophil membrane composition
Kirvela 1993 [8] / PN (Calories: 115% of REE). / no intervention / 4 months / 20 / Weight<85%, ≥2 hospitalizations within the preceding year. / Range: 14 - 24 years. / Anthropometrics, pulmonary function, serum FA, plasma prostaglandins, exercise performance
Haworth 2004 [9] / Calcium 1g + vitamin D 800 IU twice daily. / placebo / 12 months / 31 / BMD Z score≤1 in lumbar spine/total hip/distal forearm, Pancreatic insufficiency. / Adults / BMD and bone metabolism.
Eubanks 2002 [10] / MA starting dose: 10 mg/kg per day, adjusted at subsequent visits. / placebo / 6 months / 17 / Pancreatic insufficiency, FEV1>40%, growth failure, no weight gain in 6 months, weight <85%, weight <5th, weight percentile for age, or for height <5th percentile. / ≥6 years / Anthropometrics, pulmonary function
Bruzzese 2007 [11] / LGG (6x109 CFU/d). / oral rehydration solution / 6 months / 38 / Moderate or severe disease, pancreatic insufficiency, one month from last suppressive therapy Pseudomonas. / Range: 5 - 18 years. / Exacerbations, hospital admissions, FEV1, changes in body weight.
Steinkamp 2000 [12] / Dietary counseling+ dietary supplement: 1.8 g linoleic acid, 0.75 g oleic acid, 0.25 g palmitic acid, 0.2 g stearic acid, 0.02 g linolenic acid (per 100 mL). / dietary counseling only / 3 months / 36 / Weight for-height < 95% without diabetes mellitus or liver cirrhosis. / >4 years / Energy Intake, Anthropometrics, pulmonary function, plasma phospholipid FA
Caramia 2003 [13] / Oil mixture: 50% olive oil, 50% soybean oil, 8-10% of energy intake. / placebo / 2 months / 14 / Pancreatic insufficiency, heterozygotes or homozygotes for ΔF508 mutation. / Range: 6 - 15 years. / Anthropometrics, puberty status, clinical status, lung function
Keen 2010 [14] / 2 types of FA blends containing mainly n-3 or n-6 FA. / saturated FA / 3 months / 43 / Nonsmoking, severe mutations, clinically stable Pancreatic insufficiency. / Range: 7 - 41 years. / Nitric oxide (NO) and exhaled NO, immunological markers
Epifanio 2012 [15] / Cyproheptadine 12 mg/d. / placebo / 12 weeks / 25 / Weight-age ratio <85%. / Range: 5 - 18 years. / Anthropometrics, energy intake, AE.
Hillman 2008 [16] / Tablets: 1,600 IU D3+500 mg calcium carbonate 2/d. / placebo / 6 months / 15 / Children and adolescents. / Range: 7 - 13 years. / Serum minerals, bone turnover, BMC
Gontijo-Amaral 2008 [17] / 300 mg oral Mg-glycine (5-12 mgXkg-1Xd-1). / placebo / 8 weeks / 44 / Stable clinical condition. / Range: 7 - 19 years. / Respiratory muscle strength, AE
Drury 2008 [18] / 5 mg/day of vitamin K1. / 1 mg/day of vitamin K1. / 1 month / 14 / Pancreatic insufficient. / Range: 8 - 18 years. / Vitamin K status
Watson 2008 [19] / Behavioral Home-Based Nutrition Education (topics: increasing intake, managing appetite, etc). / standard care / 10 weeks / 74 / Understand written English. / >16 years / Weight change, nutrition knowledge score, self-efficacy
score, fat intake, health-related quality-of-life score
Schnabel 2007 [20] / 0.070 mg/kg or 0.039 mg/kg body weight Somatropin. Max daily dosage: 3.4 mg. / placebo / 48 weeks, followed by an open treatment period of 24 weeks. / 63 / Bone age of 8-18 years, BMI 10th and/or weight 3rd percentile despite high caloric intake. / Range: 9 - 20 years. / Change in FEV1,
height, weight, exercise tolerance.
Hardin 2005 [21] / 1 year of GH (0.3 mg/kg per week) followed by a second year (injection) / no GH for 1 year, followed by 1 year of GH / 24 months / 18 / Received EN supplementation for≥2 years
before enrollment. / Range: 9 - 13 years. / Pulmonary function, anthropometrics, hospitalizations, antibiotics, intake, protein turnover.
Oudshoorn 2007 [22] / 100 ml/d of a liquid micronutrient mixture. / placebo / 3 months / 22 / Predominantly mild lung disease. / 12.9±2.5 years (mean±SD) / Anthropometrics, pulmonary function, exercise performance, muscular strength, vitamins A and E.
Poustie 2006 [23] / Oral protein energy supplements+ routine dietetic advice. / Routine dietetic advice. / 12 months / 102 / Moderately malnourished. / Range: 2 - 15 years. / Anthropometrics, intake, pulmonary function, habitual activity scale, gastrointestinal symptoms.
Powers 2005 [24] / Nutrition counseling and child behavioral training. / standard care / 8 weeks / 14 / Mild to moderate lung disease, pancreatic insufficient / Range: 8 - 20 years. / Energy Intake, Weight, Height.
Lloyd-Still 2006 [25] / Algal oil (50 mg/kg/d of DHA 1 to 4.2 g). / placebo / 6 months / 20 / Mild to moderate lung disease, pancreatic insufficient / Range: 8 - 20 years. / FA, liver enzymes, lipid antioxidants, fecal FA, lung function, AE anthropometrics.
Kalnins 2005 [26] / A supplement (150 kcal/100 mL; 20% protein, 30% fat, 50% carbohydrate). / dietary counseling / 3 months / 13 / <90% IBW or 5% reduction in IBW over a 3-month / >10 years / Anthropometrics, pulmonary function, REE, fecal fat output.
Hardin 2006 [27] / Daily GH injections (0.3 mg/kg*wk). / no treatment / 24 months / 57 / Height and weight in 25th percentile or lower; Tanner I breast; testicular development≤ 3 cc. / Range: 7 - 12 years. / Anthropometrics, pulmonary function,
hospitalizations, antibiotic use, intake.
Grey 2003 [28] / Whey protein isolate (20 g/d). / casein placebo / 3 months / 24 / Stable with mild to moderate lung disease, not severely malnourished. / Adults / Lymphocyte glutathione levels, height, weight, Pulmonary function.
Homnick 2004 [29] / 8 mg/d Cyproheptadine for one week increased to 16 mg/d in the remaining weeks. / placebo / 12 weeks / 18 / IBW <100%, clinically stable. / ≥5 years / Appetite, weight, spirometry, antibiotic use.
Darmaun 2004 [30] / GLN/rhGH combined. / daily oral GLN (0.21 g/kg/d) or rhGH (0.3 mg/kg/wk) / 4 weeks / 9 / Weight/height, <50th percentile or height <5th percentile / 9.6±0.5 years (mean±SD) / Protein Metabolism
Ellis 1998 [31] / Hydrolyzed protein formula. / Conventional cow’s milk–based formula / 12 months / 23 / Newly diagnosed, pancreatic insufficient, fed infant formula. / < 6 months / Anthropometrics, dietary intake
Wood 2003 [32] / 200 mg vitamin E, 300 mg vitamin C, 25 mg carotene, 90 g Se, and 500 g vitamin A / Supplement: 10 mg vitamin E and 500 g vitamin A / 8 weeks / 46 / Normal vitamin E plasma concentration. / > 5 years / Changes in plasma 8-iso-PGF2, plasma FA status, clinical markers, antioxidant
defenses
Renner 2001 [33] / 3 months β-carotene 1 mg/kg/d (maximum 50) + 3 months 10 mg/day. / placebo / 6 months / 24 / No specific inclusion. / Range: 6.7-27.7 years. / Plasma β-carotene, total antioxidant capacity, antibiotics, Shwachmann score, BMI, height, MDA, pulmonary function.
Gottrand 1999 [34] / Enteral diet, "high fat" 33/67 non protein energy glucose to fat ratio. / Enteral diet, "normal fat" 60/40 non protein energy glucose to fat ratio. / 4 weeks / 8 / Receiving nighttime enteral nutrition for ≥1 month before the study. / Range: 6-19 years. / Pulmonary function, substrate oxidation, energy intake, tolerance
Beker 1997 [35] / 5 mg/week oral vitamin K1. / no supplementation / 4 weeks / 18 / Stable, afebrile, without cholestasis/ overt liver disease, normal AST/ALT, normal albumin. / Range: 13-35 years. / Plasma vitamin K1, vitamin K1-2,3-epoxide, PIVKA-II, serum Osteocalcin, urinary GLA
Van Egmond 1996 [36] / Predigested formula with 12% linoleic acid. / Predigested formula with 7% linoleic acid. / Not clear / 76 / Diagnosed by 9 mo, formula providing > 10% of intake / ≥1 year / Anthropometrics
Stark 1995 [37] / Nutritional education+ mealtime behaviors. / standard care / 6 weeks / 9 / No specific inclusion. / Range: 2-6 years. / Calorie intake, weight gain
Kurlandsky 1994 [38] / N-3 (menhaden oil 100-131 mg/kg/day, mean 112.8). / N-6 (safflower oil 102-132 mg/kg/day, mean 113.3). / 6 weeks / 14 / Ability to check pulmonary function + swallow capsules. / Range: 6-16 years. / Absorption and clinical effects of n-3 vs. n-6 fatty acids
Hanning 1993 [39] / Grocery foods - 25% of recommended energy intake. / no supplement / 6 months / 20 / Mild to moderate lung disease, no supplemental tube feeding or PN. / Range: 7-15 years. / Skeletal and respiratory muscle function
Marchand 2000 [40] / MA 10 mg/kg/d / placebo / 12 weeks / 12 / Loss/ plateau in weight>3 months, weight-for height
< 85%, negative change in weight z score. / Range: 21 months -10.4 years. / Anthropometrics, caloric intake, clinical assessment.
Shepherd 1988 [41] / EN semi-elemental high nitrogen peptide formula (1000-1500 kcal/d more in intake). / Standard diet / 2-3 weeks / 15 / Acute pulmonary exacerbations. / Range: 6.5 -17 years. / Protein turnover, mean body weight, FEV1.
Milla 1996 [42] / Equal caloric (355 kcal) and volume amount of one of five formulas with carbohydrate-to-fat ratios (0.5-1.7). / carbohydrate-to-fat ratios of 0.5 / 2 months / 5 / Glucose intolerant / Average age of 39 ± 3 years / Glucose tolerance, dyspnea, CO2 retention.
Kane 1990 [43] / Tube during admission for exacerbation: 1000 kcal, carbohydrate: low/medium/high. / Low carbohydrate formula / 8-10 days / 10 / Mild to moderate lung disease / Median age 8-14 years. / Respiratory function, nighttime oxygen therapy, energy metabolism during feedings.
Smith 1991 [44] / Taurine supplements- 30 mg/kg per day. / placebo / 4 months / 13 / Documentation of a fecal fatty acid excretion in excess. / Range: 6. 2 -20.3 years. / Lung function, anthropometrics, vitamin A level, EFA status.
Safai-Kutti 1991 [45] / Zinc- 90 mg/day for patients>12 y and half the dose for patients<12 y. / placebo / 6 months / 34 / No specific inclusion. / Range: 2 -19 years. / Clinical status, growth velocity, lung function.
Stalvey 2012 [46] / rhGH 0.043 mg/kg/day. / no treatment / 12 months / 62 / growth restriction / <14 years / Growth, LBM, safety, pulmonary function, exercise tolerance, glucose tolerance.
Powers 2003 [47] / Behavioral plus nutritional intervention. / nutritional intervention / 12 months / 12 / Pancreatic insufficiency, no other condition that affects growth. / Range: 18-48 months. / Calorie intake, anthropometrics.
Grossmann 2012 [48] / Single 250,000 IU dose of Cholecalciferol. / placebo / 1 day / 30 / Hospitalized for pulmonary exacerbation treatment. / adults / Serum 25(OH) D, PTH, calcium, lung function, survival, hospitalizations, IV antibiotics, AE.
Bruzzese 2014 [49] / 6X109 CFU of LGG once daily. Formulations were composed of maltodextrin (163 mg), gelatin capsule (75 mg), LGG (60 mg), and magnesium stearate (2 mg). / placebo / 4 weeks / 22 / Clinically stable patients with no acute intestinal or extraintestinal diseases and had not taken antibiotics for at least two weeks. / Range: 2–9 years. / Composition of intestinal microflora, Intestinalinflammation.
Fallahi 2013 [50] / One probiotic sachet each day. The powder used was 1 g Protexin Restor sachet, which contains of FOS and a mixture of 1×109 CFU/sachet bacteria. / Placebo (maltodextrin) / 4 weeks / 47 / All the patients had pancreatic insufficiency. No use of NSAID during the last two weeks. No antibiotic therapy during the study. All patients were pediatric cases referred to gastrointestinal clinic. / > 4 years / Status of intestinal inflammation (calprotectin level in fecal samples).
Bertolaso 2014 [51] / Second generation LXS (LYM-X-SORB™- organized lipid matrix): 2 packets/day (64 g powder) for ages 5.0 to 11.9 yrs, and 3 packets/day (96 g powder) for ages 12.0 to 17.9 yrs. / Placebo / 12 months / 58 / All the patients had pancreatic insufficiency and mild to moderate lung disease. / Range: 5-17.9 years / Serum vitamins A, D, E, K and plasma proteins induced by vitamin K absence, dietary intake, supplemental vitamin intake, anthropometrics.
Gifford 2014 [52] / Ferrous sulfate 325mg taken orally once a day. / Placebo / 6 weeks / 24 / Patients with hypoferremic anemia / adults / Absolute change from baseline in hemoglobin concentration attributed to ferrous sulfate, iron relatedhematologic parameters, anthopometrics, sputum iron, Akron Pulmonary Exacerbation Score (PES), sputum microbiome.
Engelen 2013 [53] / 6.7g high-leucine EAA mixture (containing 41% leucine) + 15g carbohydrates, orally or enterally. / 6.7g balanced mixture of total (EAA and non-essential) amino acids + 15g carbohydrates, orally or enterally. / 1 day / 15 / Clinically stable inpatients after antibiotic treatment with no symptoms of pulmonary exacerbation. Pancreatic insufficient. / Range: 10-21 years / Whole body protein
and Arginine metabolism, anthropometrics, lung function.
Alicandro 2013 [54] / 100 mg/ kg/day of DHA during the first month and 1 g/day in the remaining 11 months as placebo. / Placebo / 12 months / 41 / Clinically stable, pancreatic insufficient, able to perform respiratory function tests. / Range: 6-10 years / Percentage change in plasma AA:DHA ratio, number of pulmonary exacerbations compared to the previous year, lung function, anthropometrics, body composition, serum TNF-a, IL8 and CRP, serum a-tocopherol and retinol.
Nardo 2014 [55] / Lactobacillus reuteri ATCC55730: 5 drops per day (1010 colony forming units) / Placebo / 6 months / 61 / Patients with mild-to-moderate lung disease / Range: 6-29 years / Number of episodes
of pulmonary exacerbations and hospital admissions for pulmonary
exacerbations, number of gastrointestinal and upper respiratory tract infections, FEV1, fecal calprotectin, and cytokine profile in induced sputum and plasma were assessed.
Powers 2015 [56] / Behavioral intervention combined with individualized nutritional counseling targeting increased energy intake and training in behavioral child management skills. / Education and attention control treatment / 6 months / 78 / Preschool-aged children with pancreatic insufficiency. / Range: 2-6 years / Energy intake, weight z (WAZ) score, and height z (HAZ) score.

Acronyms: RTI- respiratory tract infections; EPA- eicosapentaenoic acid; DHA- Docosahexaenoic acid; GLA- Gamma-linolenic acid; STA- Stearidonic acid; FA- fatty acids; PN- parenteral nutrition; EN- enteral nutrition; BMD- Bone mineral density; FEV1- forced expiratory volume in 1 second; LGG- Lactobacillus GG; BMC- bone mineral content; IBW- ideal body weight; REE- Resting energy expenditure; EFA- essential fatty acid; rHGH- Recombinant human growth hormone; LBM- lean body mass; AE- adverse events; MDA- Malondialdehyde