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Vitamin C for asthma and exercise-induced bronchoconstriction

  1. Stephen J Milan1,*,
  2. Anna Hart2,
  3. Mark Wilkinson3

Editorial Group: Cochrane Airways Group

Published Online: 23 OCT 2013

Assessed as up-to-date: 19 DEC 2012

DOI: 10.1002/14651858.CD010391.pub2


How to Cite

Milan SJ, Hart A, Wilkinson M. Vitamin C for asthma and exercise-induced bronchoconstriction. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010391. DOI: 10.1002/14651858.CD010391.pub2.

Author Information

  1. 1

    St George's University of London, Population Health Sciences and Education, London, UK

  2. 2

    Lancaster University, Lancaster Medical School, Clinical Research Hub, Lancaster, Lancashire, UK

  3. 3

    University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK

*Stephen J Milan, Population Health Sciences and Education, St George's University of London, London, UK. smilan@sgul.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 23 OCT 2013

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Characteristics of included studies [ordered by study ID]
Anah 1980

MethodsRandomised, double-blind controlled trial. Parallel-group design


Participants41 participants: vitamin C: 22, placebo: 19
Age: vitamin C: mean 26.5 (range 15 to 42), placebo mean 27.8 (range 15 to 46)
Sex: vitamin C: males 12 (55%), placebo 10 (53%)
PEFR: vitamin C: mean 274.1 (range 200 to 340), placebo mean 279.2 (range 200 to 325)

Stated as recruited from Asthma Clinic. Each patient had the following investigations done on admission to the trial: haemoglobin or packed cell volume (PCV), white blood cell count (WBC) with eosinophil count (%), stool microscopy, peak expiratory flow rate (PEFR), plasma ascorbic acid. All had asthma for at least 4 years, but in remission. Most on maintenance therapy with bronchodilators. One on low-dose oral steroids. Maintenance therapy continued in trial. All had history of attacks in rainy season and trial ran in rainy season

Inclusion criteria: one criterion for selection was the increase in exacerbation during the rainy season. These exacerbations were precipitated by respiratory infection. Selection of participants for the study was simple: any person who agreed to participate after a full explanation of the procedure was accepted, unless he/she lived outside the city. If he/she could attend at regular intervals, including reporting to the hospital emergency service in the event of a severe attack at any time of the day or night, he/she was accepted

Exclusion criteria: those with complicating bronchitis and/or emphysema were not admitted into the study group

The trial was conducted in Benin City, Nigeria


Interventions1 g of ascorbic acid as 1 effervescent tablet once daily versus matching placebo. The tablets were dissolved in a small quantity of water. 2 identical effervescent tablets were provided for the trial by Roche (Nig.) Limited

Most were on maintenance therapy with bronchodilators. One patient was on a small dose of oral steroids (5 mg of prednisolone daily) on entry into the study. All remained on whatever drugs sustained their remission


OutcomesAsthma attacks (reporting precludes us from including these data in our definition of exacerbations as hospital admission or course of oral steroids). Stool microscopy. Eosinophil count. Data collected at 4, 8, 12, 14 weeks


Notes14-week trial

Funded by the Research Grant Committee of the College of Medical Sciences, University of Benin

Effervescent tablets were provided by Roche (Nig.) Limited


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot specified

Allocation concealment (selection bias)Low riskCoded allocation to A (vitamin C group) or B (placebo group) which was decoded on completion of the trial

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. 2 identical effervescent tablets were provided for the trial by Roche (Nig.) Limited

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. 2 identical effervescent tablets were provided for the trial by Roche (Nig.) Limited

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo indication of withdrawals

Selective reporting (reporting bias)Unclear riskSome outcomes not reported (genotype, stool microscopy and eosinophil count data not reported as the authors judged the data to be unreliable)

Anderson 1983

MethodsRandomised controlled trial, parallel-group design


Participants16 children: vitamin C: 7, control: 9
Age: vitamin C: 9.3 (2.4), control: 9.2 (1.9)
Severity: vitamin C: 4 moderate and 3 severe, control: 6 moderate and 3 severe
Sex: vitamin C: 7 males (100%), control: 5 males (56%)

Children with difficulty in asthma management who were randomly selected. Diagnostic criteria: MMEFR (resting maximal mid-expiratory flow rate): average 66% for moderate and 36% for severe

Inclusion criteria: history of recurrent respiratory infections and asthma confirmed by lung function studies

Exclusion criteria: none specified in trial report

Paediatric Respiratory Clinic H F Verwoerd Hospital, Pretoria


Interventions1 g ascorbic acid (Redoxon) as a single dose in the morning (as adjunct to standard therapy) versus nothing (as an adjunct to standard therapy) for 6 months

Co-medication: each child received 3 daily doses of sodium cromoglycate (Ludamol) and either fenoterol (Berotec) or salbutamol (Ventolin). None received glucocorticoids during the study and none was hospitalised during the trial


OutcomesExacerbations (requiring glucocorticoids or hospitalisation), IgE (serum), antibodies to streptolysin 0 (ASO), polymorphonuclear leucocyte (PMNL) migration, secretory immunoglobulin A (IgA), serum immunoglobulin and total haemolytic complement levels


NotesFunding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskThe study compared ascorbic acid to no intervention and therefore the trial was unblinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo statement that assessors were unblinded or any attempt so to do, but measurements objective

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete data

Selective reporting (reporting bias)Unclear riskNo stated primary objective; some outcomes not reported

Cohen 1997

MethodsRandomised, double-blind trial, cross-over design


Participants20 patients with asthma received both vitamin C and placebo in a randomised, cross-over design
Mean age 13.8 (7 to 28)
Sex: 13 males (65%)

Reported as: all participants demonstrated exercise-induced asthma (EIA) by having a decline of at least 15% in their forced expiratory volume in 1 second after a standard exercise test on a motorised treadmill (model Q50, Quinton Instrument Co, Seattle, Wash). The patients were advised to refrain from taking their regular medication, which consisted of inhaled steroids, antihistamines and bronchodilators, 12 hours before the test

Baseline FEV1 (L) (before exercise): 2.36 (0.85); baseline FEV1 (L) (after exercise): 1.74 (0.72)

Baseline FEV1 (% predicted) (before exercise): 86 (12); baseline FEV1 (% predicted) (after exercise): 63 (13)

The setting was a university hospital in Israel


InterventionsReported as: 2 g of oral ascorbic acid versus placebo 1 hour before a 7-minute treadmill exercise session. 8 minutes after exercise pulmonary function tests were performed. 1 week later participants received the alternative intervention


OutcomesDevelopment of exercise-induced asthma (EIA), FEV1 (L) and FEV1 (% predicted)


NotesSummary of FEV1; a single large dose of ascorbic acid before exercise prevented the development of EIA in 9 of

20 patients and reduced the airways’ responsiveness to exercise in 2 other patients

Funding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as double-blind but method of blinding (whether it was a matched placebo) is unclear in trial report

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as double-blind but method of blinding (whether it was a matched placebo) is unclear in trial report

Incomplete outcome data (attrition bias)
All outcomes
Low riskInformation included in trial report from all 20 participants

Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Fogarty 2003

MethodsRandomised, placebo-controlled, double-blind, parallel-group


Participants201 adults randomised: vitamin C: 95 (72 completed (76%)), placebo: 106 (82 completed (77%))
Age: vitamin C: 42 years, placebo: 40 years
Sex: vitamin C: 37 males (39%), placebo: 42 (40%)

Baseline lung function: mean FEV1 (L) vitamin C: 2.8 (SD not reported), placebo: 2.8 (SD not reported)

Baseline lung function: mean % predicted FEV1 (SD): vitamin C: 85.3 (15.7), placebo: 83.3 (17.5)

Inclusion criteria: stated as: patients aged 18 to 60 years with a physician diagnosis of asthma and using at least one dose of an inhaled corticosteroid daily for the last 6 months were identified from computerised records

Exclusion criteria: stated as: participants currently taking oral corticosteroids or diuretics, had used vitamin C, magnesium or calcium supplements within 3 months, had experienced exacerbation of asthma within 4 weeks, had a cumulative smoking history of 10 pack-years or more, or were pregnant or planning a pregnancy

Patients recruited from 24 GP practices, Nottingham, UK


InterventionsRun-in period: consenting individuals entered a 3-week run-in period. Participants who complied with the measurement protocol and experienced no exacerbation of asthma during the run-in period then proceeded into the supplementation study

Interventions: vitamin C 1 g/day (5.6 mmol) plus magnesium placebo versus vitamin C placebo and magnesium placebo. A third group (not included in this review) received 450 mg/day magnesium chelate. No patient included in the vitamin C versus placebo comparison was receiving magnesium


OutcomesStated as: FEV1, forced vital capacity (FVC), inhaled dose of methacholine causing a 20% fall in FEV1 (PD20) to a maximum dose of 12.25 mmol methacholine (and values above this were censored), and average morning and evening peak flow, average daily bronchodilator use and daily symptom score recorded in a diary for the preceding 2 weeks. Study included a composite measure as their primary outcome. Data collected at the beginning and after 4, 8, 12 and 16 weeks of supplementation (but only reported at 16 weeks in trial report)

We did not include data in our analyses from Fogarty 2006 (an additional study report related to this trial) due to the loss of randomisation at that stage


Notes16-week trial

Funded by: NHS National Research and Development Programme on Asthma Management administered by the National Asthma Campaign


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were assigned using a random number generator, in blocks also stratified by a regular corticosteroid dose, defined as low or high

Allocation concealment (selection bias)Low riskAllocation by an individual code number, decoded after the last participant completed the trial. Randomisation and dispensing performed independently from the recruitment of trial participants

Blinding of participants and personnel (performance bias)
All outcomes
Low riskRandomised to vitamin C 1 g/day (5.6 mmol) plus magnesium placebo, magnesium amino chelate (Lamberts Health Care, Tunbridge Wells, UK) 450 mg/day (27.6 mmol) plus vitamin C placebo, or double-matched placebo

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear in trial report

Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for withdrawal listed in study report. Loss to follow-up, but taken into account. ITT analysis and as treated analysis reported: precise details of ITT imputation not given: "assuming deterioration in all outcomes in participants who withdrew".  66/300 withdrew (some from magnesium group not included in this review)

Selective reporting (reporting bias)Unclear riskPrimary outcome measure reported, but secondary outcomes not all reported and incomplete reporting of SF-36 data

Kordansky 1979

MethodsRandomised controlled trial, cross-over design


Participants6 adults (2 women and 4 men) ranging in age from 20 to 34 selected at random
Participants with ragweed-sensitive asthma, defined by skin prick positivity. Tested out of the ragweed season. Asymptomatic and not on treatment

Inclusion criteria: ragweed-sensitive asthmatics

Trial conducted in Baltimore, USA


Interventions500 mg once daily (2 capsules) vitamin C for 7 days versus lactose placebo (2 capsules) for 7 days

Co-medication: during the study period, these patients were not receiving bronchodilators nor were they on corticosteroid therapy


OutcomesPD20 to ragweed extract challenge FEV1, PD35 SGaw, tested on day 7, 3 hours after dose of placebo/vitamin C

The FEV1 data were not reported in a format that we could use in our analyses


Notes7-day cross-over trial

Funded by the National Institute of Allergy and Infectious Diseases


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy described as double-blind but details of blinding (whether an identical placebo pill was used) were not described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStudy described as double-blind but details of blinding (whether an identical placebo pill was used) were not described

Incomplete outcome data (attrition bias)
All outcomes
Low risk6 participants completed both periods of the cross-over. No information on withdrawals included in trial report

Selective reporting (reporting bias)Unclear riskNot all outcomes summarised. Sample dose-response curves given. No tables of summary statistics

Malo 1986

MethodsRandomised controlled trial, cross-over design


Participants16 adults with asthma meeting the American Thoracic Society criteria
Age range 19 to 59, mean 43.1 (11.9) years
Sex: 3 men (19%)
Mean duration of asthma: 10.5 (14.6) years
Baseline lung function: mean % predicted FEV1 (SD): 86.6 (19.6)

Department of Chest Medicine, Hopital du Sacre-Coeur, Montreal, Canada


InterventionsRun-in: medication was withheld as follows: inhaled beta2-adrenergic agents for 8 hours and sustained release theophylline derivatives for 12 hours

Intervention: 250 ml of a transparent and odourless sweet liquid in which was dissolved either 2 g ascorbic acid or placebo. 1 hour later spirometry was measured and histamine challenge done until PC20 reached

Co-medication: all participants received beta2-adrenergic bronchodilators and/or sustained-release theophylline derivatives and 6 were also receiving beclomethasone


OutcomesFEV1, FVC, PC20 during histamine challenge

The FEV1 data were not reported in a format that we could use in our analyses


NotesFunding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised according to a 4.3.1 two-treatment cross-over design, but details of random sequence generation were not included in trial report

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy described as double-blind and details of blinding are provided as "The active and placebo medications consisted of 250 mL of a transparent and odourless sweet liquid in which was dissolved or not, respectively, 2 gm of ascorbic acid. These solutions of similar taste were prepared and coded by the hospital pharmacy"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low risk16 participants completed both periods of the cross-over. No information on withdrawals included in trial report

Selective reporting (reporting bias)Unclear riskTrial report does not include complete details of outcomes

Nadi 2012

MethodsRandomised, double-blind trial, parallel-group design


Participants60 participants with severe asthma: vitamin C: 30, placebo: 30 described as "matched"
Age: vitamin C: 48.38 (± 9.03), placebo: 40.53 (± 10.48)

Baseline lung function: mean FEV1 L (SD) vitamin C: 1.40 (0.56), placebo: 1.63 (0.68)

Inclusion criteria: bronchial asthma, where the diagnosis was established through demonstrating reversible airway obstruction. Severe asthma (stable asthma step 4, according to 2004 Global strategy for asthma management and prevention guideline)

Exclusion criteria: smokers and patients with other chronic diseases were excluded from the study

Participants recruited from Ekbatan hospital in Hamadan (Iran)


Interventions1000 mg vitamin C daily versus placebo

Co-interventions: standard asthma treatment (according to stepwise therapy in 4th step of bronchial asthma) in both groups, in which patients were controlled appropriately


OutcomesFEV1, FVC and FEV1/FVC leukocyte vitamin C level. Data recorded at baseline and 1 month


Notes1-month trial

Funding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not described. Participants were randomly divided into 2 groups, A and B (including 30 patients in each group), and were matched according to their age, weight, height, gender, BMI and drug consumption

Allocation concealment (selection bias)Unclear riskDescribed as "Both patients and physician were unaware of details of patient’s distributions", however no further details available in trial report

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blind – however details of the placebo (whether it was matched to the intervention) are not included in trial report

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble-blind – however details of the placebo (whether it was matched to the intervention) are not included in trial report

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details of withdrawals in trial report

Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

O'Sullivan 2000

MethodsRandomised, double-blind, controlled trial, cross-over design


Participants10 participants diagnosed with mild asthma according to America Thoracic Society criteria. Very limited details in trial report (conference abstract)

Location of trial not included in abstract


InterventionsEach participant completed 2 treatment periods with ingestion of either 2 g of ascorbic acid or placebo 45 minutes prior histamine broncho-provocation


OutcomesFEV1 and bronchial hyper-responsiveness to inhaled histamine


NotesFunding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy described as double-blind but unclear whether an identical placebo was used

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo indication of withdrawals

Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Schachter 1982

MethodsRandomised, double-blind, controlled trial, cross-over design


Participants12 adults with exercise-induced asthma, never on corticosteroids or admitted to hospital
Mean age 26 (5) years
Sex: 5 males (41.7%)

Baseline lung function: mean % predicted FEV1 (SD): 75 (18.1)

Participants were diagnosed with asthma as defined by the American Thoracic Society’s criteria

Inclusion criteria: all 12 participants gave a characteristic description of exercise-induced bronchoconstriction (EIB). Those participants who demonstrated sufficient EIB (20% reduction in maximal expiratory flow at 40% of the vital capacity below total lung capacity on the partial expiratory flow-volume curve (MEF40%(P)) after exercise were invited to proceed to the remaining challenges

Trial conducted in New Haven, Connecticut, USA


InterventionsAll 12 participants were instructed to take no medications for at least 8 hours prior to each challenge experiment. They were similarly instructed to refrain from foods or beverages containing large amounts of methylxanthines or ascorbic acid (coffee, fruits, juices, etc.)

Intervention: single-dose vitamin C (500 mg) orally 1 hour before exercise challenge versus placebo (sucrose). The vitamin C and placebo were given in identical capsules in a double-blind random order


OutcomesFEV1, FVC, maximal expiratory flow (MEF) and PEFR. Measured at before exercise, immediately after exercise, 5 minutes after exercise and post-bronchodilator following exercise


NotesTrial conducted on 2 subsequent days. Participants underwent exercise challenge 90 minutes post-dose. No details of washout period provided in report

Funding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. Vitamin C and placebo in identical capsules

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Vitamin C and placebo in identical capsules

Incomplete outcome data (attrition bias)
All outcomes
Low riskData provided for 12 participants

Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Schertling 1990

MethodsRandomised, double-blind, controlled trial, cross-over design


Participants29 participants with infection-related bronchial asthma
Age: aged 18 to 60 years
Sex: 18 men (62%) and 11 women

Inclusion criteria: 18 years of age or older with infection-associated asthma

Exclusion criteria: inhaled and systemic corticosteroids, kidney diseases, acute and severe purulent infections

Participants recruited from an ambulatory healthcare centre in Berlin, East Germany


Interventions2-week run-in period

Intervention: 5 g/day oral ascorbic acid in 3 sugar-coated pills versus oral placebo (identical capsules)

2 weeks on first intervention, 1 week washout period and 2 weeks on second intervention

The order of the test periods was chosen randomly


OutcomesDaily asthma symptom score; 4 measurements per day of expiratory peak flow throughout the entire study; 3 checks throughout study of bronchial hyperreactivity, using histamine provocation; broncho-alveolar lavage at the end of testing periods, with determination of alveolar differential cell count and measurement of metabolic activity of broncho-alveolar cells, using chemiluminescence; global assessment of effectiveness and tolerance by doctor and patient


Notes2 weeks on daily oral ascorbic acid or placebo

Funding source not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe sequence of testing periods was chosen randomly. Details of random sequence generation not reported

Allocation concealment (selection bias)Unclear riskInsufficient details in trial report

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient details in trial report

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information included in trial report about masking for data collectors/analysers

Incomplete outcome data (attrition bias)
All outcomes
High riskData provided on 23 or 24 participants

Selective reporting (reporting bias)Unclear riskNone apparent

Tecklenburg 2007

MethodsRandomised, double-blind, trial, cross-over design


Participants8 participants
Mean age: 24.5 (4.8)
Sex: 2 males (25%)

All participants were diagnosed with clinically treated mild-to-moderate persistent asthma with an FEV1 greater than 70% of predicted and documented EIB (usual diet) as indicated by a drop of greater than 10% in postexercise FEV1 compared with pre-exercise values. Physician-diagnosed asthma. All participants had a history of chest tightness, shortness of breath and intermittent wheezing following exercise

Baseline lung function: mean FEV1 L (SD) 3.82 (0.37)

Baseline lung function: mean % predicted FEV1 (SD): 97.0 (6.1)

Inclusion criteria: exercise-induced bronchoconstriction

Participants: university students and the local community
Indiana, USA


InterventionsRun-in: participants were asked to discontinue taking leukotriene receptor antagonists (LTRAs; N = 3 montelukast (Singulairs)) 12 h prior to testing, 10, 13, 14 and 4 days prior to testing to abstain from taking combined inhaled corticosteroids (ICS) and long-acting b2-agonists (N = 2, fluticasone propionate (Flovents) and salmeterol (Advairs)) or combined long-acting b2-agonists and LTRAs (N = 3 salmeterol (Advairs) and montelukast (Singulairs)). In addition, all participants were asked to refrain from taking caffeine, and to avoid physical activity for 12 h and 24 h, respectively, before exercise testing. Participants were asked to abstain from taking antioxidant supplements other than those given during the course of the study. Participants were advised to avoid foods that were high in vitamin C during the study

Intervention: pharmaceutical grade ascorbic acid supplement (1500 mg/day: 3 500 mg capsules)(NOW foods, Bloomingdale, IL) versus a matched (colour/size) placebo (3 capsules/day of sucrose)(NOW foods, Bloomingdale, Illinois)


OutcomesPulmonary function (FEV1) pre- and postexercise, symptoms, exhaled nitric oxide and urine analysis


NotesParticipants were randomised to active treatment or placebo for 2 weeks. 1-week wash-out period. Participants crossed over to the alternative condition for the following 2 weeks

Study was funded, in part, by the Gatorade Sports Science Institute


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskMatching placebo manufactured by the same company as the active treatment

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMatching placebo manufactured by the same company as the active treatment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo indication of withdrawals

Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Al-BiltagiThis study was retracted by the authors in 2012 due to data analysis issues. Dr Al-Biltagi has confirmed that there are no plans to re-analyse the data and that the research is due to be repeated

Retraction. Omega-3 fatty acids, vitamin C and Zn supplementation in asthmatic children: a randomised self-controlled study. Acta Paediatrica 2012;101(8):891

Aliyali 2010Study did not compare vitamin C to placebo/no treatment

Bagnato 1999Study did not compare vitamin C to placebo/no treatment

Baumann 2005Study did not compare vitamin C to placebo/no treatment

Bede 2008Study did not compare vitamin C to placebo/no treatment

Belousova 2006Study did not compare vitamin C to placebo/no treatment

Bernorio 1996Study did not compare vitamin C to placebo/no treatment

Bime 2012Not a trial of vitamin C

Cakmak 2004AStudy did not compare vitamin C to placebo/no treatment

Carlsten 2011Study did not compare vitamin C to placebo/no treatment

Carlsten 2011aStudy did not compare vitamin C to placebo/no treatment

Chazan 1981Study not randomised

Covar 2010Study did not compare vitamin C to placebo/no treatment

Cristofalo 1999Study did not compare vitamin C to placebo/no treatment: combination intervention as vitamin C given with N-acetylcysteine

Cuomo 2004Study did not compare vitamin C to placebo/no treatment: intervention was a mixture of antioxidants

Daniliak 1995Study did not compare vitamin C to placebo/no treatment

Dauletbaev 2001Study did not compare vitamin C to placebo/no treatment; not randomised

De Lucia 1991Study did not compare vitamin C to placebo/no treatment

Dunstan 2007Study did not compare vitamin C to placebo/no treatment: combination intervention

Echazarreta 2000Study did not compare vitamin C to placebo/no treatment

Echazarreta 2005Study did not compare vitamin C to placebo/no treatment

Ensom 2003Study did not compare vitamin C to placebo/no treatment

Falk 2005Study did not compare vitamin C to placebo/no treatment

Greenough 2010Participants not diagnosed with asthma; a prophylactic study

Gvozdjakova 2005Study did not compare vitamin C to placebo/no treatment

Gvozdjakova 2005bStudy did not compare vitamin C to placebo/no treatment: combination intervention

Gvozdjakova 2006Study did not compare vitamin C to placebo/no treatment: combination intervention

Hernandez 2009Study did not compare vitamin C to placebo/no treatment: combination intervention

Hosseini 2001Study did not compare vitamin C to placebo/no treatment

Houdard 1969Study did not compare vitamin C to placebo/no treatment

Jabbari 2005Study did not compare vitamin C to placebo/no treatment

Jahnova 2002Study did not compare vitamin C to placebo/no treatment

Kiss 2000Study did not compare vitamin C to placebo/no treatment: combination intervention

Kligler 2011Study did not compare vitamin C to placebo/no treatment

Kolpakova 2007Study did not compare vitamin C to placebo/no treatment

Kongerud 2003Study did not compare vitamin C to placebo/no treatment

Kriukov 2003Study not focused on participants with asthma: evaluation of antioxidants in the prophylaxis of respiratory diseases in young servicemen

Kurth 2008Study did not compare vitamin C to placebo/no treatment

Labhe 2001Study did not compare vitamin C to placebo/no treatment

Lau 2004Study did not compare vitamin C to placebo/no treatment

Lipman, 1964Study did not compare vitamin C to placebo/no treatment

Lisitsa 2007Study did not compare vitamin C to placebo/no treatment

Liu 2003Study did not compare vitamin C to placebo/no treatment: intervention was a combination of vitamins C and E

Ma 2013Study did not compare vitamin C to placebo/no treatment: intervention was enhanced diet and antioxidants

Medvedeva 2002Study did not compare vitamin C to placebo/no treatment

Mohsenin 1983Not a randomised controlled trial

Murphy 2002Study did not compare vitamin C to placebo/no treatment

Neuman 1999Study did not compare vitamin C to placebo/no treatment

Neuman 2000Study did not compare vitamin C to placebo/no treatment

Nikitin 1993Study did not compare vitamin C to placebo/no treatment.

Olekhnovich 1982Study did not compare vitamin C to placebo/no treatment: the comparison was between vitamin E (intramuscular or orally) and lecithin versus lecithin, and there is no indication of randomisation

Onur 2011Study did not compare vitamin C to placebo/no treatment

Panahi 2012Study did not compare vitamin C to placebo/no treatment

Panina 2002Study did not compare vitamin C to placebo/no treatment

Pearson 2004Study did not compare vitamin C to placebo/no treatment

Peden 2005Study did not compare vitamin C to placebo/no treatment

Pennings 1999Study did not compare vitamin C to placebo/no treatment

Peters 2001Study did not compare vitamin C to placebo/no treatment

Prieto 1988Study did not compare vitamin C to placebo/no treatment

Ratanamaneechat 2010Study did not compare vitamin C to placebo/no treatment

Romieu 1998Study did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2001Study did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2002Study did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2002aStudy did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2003Study did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2003aStudy did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2004Study did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2004aStudy did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2004bStudy did not compare vitamin C to placebo/no treatment: combination intervention

Romieu 2004cStudy did not compare vitamin C to placebo/no treatment: combination intervention

Shaheen 2007Study did not compare vitamin C to placebo/no treatment

Shimizu 1996Study did not compare vitamin C to placebo/no treatment

Smith 2004Study did not compare vitamin C to placebo/no treatment

Szlagatys 2005Study did not compare vitamin C to placebo/no treatment

Ting 1983Not a randomised controlled trial

Trenca 2001Study did not compare vitamin C to placebo/no treatment: combination intervention

Tug 2007Study did not compare vitamin C to placebo/no treatment

Tunnicliffe 2003Study did not compare vitamin C to placebo/no treatment

Varshavskii 2003Study did not compare vitamin C to placebo/no treatment

Vazquez-Armenta 2012Not a trial of vitamin C, but of alpha-lipoic acid

Voelker 1997A summary report of a trial (almost certainly Trenca 2001) using a combination intervention

Voitsekhovskaia 2007Study did not compare vitamin C to placebo/no treatment

Wood 2007Study did not compare vitamin C to placebo/no treatment

Wood 2008Study did not compare vitamin C to placebo/no treatment

Wood 2012Study did not compare vitamin C to placebo/no treatment

Wood 2012aStudy did not compare vitamin C to placebo/no treatment

Yamamoto 2013Not a trial of vitamin C, but of N-acetylcysteine supplementation to people exposed to diesel exhaust

 
Characteristics of ongoing studies [ordered by study ID]
IRCT138904224359N1

Trial name or titleEffect of Vitamin E and C supplements on improving asthma

MethodsRandomised controlled trial

ParticipantsHistory of at least 1 year asthma, age 18 to 50 years
Exclusion criteria: suffering from diseases other than asthma, smoking, consumption of contraceptive pills

Interventions800 mg of vitamin C daily for 12 weeks versus placebo (study also includes a vitamin E condition and a vitamin E + vitamin C condition)

OutcomesAsthma severity and serum levels

Starting dateNovember 2010

Contact informationDr Hesamodin Nabavi Zadeh

Yasuj University of Medical Sciences

NotesStudy description stated as: "The purpose of this double blind clinical trial is to determine the effect of vitamin E & C, alone and in combination, on the improvement of asthma. 80 asthmatic patients, referred to Mofateh Special Clinics and Yasuj Imam Sajjad Hospital, will be randomly assigned into one of following groups to receive 400 mg Vitamin E per day, 800 mg vitamin C, 400 mg Vitamin E as well as 800 mg vitamin C, or placebo for 12 weeks. Holms-Rahe questionnaire was used to investigate daily stress. Dietary intake is measured using 24-hour dietary recalls questionnaire and respiratory factors are measured by peak flow meter and Spiro meter. Severity of asthma and the serum levels of vitamin C and E are measured before and after the intervention."

Study results not posted at time of completion of this review

NCT01057615

Trial name or titleEffect of Fish Oil and Vitamin C on Exercise-Induced Bronchoconstriction and Airway Inflammation in Asthma

MethodsRandomised controlled trial

ParticipantsDiagnosis of asthma, based on medication use as well as history and symptoms as outlined in the NHLBI Guidelines for the Diagnosis and Management of Asthma

InterventionsFish oil versus vitamin C versus fish oil + vitamin C

OutcomesPulmonary function and exhaled nitric oxide to measure airway inflammation

Starting dateJanuary 2010

Contact informationTimothy D Mickleborough, PhD

Indiana University

NotesStudy description stated as: "The aim of this study is to extend previous findings that nutritional supplementation or dietary modification can ameliorate exercise-induced bronchoconstriction. It has been shown in separate studies that fish oil and ascorbic acid (vitamin C) individually protect against EIB by improving pulmonary function and reducing airway inflammation. The main aim of this study is to determine the comparative and additive effects of fish oil and ascorbic acid supplementation on EIB and airway inflammation in asthmatic individuals"

Study results not posted at time of completion of this review

 
Summary of findings for the main comparison. Summary of findings: Vitamin C supplementation compared with placebo for asthma

Vitamin C supplementation compared with placebo for asthma

Patient or population: adults and children with asthma

Settings: community

Intervention: vitamin C supplementation

Comparison: placebo

OutcomesAnalyses in study reportNo of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Health-related quality of life (HRQL)There was no evidence of a difference in HRQL between the groups after 16 weeks treatment as measured by the available SF-36 data201 adults (1 study)⊕⊕⊝⊝
low
1, 2
Authors' note: "SF-36 data on physical functioning were incomplete and this section was excluded from analysis"

Asthma exacerbationsNo exacerbations in either group16 children (1 study)⊕⊝⊝⊝
very low1,3

Lung function: FEV1 (ml) (change from 0 to 16 weeks)MD -11 (95% CI -92 to 70)201 adults (1 study)⊕⊕⊕⊝
moderate1
The 95% CI excludes a clinically important mean difference in FEV1, so the outcome was not downgraded for imprecision

Asthma symptoms (change from 0 to 16 weeks)MD 0 (95% CI -0.2 to 0.1)201 adults (1 study)⊕⊕⊕⊝
moderate1

Adverse eventsNo adverse events in either group41 adults (1 study)⊕⊝⊝⊝
very low1,3

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

FEV1: forced expiratory volume in one second; MD: mean difference

 1One point deducted to reflect selective reporting as data reported by only one trial.
2One point deducted because results were not available from all components of the quality of life instrument which reduces our confidence in this result.
3We deducted two points for imprecision and unclear randomisation.
 
Summary of findings 2. Summary of findings: Vitamin C supplementation compared with placebo for exercise -induced bronchoconstriction/asthma

Vitamin C supplementation compared with placebo for exercise-induced bronchoconstriction/asthma

Patient or population: adults and children with exercise-induced bronchoconstriction/asthma

Settings: community

Intervention: vitamin C supplementation

Comparison: placebo

OutcomesAnalyses in study reportNo of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Health-related quality of life (HRQL)See commentSee commentSee commentNo between-group data reported

Asthma exacerbationsSee commentSee commentSee commentNot reported

Lung function: FEV1 % drop

Postexercise
Reported that the maximum percentage drop in FEV1 postexercise on the vitamin C diet was -6.4% (95% CI -12.0% to -0.8%; the effect size using omega-squared (ES) was 0.40) which is indicative of an attenuated EIB response. This was significantly different (P < 0.05) from the maximum drop of -12.9% (95% CI -18.6% to -12.3%) on placebo8 adults (1 study)⊕⊕⊝⊝
low1,2
Cross-over study

Asthma symptomsReported that a significant improvement (P < 0.05) in mean asthma symptom scores was observed (6.3; 95% CI 5.8 to 6.8) on the vitamin C diet compared to the placebo diet (5.8; 95% CI 5.1 to 6.2)8 adults (1 study)⊕⊕⊝⊝
low1,2
Cross-over study

Adverse eventsSee commentSee commentSee commentNot reported

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

CI: confidence interval; EIB: exercise-induced bronchoconstriction; FEV1: forced expiratory volume in one second

 1One point deducted for selective reporting as data provided by only one small trial.
2One point deducted to reflect the 'Risk of bias' assessment for this trial (unclear randomisation).
 
Table 1. Outcomes: chronic asthma

Vitamin C supplementation versus control (asthma)

OutcomeStudiesNAgeStudy IDStudy reported result

Health-related quality of life1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference in HRQL between the groups after 16 weeks treatment as measured by the available SF-36 data*

Asthma exacerbations116 children
Vitamin C: 7
No treatment: 9
Vitamin C mean: 9.3 years (± 2.4)
Control mean: 9.2 years (± 1.9)
Anderson 1983No exacerbations in either group

FEV1 (L) (at one month)160 participants
Vitamin C: 30
Placebo: 30
Vitamin C mean: 48.38 years (± 9.03)
Placebo mean: 40.53 years (± 10.48)
Nadi 2012No direct comparison between vitamin C and placebo reported. Before versus after treatment comparison in vitamin C (P = 0.65) and in placebo (P = 0.044)

FEV1 (ml) (change from 0 to 16 weeks)1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD -11 (95% CI -92 to 70), P = 0.78

FEV1 (% predicted)110 participants (cross-over design)Very limited details in trial report (conference abstract)O'Sullivan 2000No significant change in FEV1 after vitamin C administration (95 ± 2.7% versus 94.2 ± 3.2%)

PEFR (L/min) (change from 0 to 16 weeks) AM1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD 0.9 (95% CI -11.8 to 13.5), P = 0.89

PEFR (L/min) (change from 0 to 16 weeks) PM1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD 2.2 (95% CI -10.0 to 14.3), P = 0.73

Asthma symptoms (change from 0 to 16 weeks)1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD 0 (95% CI -0.2 to 0.1), P = 0.33

Adverse events141 participants
Vitamin C: 22
Placebo: 19
Vitamin C mean: 26.5 years (range 15 to 42)
Placebo mean: 27.8 years (range 15 to 46)
Anah 1980No adverse events in either group

 *Authors note: "SF-36 data on physical functioning were incomplete and this section was excluded from analysis".
FEV1: forced expiratory volume in one second
HRQL: health-related quality of life
PEFR: peak expiratory flow rate
 
Table 2. Outcomes: exercise-induced bronchoconstriction/asthma

Vitamin C supplementation versus placebo (exercise-induced bronchoconstriction/asthma)

OutcomeStudiesNAgeStudy IDStudy reported result

Health-related quality of life

 
00

Asthma exacerbations

 
00 — — —

FEV1 (L) (change scores)

 

Immediately after exercise112 participants (cross-over design)Mean age 26 years (± 5)

 
Schachter 1982No significant difference between vitamin C and placebo
Vitamin C: mean +0.21 (standard error (SE) ± 0.06)
Placebo mean +0.08 (SE ± 0.08)
t = 1.46 (P = 0.18)

5 minutes after exercise112 participants (cross-over design)Mean age 26 years (± 5)Schachter 1982No significant difference between vitamin C and placebo
Vitamin C: mean - 0.24 (SE ± 0.06)
Placebo mean: -0.44 (SE ± 0.14)
t = 2.13 (P = 0.057)

Post-bronchodilator112 participants (cross-over design)Mean age 26 years (± 5)Schachter 1982Post-bronchodilator scores significantly better on vitamin C
Vitamin C: mean + 0.43 (SE ± 0.12)
Placebo mean + 0.22 (SE ± 0.10)
t = 3.42 (P < 0.01)

FEV1 % drop postexercise

 
18 participants (cross-over design)Mean age: 24.5 years (4.8)Tecklenburg 2007A significant advantage in favour of vitamin C
Reported maximum % drop in FEV1 postexercise on vitamin C diet was -6.4% (95% CI -12.0 to -0.8%; effect size using omega-squared (ES) 0.40); indicative of an attenuated EIB response. This was significantly different (P < 0.05) from the maximum drop of -12.9% (95% CI -18.6 to -12.3%) on placebo

PEF (change scores)

 

Immediately after exercise112 participants (cross-over design)Mean age 26 years (± 5)Schachter 1982A significant advantage in favour of vitamin C
Vitamin C: mean +0.59 (SE ± 0.16)
Placebo mean +0.10 (SE ± 0.25)
t = 2.3 (P < 0.05)

5 minutes after exercise112 participants (cross-over design)Mean age 26 years (± 5)Schachter 1982No significant difference between vitamin C and placebo
Vitamin C: mean -0.73 (SE ± 0.28)
Placebo mean -0.95 (SE ± 0.40)
t = 0.90 (NS)

Post-bronchodilator112 participants (cross-over design)Mean age 26 years (± 5)Schachter 1982A significant advantage in favour of vitamin C
Vitamin C: mean +0.83 (SE ± 0.26)
Placebo mean +0.39 (SE ± 0.29)
t = 2.69 (P < 0.05)

Asthma symptoms

 
18 participants (cross-over design)

 
Mean age: 24.5 years (4.8)

 
Tecklenburg 2007A significant advantage in favour of vitamin C
Reported asa significant improvement (P < 0.05) in mean asthma symptom scores (mean score 6.3; 95% CI 5.8 to 6.8) on the vitamin C diet compared to the placebo diet (mean score 5.8; 95% CI 5.1 to 6.2)

 

Adverse events00 — — —

 *Tecklenburg 2007 used Asthma Quality of Life Questionnaire symptom score component. These data are reported in the table under symptoms.
CI: confidence interval
FEV1: forced expiratory volume in one second
NS: non-significant
SE: standard error