Table 1:
Characteristics of the 42 eligible trials and their participants
| Study first author, year | Setting | Participants | Mean age, years (s.d.) [range] | Male: Female | 25(OH)D assay, EQA scheme | Mean baseline 25(OH)D, nmol/L (s.d.) | Baseline 25(OH)D <25 nmol/L (%) | Mean attained 25(OH)D, intervention arm, nmo/L (s.d.) | Intervention: Control (total) | Oral dose of vitamin D3, intervention arm | Control | Trial duration | ARI definition | ARI primary or secondary outcome? | N contributing data / N randomised (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Li-Ng 20095 | USA | Healthy adults | 57.9 (13.6) [21.4 −80.6] | 34:128 | RIA (DiaSorin), DEQAS | 63.7 (25.5) | 3/150 (2.0) | 88.5 (23.2) | 84:78 (162) | 50 μg daily | Placebo | 3 mo | URI: ≥2 URI symptoms in absence of allergy symptoms | Primary | 157/162 (96.9) |
| Urashima 20106 | Japan | Schoolchildren | 10.2 (2.3) [6.0 – 15.0] | 242:188 | Not determined | Not determined | Not determined | Not determined | 217:213 (430) | 30 μg daily | Placebo | 4 mo | URI: influenza A/B diagnosed by RIDT or RIDT-negative ILI | Primary | 334/430 (77.7) |
| Manaseki-Holland 20107 | Afghanistan | Pre-school children with pneumonia | 1.1 (0.8) [0.1 – 3.3] | 257:196 | Not determined | Not determined | Not determined | Not determined | 224:229 (453) | 2.5 mg bolus once | Placebo | 3 mo | LRI: repeat episode of pneumonia – age-specific tachypnoea without wheeze | Secondary | 453/453 (100.0) |
| Laaksi 20108 | Finland | Military conscripts | 19.1 (0.6) [18.0 – 21.0] | 164:0 | EIA (IDS OCTEIA) | 75.9 (18.7) | 0/73 (0.0) | 71.6 (22.9) | 80:84 (164) | 10 μg daily | Placebo | 6 mo | ARI: medical record diagnosis | Primary | 164/164 (100.0) |
| Majak 20119 | Poland | Children with asthma | 10.9 (3.3) [6.0 – 17.0] | 32:16 | RIA (BioSource Europe), RIQAS | 88.9 (38.2) | 0/48 (0.0) | 37.6 (13.1) | 24:24 (48) | 12.5 μg daily | Placebo | 6 mo | ARI: self-report | Secondary | 48/48 (100.0) |
| Trilok-Kumar 201110 | India | Low birthweight infants | 0.1 (0.0) [0.0 – 0.3] | 970:1109 | -- | Not determined | Not determined | 55.0 (22.5) | 1039:1040 (2079) | 35 μg weekly | Placebo | 6 mo | ARI: medical record diagnosis of events causing hospitalisation | Secondary | 2064/2079 (99.3) |
| Lehouck 201211 | Belgium | Adults with COPD | 67.9 (8.3) [48.0 – 86.0] | 145:37 | RIA (Diasorin), DEQAS | 49.8 (29.2) | 31/182 (17.0) | 130.0 (44.7) | 91:91 (182) | 2.5 mg bolus monthly | Placebo | 1 yr | URI: self-report | Secondary | 175/182 (96.2) |
| Manaseki-Holland 201212 | Afghanistan | Infants | 0.5 (0.3) [0.0 – 1.0] | 1591:1455 | -- | Not determined | Not determined | 32.7 (17.1) | 1524:1522 (3046) | 2.5 mg bolus 3-monthly | Placebo | 1.5 yr | LRI: pneumonia confirmed by chest radiograph | Primary | 3011/3046 (98.9) |
| Camargo 201213 | Mongolia | 3rd/4th grade schoolchildren | 10.0 (0.9) [7.0 – 12.7] | 129:118 | LC-MS/MS, DEQAS | 18.9 (9.7) | 192/245 (78.4) | 49.1 (15.1) | 143:104 (247) | 7.5 μg daily | Placebo | 7 wk | ARI: parent-reported ‘chest infections or colds’ | Secondary | 244/247 (98.8) |
| Murdoch 201214 | New Zealand | Healthy adults | 48.1 (9.7) [18.0 – 67.6] | 81:241 | LC-MS/MS, DEQAS | 72.1 (22.1) | 5/322 (1.6) | 123.6 (27.5) | 161:161 (322) | 2 × 5 mg bolus monthly then 2.5 mg bolus monthly | Placebo | 1.5 yr | URI: assessed with symptom score | Primary | 322/322 (100.0) |
| Bergman 201215 | Sweden | Adults with increased susceptibility to ARI | 53.1 (13.1) [20.0 – 77.0] | 38:102 | CLA (DiaSorin), DEQAS | 49.3 (23.2) | 15/131 (11.45) | 94.9 (38.1) | 70:70 (140) | 100 μg daily | Placebo | 1 yr | URI: assessed with symptom score | Secondary | 124/140 (88.6) |
| Marchisio 201316 | Italy | Children with recurrent acute otitis media | 2.8 (1.0) [1.3 – 4.8] | 64:52 | CLA (DiaSorin), ISO9001 | 65.3 (17.3) | 2/116 (1.7) | 90.3 (21.1)] | 58:58 (116) | 25 μg daily | Placebo | 6 mo | URI: doctor-diagnosed acute otitis media | Primary | 116/116 (100.0) |
| Rees 201317 | USA | Adults with previous colorectal adenoma | 61.2 (6.6) [47.1 – 77.9] | 438:321[a] | RIA (IDS), DEQAS | 62.5 (21.3) | 0/759 (0.0) | 186.9 (455.1) | 399:360 (759) | 25 μg daily | Placebo | 13 mo (average) | URI: assessed from daily symptom diary | Secondary | 759/759 (100.0) |
| Tran 201418 | Australia | Healthy older adults | 71.7 (6.9) [60.3 – 85.2] | 343:301 | CLA (DiaSorin), DEQAS | 41.7 (13.5) | 66/643 (10.3) | 71.0 (19.6) | 430:214 (644) | 0.75 mg bolus vs. 1.5 mg bolus monthly | Placebo | 1 yr | URI: self-reported cold | Secondary | 594/644 (92.2) |
| Goodall 201419 | Canada | Healthy university students | 19.6 (2.2) [17.0 – 33.0] | 218:382 | Not determined | Not determined | Not determined | Not determined | 300:300 (600) | 0.25 mg weekly (factorial with gargling) | Placebo | 8 wk | URI: self-reported cold | Primary | 492/600 (82.0) |
| Urashima 201420 | Japan | High school students | 16.5 (1.0) [15.0 – 18.0] | 162:85 | Not determined | Not determined | Not determined | Not determined | 148:99 (247) | 50 μg daily | Placebo | 2 mo | URI: influenza A diagnosed by RIDT or RIDT-negative ILI | Primary | 247/247 (100.0) |
| Grant 201421 | New Zealand | Pregnant women and offspring | Offspring unborn at baseline | 0:260 (pregnant women) 121:128 (offspring) | LC-MS/MS, DEQAS | 54.8 (25.8) | 30/200 (15.0) | 92.9 (41.6) | 173:87 (pregnant women, 260) 164:85 (offspring, 249) | Pregnant women: 25 μg vs. 50 μg daily. Offspring: 10 μg vs. 20 μg daily | Placebo | 9 mo (3 mo in pregnancy + 6 mo in infancy) | ARI: doctor-diagnosed ARI precipitating primary care consult | Secondary | 236/260 (90.8) |
| Martineau 2015a22 [ViDiCO] | UK | Adults with COPD | 64.7 (8.5) [40.0 – 85.0] | 144:96 | LC-MS/MS, DEQAS | 46.1 (25.7) | 50/240 (20.8) | 67.3 (27.5) | 122:118 (240) | 3 mg bolus 2-monthly | Placebo | 1 yr | URI: assessed from daily symptom diary | Co-primary | 240/240 (100.0) |
| Martineau 2015b23 [ViDiAs] | UK | Adults with asthma | 47.9 (14.4) [16.0 – 78.0] | 109:141 | LC-MS/MS, DEQAS | 49.6 (24.7) | 36/250 (14.4) | 69.4 (21.0) | 125:125 (250) | 3 mg bolus 2-monthly | Placebo | 1 yr | URI: assessed from daily symptom diary | Co-primary | 250/250 (100.0) |
| Martineau 2015c24 [ViDiFlu] | UK | Older adults and their carers | 67.1 (13.0) [21.4 – 94.0] | 82:158 | LC-MS/MS, DEQAS | 42.9 (23.0) | 60/240 (25.0) | 84.8 (24.1) | 137:103 (240) | Older adults: 2.4 mg bolus 2-monthly + 10 μg daily Carers: 3 mg 2-monthly | Older adults: placebo + 10 μg daily Carers: placebo | 1 yr | URI & LRI, both assessed from daily symptom diary | Co-primary | 240/240 (100.0) |
| Simpson 201525 | Australia | Healthy adults | 32.2 (12.2) [18.0 – 52.0] | 14:20 | LC-MS/MS, DEQAS | 67.9 (23.0) | 0/33 (0.0) | Not determined | 18:16 (34) | 0.5 mg weekly | Placebo | 17 wk | ARI assessed with symptom score | Primary | 34/34 (100.0) |
| Dubnov-Raz 201526 | Israel | Adolescent swimmers with vitamin D insufficiency | 15.2 (1.6) [12.9 – 18.6] | 34:20 | RIA (DiaSorin), DEQAS | 60.4 (11.9) | 0/54 (0.0) | 73.7 (16.6) | 27:27 (54) | 50 μg daily | Placebo | 12 wk | URI assessed with symptom score | Primary | 25/54 (46.3) |
| Denlinger 201627 | USA | Adults with asthma | 39.2 (12.9) [18.0 – 85.0] | 130:278 | CLA (DiaSorin), VDSP | 47.0 (16.9) | 55/408 (13.5) | 104.3 (32.4) | 201:207 (408) | 2.5 mg bolus then 100 μg daily | Placebo | 28 wk | URI assessed with symptom score | Secondary | 408/408 (100.0) |
| Tachimoto 201628 | Japan | Children with asthma | 9.9 (2.3) [6.0 – 15.0] | 50:39 | RIA (DiaSorin), CAP | 74.9 (24.6) | 1/89 (1.1) | 85.7 (24.5) | 54:35 (89) | 20 μg daily, first 2 mo. | Placebo | 6 mo | URI: assessed with symptom score | Secondary | 89/89 (100.0) |
| Ginde, 201629 | USA | Institutionalised older adults | 80.7 (9.9) [60.0 – 95.0] | 45:62 | LC-MS/MS, VDSP | 57.3 (22.7) | 12/107 (11.2) | Not determined | 55:52 (107) | 2.5 mg bolus monthly + ≤25 μg per day equivalent | Placebo + 10–25 μg per day equivalent | 1 yr | ARI: medical record diagnosis | Primary | 107/107 (100.0) |
| Gupta 201631 | India | Children with pneumonia | 1.4 (1.1) [0.5 – 5.0] | 226:98 | RIA (Immunotech SAS/ DiaSorin) | 43.9 (33.4) | 104/312 (33.3) | 64.1 (43.9) | 162:162 (324) | 2.5 mg bolus, single dose | Placebo | 6 mo | Physician confirmed recurrent pneumonia | Co-primary | 314/324 (96.9) |
| Aglipay 201732 | Canada | Healthy children | 2.7 (1.5) [1.0 – 5.0] | 404:296 | CLA (Roche ELECSYS) | 90.9 (20.9) | 1/703 (0.1) | High dose: 121.6 (2.2); Low dose: 91.9 (1.7) | 349:354 | 50 μg daily | 10 μg daily | 4–8 mo (mean 6.3 mo) | URI: lab confirmed | Primary | 699/703 (99.4) |
| Arihiro 201833 | Japan | Adults with diagnosis of inflammatory bowel disease | 44.7 (1.3) [18.0 – 82.0] | 136:87 | RIA (Diasorin) | 58.6 (22.0) | 5/223 (2.2) | 80.4 (21.5) | 119:118 (237) | 12.5 μg daily | Placebo | 6 mo | Lab confirmed influenza | Primary | 223/237 (94.1) |
| Hibbs 201834 | USA | African American preterm infants | Offspring unborn at baseline | 166:133[b] | RIA | 55.4 (22.2) | 0/300 (0.0) | 95.0 (21.2) | 153:147 (300) | 10 μg daily, regardless of dietary intake | 10 μg daily, only if dietary intake was <5 μg daily | 1 yr | ARI: self-reported URI/LRI | Secondary | 300/300 (100.0) |
| Lee 201835 | USA | Children and young adults with sickle cell disease | 9.9 (3.9) [3.0 – 20.0] | 30:32 | LC-MS/MS, DEQAS | 35.7 (16.5) | 18/62 (29.0) | 92.4 (23.7) | 31:31 (62) | 2.5 mg bolus monthly | 0.3 mg monthly | 2 yrs | Self-reported respiratory events, including ARI | Primary | 62/62 (100.0) |
| Loeb 201836 | Vietnam | Healthy children and adolescents | 8.5 (4.0) [3.0 – 17.0] | 621:679 | CLA (DiaSorin), DEQAS | 65.5 (16.8) | 5/1153 (43.4) | 91.8 (23.6) | 650:650 (1300) | 0.35 mg weekly | Placebo | 8 mo | RT-PCR confirmed influenza A or B | Primary | 1153/1300 (88.7) |
| Rosendahl 201837 | Finland | Healthy infants | Offspring unborn at baseline | 495:492 | CLA (IDS-iSYS) VDSP | 81.5 (25.9) | 0/879 (0.0) | 117.7 (26.1) | 492:495 (987) | 30 μg daily | 10 μg daily | 2 yrs | Parent reported infections, including ARI | Co-primary | 897/987 (90.9) |
| Shimizu 201838 | Japan | Healthy adults | 52.7 (6.5) [45.0 – 74.0] | 66:149 | RIA (DiaSorin) | 48.9 (13.5) | 1/214 (0.5) | 114.6 (32.7) | 126:126 (252) | 10 μg daily (25[OH] D)[c] | Placebo | 4 mo | URI: self-reported | Primary | 215/252 (85.3) |
| Aloia 201939 | USA | Healthy African American women aged over 60 years | 69.0 (5.3) [65.4 – 72.5] | 0:260 | LC-MS/MS, NIST | 54.4 (16.7) | 9/258 (3.5) | 117.0 (28.0) | 130:130 (260) | 50 μg daily | Placebo | 3 mo | ARI: self-reported cold/flu | Secondary | 260/260 (100.0) |
| Hauger 201940 | Denmark | Healthy children | 6.6 (1.5) [4.0 – 8.0] | 61:69 | LC-MS/MS, DEQAS | 56.8 (12.5) | 0/118 (0.0) | 20 μg arm: 75.8 (11.5) 10 ug arm: 61.8 (10.6) | 43:44:43 (130) | 20 μg / 10 μg daily | Placebo | 5 mo | ARI: self-reported | Secondary | 118/130 (90.8) |
| Camargo 202041 | New Zealand | Older adults | 66.4 (8.3) [50.0 –84.0] | 2,935:2,121 | LC-MS/MS, DEQAS | 63.4 (23.6) | 89/5056 (1.8) | 135.0 (39.9) | 2558:2552 (5110) | 5 mg bolus loading dose; then 2.5 mg bolus monthly | Placebo | 3 yrs | ARI: self-reported cold/flu | Secondary | 5056/5110 (98.9) |
| Ganmaa, 202042 | Mongolia | Healthy school children | 9.4 (1.6) [6.0 – 13.0] | 4485:4366 | EIA (Biomerieux), DEQAS | 29.7 (10.5) | 2813/8851 (31.8) | 77.4 (22.7) | 4418:4433 (8851) | 0.35 mg weekly | Placebo | 3 yrs | ARI: self-reported | Secondary | 8851/8851 (100.0) |
| Mandlik 202043 | India | Healthy children | 8.1 (1.2) [6.0 – 12.0] | 158:127 | EIA (DLD diagnostics) | 58.9 (10.9) | 0/237 (0.0) | 80 (23.3) | 135:150 (285) | 25 μg daily + 500 mg calcium | Placebo | 6 mo | URI: self-reported | Secondary | 244/285 (85.6) |
| Pham 202044 | Australia | Older adults | 69.3 (5.5) [60.0 – 86.0] | 8678:7322 | LC-MS/MS, VDSP | Not determined | Not determined | 114.8 (30.3)[d] | 8000:8000 (16000) | 1.5 mg bolus monthly | Placebo | 5 yrs | ARI: self-reported | Secondary | 16,000/16,000 (100.0) |
| Rake 202045 | England | Healthy older adults | 72.2 (4.9) [65.0 – 84.0] | 408:379 | CLA (Cobas 6000 Roche) | 50.2 (27.1) | 127/787 (16.1) | 109.2 (33.9) | 395:392 (787) | 2.5 mg bolus monthly | Placebo | 2 yrs | URI/LRI: GP recorded | Secondary | 787/787 (100.0) |
| Golan-Tripto, unpublished46 | Israel | Prematurely born infants | 0 (0) | 21:29 | CLA (DiaSorin) | 33.6 (29.7) | 19/46 (41.3) | 20 μg arm: 78.0 (75.0) 10 ug arm: 81.0 (73.0) | 25:25 (50) | 20 μg daily | 10 μg daily | 1 yr | ARI: GP recorded | Secondary | 25/50 (50.0) |
| Reyes, unpublished47 | Chile | Healthy pre-school children | 2.2 (0.5) [1.3 – 3.3] | 168:135 | LC-MS/MS | 62.2 (15.5) | 1/194 (0.5) | 0.14 mg arm: 82.4 (24.5) 0.28 mg arm: 104.6 (52.9) | 99:103:101 (303) | 0.14 mg / 0.28 mg weekly | Placebo | 6 mo | ARI: self-reported | Primary | 194/303 (64.0) |
[a]
Sex missing for two participants randomised to intervention arm and subsequently excluded from analysis due to lack of outcome data.
[b]
Sex missing for one participant.
[c]
equivalent to 30 ug vitamin D3.60 1 μg vitamin D3 = 40 international units (IU); 25(OH)D concentrations reported in ng/ml were converted to nmol/L by multiplying by 2.496.
[d]
from subset of participants randomised to intervention; for comparison, mean 25(OH)D at follow-up in subset of participants randomised to placebo was 77.5 nmol/L (sd 25.2 nmol/L); 25(OH)D, 25-hydroxyvitamin D; RIDT, rapid influenza diagnostic test; COPD, chronic obstructive pulmonary disease; D3, vitamin D3 (cholecalciferol); p.o., per os (orally); mo, month; yr, year; wk, week. ARI, acute respiratory infection; CAP, College of American Pathologists, CLA, chemiluminescent assay; DEQAS, Vitamin D External Quality Assessment Scheme; EIA, enzyme immunoassay; EQA, external quality assessment; GP, general practitioner; LC-MS/MS, liquid chromatography tandem-mass spectrometry, RIA, radio-immunoassay; URI, upper respiratory infection; LRI, lower respiratory infection; ILI, influenza-like illness; RIQAS, Randox International Quality Assessment Scheme; VDSP, Vitamin D Standardisation Program of the Office of Dietary Supplements, National Institutes of Health, USA