Vitamin C supplementation for asthma: Feedback submitted by Harri Hemila, 24 March 2009

Cochrane Library  Cochrane Database of Systematic Reviews Vitamin C supplementation for asthma (Review)  Kaur B, Rowe BH, Stovold E  KaurB, RoweBH, StovoldE. Vitamin C supplementation for asthma. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000993. DOI: 10.1002/14651858.CD000993.pub3.  www.cochranelibrary.com  Vitamin C supplementation for asthma (Review)  Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews T A B L E  O F  C O N T E N T S HEADER......................................................................................................................................................................................................... 1 ABSTRACT..................................................................................................................................................................................................... 1 PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2 BACKGROUND.............................................................................................................................................................................................. 3 OBJECTIVES.................................................................................................................................................................................................. 3 METHODS..................................................................................................................................................................................................... 3 RESULTS........................................................................................................................................................................................................ 4 Figure 1.................................................................................................................................................................................................. 6 Figure 2.................................................................................................................................................................................................. 7 DISCUSSION.................................................................................................................................................................................................. 8 AUTHORS' CONCLUSIONS........................................................................................................................................................................... 8 ACKNOWLEDGEMENTS................................................................................................................................................................................ 8 REFERENCES................................................................................................................................................................................................ 9 CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 11 DATA AND ANALYSES.................................................................................................................................................................................... 17 Analysis 1.1. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 1 Change in FEV1 (L) - post-exercise challenge................................................................................................................................................................................................ 17 Analysis 1.2. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 2 FVC (L) - post-exercise challenge........... 17 Analysis 1.3. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 3 PEFR (L/min) - post-exercise challenge.... 18 Analysis 2.1. Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 1 FEV1 (% drop) post-exercise................... 18 Analysis 2.2. Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 2 Symptom scores (Asthma Quality of Life Questionnnaire)..................................................................................................................................................................................... 18 Analysis 3.1. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 1 IgE (IU/ml serum) - absolute values......... 19 Analysis 3.2. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 2 FEV1 mL 4 months................................... 19 Analysis 3.3. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 3 Peak Flow (L/min) 4 months.................... 19 Analysis 3.4. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 4 Geometric mean decrease in inhaled corticosteroid use (μg).......................................................................................................................................................................... 20 ADDITIONAL TABLES.................................................................................................................................................................................... 20 FEEDBACK..................................................................................................................................................................................................... 20 WHAT'S NEW................................................................................................................................................................................................. 22 HISTORY........................................................................................................................................................................................................ 22 CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 23 DECLARATIONS OF INTEREST..................................................................................................................................................................... 23 SOURCES OF SUPPORT............................................................................................................................................................................... 23 INDEX TERMS............................................................................................................................................................................................... 23 Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. i Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews [Intervention Review] Vitamin C supplementation for asthma Balvinder Kaur1, Brian H Rowe2, Elizabeth Stovold3 1Department of Primary Care and Public Health, Faculty of Medicine, Imperial College London, London, UK. 2Department of Emergency Medicine, University of Alberta, Edmonton, Canada. 3Population Health Sciences and Education, St George's, University of London, London, UK Contact address: Emma J Welsh, Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, Tooting, London, SW17 0RE, UK. [email protected]. Editorial group: Cochrane Airways Group. Publication status and date: Stable (no update expected for reasons given in 'What's new'), comment added to review, published in Issue 8, 2012. Citation: KaurB, RoweBH, StovoldE. Vitamin C supplementation for asthma. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000993. DOI: 10.1002/14651858.CD000993.pub3. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. A B S T R A C T Background Vitamin C is one of the key antioxidant vitamins which is abundant in the extracellular fluid lining the lung and low vitamin C intake has been associated with pulmonary dysfunction. Objectives To evaluate the evidence for the efficacy of vitamin C in the treatment of asthma. Search methods The Cochrane Airways Review Group asthma register was searched and bibliographies of studies identified were also checked for further trials. This review has been updated by searches to August 2008. Selection criteria Only randomised controlled trials were eligible for inclusion. Studies were considered for inclusion if they dealt with the treatment of asthma using vitamin C supplementation. Two independent reviewers identified potentially relevant studies using pre-defined criteria and selected studies for inclusion. Data collection and analysis Data were abstracted independently by two reviewers. Information on patients, methods, interventions, outcomes and results was extracted using standard forms. Main results Nine studies met the review entry criteria, randomising a total of 330 participants. Study design varied and the reporting was generally poor. Five trials contributed numerical data to the review. They provided outcome data on lung function, symptom scores, IgE levels and inhaled steroid use. One small study showed a significant difference in % drop in FEV1 post-exercise. Authors' conclusions At present, evidence from randomised-controlled trials is insufficient to recommend a specific role for vitamin C in the treatment of asthma. Further methodologically strong and large-scale randomised controlled trials are needed in order to address the question of the effectiveness of vitamin C in asthma. Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews P L A I N  L A N G U A G E  S U M M A R Y Vitamin C supplementation for asthma Asthma is a chronic inflammatory disease of the airways characterised by wheeze and breathlessness. One theory for the observed increase in the number of people with asthma is the 'western' diet with it's lack of nutrients from fresh food. We reviewed evidence from nine trials of the antioxidant vitamin C as a treatment for asthma. In general the trials were small, varied greatly in their design and the reporting was poor. From the available evidence it is not possible to recommend either the use or avoidance of vitamin C supplements in asthma. Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews B A C K G R O U N D Asthma is now recognised as a chronic inflammatory disease resulting in reversible airways bronchoconstriction (Holgate 1990). The incidence and prevalence of asthma has increased in many countries over the past few decades. The most marked increase has been observed in children (Strachan 1999; Lewis 1996). This may be due to changing environmental exposures or the increased susceptibility of populations with reduced host resistance (Seaton 1994). One hypothesised cause for this increase is that changes in "western" diet have produced a reduction in host resistance over time. In particular recent interest has focused on the association between anti-oxidants in diets and health outcomes. Cross-sectional studies show that infrequent fruit consumption is associated with reduced lung function, both in children (Cook 1997) and adults (Butland 1999). In addition, the National Food Survey has documented a drop in the consumption of antioxidant food sources such as fresh fruit and vegetables in countries such as Great Britain since the 1950's (Seaton 1994). Vitamin C is one of the key antioxidant vitamins which is abundant in the extracellular fluid lining the lung. Low vitamin C intake is associated with pulmonary dysfunction (Schwartz 1994). Both adults (Olusi 1979) and children (Aderele 1985) with asthma have been found to have lower concentrations of vitamin C when compared to normal subjects. Patients with asthma may have low supplies of vitamin C or an increased demand for vitamin C in the face of an oxidant load resulting in depletion. There is a need to clarify whether supplementation with vitamin C may bring benefits in reducing morbidity, improving pulmonary function or quality of life in patients with asthma. There have been three recent reviews of the literature on the role of vitamin C in asthma (Bielory 1994; Hatch 1995; Monteleone 1997). However, the review by Bielory et al (Bielory 1994) only searched the English language literature using MEDLINE and gave no further details as to how the studies had been located. The other two reviews did not specify their methodology. These reviews reached different conclusions. Bielory et al (Bielory 1994) concluded that the role of vitamin C in asthma was unclear and that current literature did not support its use. The review by Hatch et al (Hatch 1995) found 7 out of 11 studies indicated that vitamin C supplementation might reverse or improve asthma symptoms. The review by Monteleone et al (Monteleone 1997) offers the opinion that vitamin C provides a short term protective effect on airway responsiveness, but less clear impact on other objective lung function measurements. All three reviews recommend further studies into the role of vitamin C in asthma. As a first step, a review using the Cochrane methodology is needed to systematically weigh the quality of the existing evidence before recommending any future studies. O B J E C T I V E S To determine the overall efficacy of vitamin C supplementation in patients with stable chronic asthma. M E T H O D S Criteria for considering studies for this review Types of studies To be eligible, all studies needed to be randomised-controlled trials (RCTs). Double-blinded trials were preferred, but single blind and open studies were also reviewed for possible inclusion. Types of participants Studies were considered for inclusion if they recruited adults and/ or children with chronic stable asthma, seasonal asthma or those with exercise-induced bronchospasm. Studies of other allergic conditions such as hay fever, allergic rhinitis and eczema were only considered if the results for subjects with asthma were presented separately. Vitamin C studies, which reported outcomes on patients with asthma separately as a sub-group, were also considered for inclusion. Types of interventions Vitamin C supplementation compared to placebo or "standard care". We considered studies that administered vitamin C via any route, dosage or dose interval. Both single dose and longer -term studies were considered for inclusion. Types of outcome measures Primary outcome measures 1) Lung function (e.g. FEV1, PEFR) 2) Symptoms (e.g. symptom scores) Secondary outcome measures 3) Functional outcomes (e.g. quality of life, sickness absence, exercise capacity) 4) Non-specific bronchial hyper-reactivity (BHR) to histamine or methacholine 5) Immunological markers (IgE levels) 6) Asthma medication requirements (e.g. additional steroid or bronchodilator usage) 7) Health service utilisation (e.g. GP attendance, hospital admissions) 8) Asthma exacerbations Search methods for identification of studies Electronic Searches Trials were identified using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts (please see the Airways Group Module for further details). All records in the Specialised Register coded as 'asthma' were searched using the following terms: ascorbic* or "vitamin c" or antioxid* The most recent search was conducted in August 2008. Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Other sources Reference lists of all primary studies and review articles were reviewed for additional references. Authors of identified trials were contacted. Data collection and analysis Retrieval of studies All trials that appeared potentially relevant were assessed by two independent reviewers for relevance using abstract and title from the electronic search. Using texts from all potentially relevant articles, final inclusion was also determined independently by two reviewers. Disagreements about study inclusion were resolved with discussion. Assessment of methodological quality The quality of included studies was assessed using the Cochrane approach. A risk of bias table was completed for each study assessing the reporting of method of randomisation, allocation concealment and blinding. Each item was judged as being adequate, unclear or inadequate. Any disagreements between reviewers were resolved by discussion. Data abstraction Data were extracted independently by two reviewers and entered in the Cochrane Collaboration Software, Review Manager (RevMan). For studies where the original data were not presented, when possible, they were extracted from graphically representations. Study outcomes that were reported post-bronchial challenge (e.g. exercise or histamine) were analysed separately from outcomes that did not involve bronchial challenge or when results were reported before such challenges (but post-dose vitamin C administration). Statistical considerations Outcomes from included trials were combined using RevMan. For continuous outcomes the weighted mean difference (WMD) with fixed effect was used to estimate the individual effect sizes and 95% confidence intervals (95% CI). If there were any dichotomous outcomes the Peto fixed or random effect model was to be used to estimate the pooled odds ratio (OR) and 95% CI. The main planned comparison for statistical consideration was any form or dose of vitamin C supplementation versus placebo or "standard care". If there were adequate included studies, the following pre-defined sub-group analysis were planned: 1. Single dose versus chronic administration of vitamin C 2. Dietary advice to increase vitamin C consumption versus no intervention 3. Oral vitamin C versus intravenous vitamin C supplementation 4. Adults versus children 5. Males versus females R E S U L T S Description of studies Details of the search history and results can be found in Table 1. For the 2008 update, 39 new references were identified and the full text of 15 of these were retrieved. One additional included study (Tecklenburg 2007), an extension to a previously included study (Fogarty 2003), and 5 further excluded studies were identified. The review now contains a total of nine studies which meet the inclusion criteria. Further details can be found in the table, "Characteristics of included studies". A total of twelve studies were excluded after examining the full-text paper. Please see "Characteristics of excluded studies" for further details. The included studies were conducted in the USA (Kordansky 1979; Schachter 1982,Tecklenburg 2007), Nigeria (Anah 1980), South Africa (Anderson 1983), Canada (Malo 1986), Israel (Cohen 1997) and the UK (Fogarty 2003; O'Sullivan 2000). Three studies examined the impact of vitamin C supplementation on exercise challenge tests in subjects with a confirmed diagnosis of exercise-induced asthma (Cohen 1997; Schachter 1982, Tecklenburg 2007). Two studies examined the impact of vitamin C administration on bronchial hyper responsiveness to histamine challenge tests in participants with asthma (Malo 1986; O'Sullivan 2000). Four studies examined the impact of vitamin C on bronchial hyper responsiveness to allergen challenge in subjects sensitive to ragweed allergen (Kordansky 1979), frequency of asthma exacerbations due to infection (Anah 1980), lung function and immunological markers in patients with asthma (Anderson 1983) and clinical control of asthma in primary care (Fogarty 2003). Three of the studies (Anah 1980; Anderson 1983; Fogarty 2003) followed a parallel study design and the remaining 6 used crossover designs. Data from the two types of study designs were presented separately in RevMan. No usable data could be extracted from the reports of four studies (Anah 1980;Kordansky 1979; Malo 1986; O'Sullivan 2000), despite attempts at author contact. Seven studies (Anah 1980; Fogarty 2003; Kordansky 1979; Malo 1986; O'Sullivan 2000; Schachter 1982, Tecklenburg 2007) involved adult patients, one study (Anderson 1983) involved only children and one (Cohen 1997) had both adults and children. The smallest study had six participants (Kordansky 1979). Others ranged from 8 to 41. The largest was Fogarty 2003 with 210 participants. This review contains a total of 330 randomised participants. All treatments were administered orally, either as tablets or as an oral solution. Three studies (Anah 1980; Anderson 1983; Fogarty 2003) featured long-term supplementation with 1 g vitamin C daily for 14 weeks, 6 months and 16 weeks, respectively. Another long-term study (Kordansky 1979) used 500 mg vitamin C supplementation daily for seven days. One study looked at supplementation with 1500mg over a short -term period of two weeks (Tecklenburg 2007) and the remaining four studies (Cohen 1997; Malo 1986; O'Sullivan 2000; Schachter 1982) used single doses of vitamin C 2g, 2g, 2g and 500 mg, respectively. Two of the crossover studies (Cohen 1997, Tecklenburg 2007) mentioned a washout period. None of the other crossover studies (Kordansky 1979; Malo 1986; O'Sullivan 2000; Schachter 1982) reported a washout period. It has been suggested that after a single oral dose of vitamin C, at least 1-2 days is required for excretion depending on pre-existing body levels (Bates 2001). Included studies reported disparate outcome measures, which made aggregation for the purpose of a meta-analysis difficult. Most of the studies did not report the actual data in the published papers or did not provide sufficient data for a meta-analysis, although Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews attempts were made to contact the authors for data. Outcome measures included a variety of lung function tests, symptoms and symptom scores, immune markers and reduction in the use of inhaled steroids. Risk of bias in included studies In general, the reporting quality of the studies was poor. All the included studies were reported as being randomised, however, only one study (Fogarty 2003) reported the method of randomisation and just three of the nine studies reported the method of allocation concealment (Anah 1980, Fogarty 2003, Malo 1986). Four studies reported the method of blinding (Anah 1980, Malo 1986, Schachter 1982, Tecklenburg 2007), while one study was inadequately blinded (Anderson 1983) and the remaining four were unclear. None of the studies adequately reported all three methods of randomisation, allocation concealment or blinding. Anah 1980, Fogarty 2003 and Malo 1986 gave the most detailed account. An overview of our judgments of are presented in Figure 1 and Figure 2.  Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Figure 1.  Methodological quality summary: review authors' judgements about each methodological quality item for each included study.   Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Figure 2.  Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.  Effects of interventions Of the nine included studies, five have contributed numerical data to the review: Anderson 1983, Cohen 1997, Fogarty 2003, Schachter 1982 and Tecklenburg 2007. Four studies (Anah 1980; Kordansky 1979; Malo 1986; O'Sullivan 2000) did not report data in an manner that permitted further analysis and author contact has been unsuccessful. However, none of these studies found a significant difference for the effect of vitamin C on lung function or symptoms. Studies could not be combined statistically, because those which addressed similar comparisons used different interventions or outcome variables. For example, there were three studies where the protective effects of vitamin C were investigated using exercise challenge. All three reported pulmonary function outcomes, but Cohen 1997 only reported results from 11 of the 20 randomised participants (who were found to have a fall in FEV1 of less than 15% following vitamin C), Schachter 1982 reported absolute change post-exercise and Tecklenburg 2007 was a two week intervention study rather a single dose study, and reported maximum percentage fall from baseline. Primary outcomes Lung function Single dose studies Change in FEV1 (L) - post-exercise challenge: (MD 0.13; 95% CI -0.05 to 0.31) (, Schachter 1982). Cohen reported that 11 of the 20 participants had a change of FEV1 after exercise of less than 15% following vitamin C but all 20 participants had a change of 15% or more following placebo. Mean changes were only presented for the 11 participants who had better results with vitamin C, and these are not included as this is a biased estimate of the true expected treatment effect. Change in FVC (L) - post-exercise challenge: (MD 0.13; 95% CI -0.03 to 0.29) (Schachter 1982) Change in PEFR (L/min) - post-exercise challenge: (MD 0.49; 95% CI -0.07 to 1.05) (Schachter 1982) Short term studies FEV1 (%) drop post-exercise: a significant difference was shown in favour of vitamin C: (MD 6.50%; 95% CI 0.05 to 12.95) (Tecklenburg 2007) Long term studies FEV1 mL at four months:(MD -11.00; 95% CI -91.36 to 69.36) (Fogarty 2003) Peak flow L/min (morning and evening) at 4 months: (Mean difference am 0.90; 95% CI -11.74 to 13.54) and (Mean difference pm 2.20; 95% CI -9.95 to 14.35) (Fogarty 2003) Symptom Scores One study (Tecklenburg 2007) reported data on symptom scores (Asthma Quality of Life Questionnaire). There was no significant difference (MD 0.50; 95% CI -0.24 to 1.24). Secondary outcomes IgE (IU/ml serum) - absolute values at one month: (MD 4.00; 95% CI -140.42 to 148.42) (Anderson 1983) IgE (IU/ml serum) - absolute values at three months: (MD -312.00; 95% CI -628.21 to 4.21) (Anderson 1983) IgE (IU/ml serum) - absolute values at six months: (MD -143.00; 95% CI -425.38 to 139.38)(Anderson 1983) Decrease in inhaled corticosteroid use (µg): no significant difference (Fogarty 2003) There were no data from any of the included studies for health service utilisation. Data on acute exacerbations was provided by one study (Anah 1980). There were nine exacerbations in the intervention group which had 22 patients and 35 exacerbations in the placebo group which had 19 patients. Thus some patients had more than one exacerbation. Data concerning the number of patients who had one or more exacerbations would be more meaningful since it would not be subjected to bias from a few patients with recurrent exacerbations. Adverse effects Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Outcomes PD20 FEV1, PD35 SGaw, tested on day 7, 3hrs after dose of placebo/vitamin C Notes Data not presented in an abstractable format, no reply from author to date. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Method of randomisation not described Allocation concealment (selection bias) Unclear risk Method of allocation not described Blinding (performance bias and detection bias) All outcomes Unclear risk Study described as double blind but method of blinding (e.g. identical placebo pill) not described Kordansky 1979(Continued)   Methods Randomised double blind placebo controlled crossover study. Participants 16 adults (3M; 13F) with asthma that met the ATS criteria. Age range 19-59, mean 43.1 (SD 7.7) yrs, mean duration of asthma 10.5 yrs (SD 14.6). Interventions The subjects were studied on 4 different days. Subjects received treatment or placebo which consisted of 250ml of a transparent and odourless sweet liquid in which was dissolved either 2g ascorbic acid or placebo. One hour later spirometry measured and histamine challenge done until PC20 reached. Outcomes FEV1, FVC, PC20 Notes Data not presented in an abstractable format. Values reported for different days rather than different groups. No reply from author to date. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Method of randomisation not described Allocation concealment (selection bias) Low risk Concealment of treatments were done using codes. The oral solutions were prepared by hospital pharmacy. Blinding (performance bias and detection bias) All outcomes Low risk Oral solutions were described as being of similar taste Malo 1986   Methods Randomised double-blind, cross-over placebo controlled study. O'Sullivan 2000 Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Participants Ten mild (ATS criteria) asthmatic participants. Interventions Each participant completed two treatment periods with ingestion of either 2g of ascorbic acid or placebo 45 minutes prior histamine bronchoprovocation. Outcomes Spirometry was measured before, during and after the histamine challenges. Notes Abstract only published, data not presented in an abstractable format, no reply from author to date. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Method of randomisation not described Allocation concealment (selection bias) Unclear risk Method of allocation not described Blinding (performance bias and detection bias) All outcomes Unclear risk Study described as double blind but method of blinding (e.g. identical placebo pill) not described O'Sullivan 2000(Continued)   Methods Randomised double-blind controlled trial, crossover design. Participants 12 adults (5 male, 7 female) with exercise-induced asthma, never on corticosteroids or admitted to hospital. Interventions Single dose of 500 mg vitamin C orally or sucrose placebo. Study done on 2 subsequent days. 90 minutes post does subjects underwent exercise challenge. No washout indicated. Exercise challenge in incremental workload and until subjects heart rate reach 170bpm or the subject fatigued. Pulmonary function was measured before & after oral dose and after exercise. Outcomes FVC, FEV1, PEFR before and after exercise challenge on cyclegometer to 170bpm or exhaustion. Notes  Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Method of randomisation not described Allocation concealment (selection bias) Unclear risk Method of allocation not described Blinding (performance bias and detection bias) All outcomes Low risk Identical placebo capsule Schachter 1982   Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Methods Randomised, double-blind, crossover trial over 5 consecutive weeks Participants Eight participants (2 male, 6 female) with physician diagnosed mild-to-moderate asthma and documented exercise-induced bronchoconstriction. Particpants were recruited from University population and the local community and were active. Interventions Ascorbic acid supplement 1500mg/day (3x500mg capsules) or placebo (sucrose) (3 capsules). Manufactured by NOW Foods. Particpants were randomised to active treatment or placebo for two weeks. There was a wash-out period of one week and then the participants crossed over. Particpants were advised to avoid foods that were high in vitamin C during the study. Outcomes Pulmonary function (FEV1) pre-and post-exercise; Exhaled nitric oxide (FENO) preand post-exercise; symptom questionnaire Notes Study conducted in the USA Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Method of randomisation not described Allocation concealment (selection bias) Unclear risk Method of allocation concealment not described. Blinding (performance bias and detection bias) All outcomes Low risk Matching placebo manufactured by the same company as the active treatment. Tecklenburg 2007  Characteristics of excluded studies [ordered by study ID]  Study Reason for exclusion Cuomo 2004 Study used a combined supplement of vitamin C, vitamin E and other antioxidants Forastiere 2000 Not a randomised controlled trial (before and after questionnaire survey). Gvozdjakova 2005 Study used a combined supplement of vitamin C, Coenzyme Q10 and α-tocopherol. Kongerud 2003 Not a randomised controlled trial and intervention not testing efficacy of vitamin C. Study examined the levels of ascorbic acid in induced sputum of asthmatic patients compared to healthy volunteers. Miric 1991 Not a randomised controlled trial. All subjects given placebo first than followed later with all patients receiving vitamin C. Mohsenin 1983 Study did not have a placebo arm (only had before and after effects of vitamin C administration). Mohsenin 1987 Study used healthy subjects and excluded subjects who had asthma. Murphy 2002 Study used a combination of vitamin C and α-tocopherol Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 16 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Study Reason for exclusion Omenaas 2003 Postal questionnaire not a randomised controlled trial. Panina 2002 Study used a complex of oral antioxidants. It is not clear that the study was randomised. Romieu 2002 Study used both vitamin C and E in the intervention group. Ting 1983 Study did not have a placebo arm and was not randomised (only had before and after effects of vitamin C).   D A T A  A N D  A N A L Y S E S  Comparison 1.  Oral vitamin C vs placebo (single-dose studies) Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Change in FEV1 (L) - post-exercise challenge 1  Mean Difference (IV, Fixed, 95% CI) Totals not selected 2 FVC (L) - post-exercise challenge 1  Mean Difference (IV, Fixed, 95% CI) Totals not selected 3 PEFR (L/min) - post-exercise challenge 1  Mean Difference (IV, Fixed, 95% CI) Totals not selected   Analysis 1.1.  Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 1 Change in FEV1 (L) - post-exercise challenge. Study or subgroup Vitamin C group Placebo group Mean Difference Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI Schachter 1982 12 0.2 (0.2) 12 0.1 (0.3) 0.13[-0.05,0.31] Favours Placebo 10.5-1 -0.5 0 Favours Vitamin C   Analysis 1.2.  Comparison 1 Oral vitamin C vs placebo (singledose studies), Outcome 2 FVC (L) - post-exercise challenge. Study or subgroup Vitamin C group Placebo group Mean Difference Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI Schachter 1982 12 0.1 (0.2) 12 -0 (0.2) 0.13[-0.03,0.29] Favours Placebo 10.5-1 -0.5 0 Favours Vitamin C   Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 17 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Analysis 1.3.  Comparison 1 Oral vitamin C vs placebo (singledose studies), Outcome 3 PEFR (L/min) - post-exercise challenge. Study or subgroup Vitamin C group Placebo group Mean Difference Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI Schachter 1982 12 0.6 (0.5) 12 0.1 (0.8) 0.49[-0.07,1.05] Favours Placebo 42-4 -2 0 Favours Vitamin C   Comparison 2.  Oral vitamin C vs placebo (short term studies) Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 FEV1 (% drop) post-exercise 1  Mean Difference (Fixed, 95% CI) Totals not selected 2 Symptom scores (Asthma Quality of Life Questionnnaire) 1  Mean Difference (Fixed, 95% CI) Totals not selected   Analysis 2.1.  Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 1 FEV1 (% drop) post-exercise. Study or subgroup Experimental Control Mean Difference Mean Difference Mean Difference N N (SE) IV, Fixed, 95% CI IV, Fixed, 95% CI Tecklenburg 2007 0 0 6.5 (3.29) 6.5[0.05,12.95] Favours placebo 10050-100 -50 0 Favours vitamin C   Analysis 2.2.  Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 2 Symptom scores (Asthma Quality of Life Questionnnaire). Study or subgroup Vitamin C Placebo Mean Difference Mean Difference Mean Difference N N (SE) IV, Fixed, 95% CI IV, Fixed, 95% CI Tecklenburg 2007 0 0 0.5 (0.38) 0.5[-0.24,1.24] Favours Placebo 10050-100 -50 0 Favours Vitamin C   Comparison 3.  Oral vitamin C vs placebo (long-term studies) Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 IgE (IU/ml serum) - absolute values 1  Mean Difference (IV, Fixed, 95% CI) Totals not selected 1.1 1 month 1  Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0] Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1.2 3 months 1  Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0] 1.3 6 months 1  Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0] 2 FEV1 mL 4 months 1  Mean Difference (Fixed, 95% CI) Totals not selected 3 Peak Flow (L/min) 4 months 1  Mean difference (Fixed, 95% CI) Totals not selected 3.1 Morning 1  Mean difference (Fixed, 95% CI) 0.0 [0.0, 0.0] 3.2 Evening 1  Mean difference (Fixed, 95% CI) 0.0 [0.0, 0.0] 4 Geometric mean decrease in inhaled corticosteroid use (μg) 1  Mean Difference (IV, Fixed, 95% CI) Totals not selected   Analysis 3.1.  Comparison 3 Oral vitamin C vs placebo (longterm studies), Outcome 1 IgE (IU/ml serum) - absolute values. Study or subgroup Vitamin C group Placebo group Mean Difference Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI 3.1.1 1 month  Anderson 1983 7 246 (124.9) 9 242 (169.7) 4[-140.42,148.42]   3.1.2 3 months  Anderson 1983 7 211 (93.1) 9 523 (472.4) -312[-628.21,4.21]   3.1.3 6 months  Anderson 1983 7 253 (147) 9 396 (398.8) -143[-425.38,139.38] Favours Vitamin C 1000500-1000 -500 0 Favours Placebo   Analysis 3.2.  Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 2 FEV1 mL 4 months. Study or subgroup Vitamin C Placebo Mean Difference Mean Difference Mean Difference N N (SE) IV, Fixed, 95% CI IV, Fixed, 95% CI Fogarty 2003 95 106 -11 (41) -11[-91.36,69.36] Favours placebo 1000500-1000 -500 0 Favours Vitamin C   Analysis 3.3.  Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 3 Peak Flow (L/min) 4 months. Study or subgroup Vitamin C Placebo Mean difference Mean difference Mean difference N N (SE) IV, Fixed, 95% CI IV, Fixed, 95% CI 3.3.1 Morning  Favours placebo 10050-100 -50 0 Favours Vitamin C Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 19 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews Study or subgroup Vitamin C Placebo Mean difference Mean difference Mean difference N N (SE) IV, Fixed, 95% CI IV, Fixed, 95% CI Fogarty 2003 95 106 0.9 (6.45) 0.9[-11.74,13.54]   3.3.2 Evening  Fogarty 2003 95 106 2.2 (6.2) 2.2[-9.95,14.35] Favours placebo 10050-100 -50 0 Favours Vitamin C   Analysis 3.4.  Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 4 Geometric mean decrease in inhaled corticosteroid use (μg). Study or subgroup Vitamin C Placebo Mean Difference Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI Fogarty 2003 29 49 (156.6) 32 11 (37.5) 38[-20.46,96.46] Favours placebo 10050-100 -50 0 Favours vitamin C   A D D I T I O N A L  T A B L E S  Search dates Results January 2001 Thirty-five abstracts were identified from the search of the Cochrane Airways Group register, of which 6 met the inclusion criteria (Anah 1980, Anderson 1983, Cohen 1997, Kordanksy 1979, Malo 1986, Schachter 1987) and 5 were added as excluded studies. January 2001 - April 2004 Twenty-four abstracts were identified by the updated search. Two additional included studies (Fogarty 2003, O'Sullivan 2000) and 4 excluded studies were added to the review. Table 1.  Search history  F E E D B A C K Feedback submitted by Harri Hemila, 24 March 2009 Summary "The Cochrane review vitamin C for asthma (2009 version) has errors in the extraction of data and in the analysis. Schachter 1982 carried out a trial with participants who had exercise-induced bronchoconstriction (EIB) so that each of the 12 participants was administered placebo and vitamin C at different times. Thus, each participant served as his or her own control (cross-over). In Table III Schachter reported pre-post-exercise change of FEV1, so that the later FEV1 was measured 5 minutes after the exercise. Because two observations are measured from the same participant, the placebo period and vitamin C period difference in FEV1 change should be analysed using the paired t-test. The FEV1 data in Schachter's Table III gives the mean difference between the vitamin C and placebo periods as 0.20 (SD 0.33) litres/s. Schachter 1982 calculated t = 2.13 in their paper, corresponding to P[1-tail] = 0.028. The review presents Schachter's FEV1 changes in Analysis 1.2. However, data in Analysis 1.2 were extracted from Schachter's Table II, which presents post-exercise FEV1 value measured immediately after the exercise. In EIB the fall in FEV1 occurs 5 to 20 minutes after the end of exercise (Rundell 2009), and even Schachter reported that, on the screening day, there was no fall in FEV1 immediately after exercise, but a significant fall 5 minutes after the exercise (Schachter 1982 Fig. 2). Therefore, extracting the FEV1 changes from Schachter's Table II (FEV1 immediately after the exercise) is not reasonable if the purpose is to examine the effect of vitamin C on EIB. Cohen 1997 carried out an EIB trial with 20 participants who were administered placebo and vitamin C at different times (cross-over). Postexercise FEV1 was measured 8 minutes after the end of the exercise. The observations are paired also in this case and the results should Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews be analysed using a paired test. 9 participants had FEV1 decrease >15% on both vitamin C and placebo treatments. 11 participants had >15% FEV1 decrease on placebo but <15% FEV1 decrease on vitamin C (Cohen 1997 Fig. 2). None of the participants had the opposite effect: <15% FEV1 decrease on placebo and >15% FEV1 decrease on vitamin C. In the paired 2x2 table analysis, the question is whether the difference between the corners (here 11 and 0) is statistically significant. This difference gives z = (11-0)/sqrt(11+0) = 3.31, corresponding to P[1-tail] = 0.0005. A basic principle in controlled trial analysis requires that all randomised participants should be included in the analysis (the ITT principle). However, the review does not give the results for all of Cohen's 20 participants (Cohen 1997 Fig. 2); Analysis 1.2 gives the results for only the 11 participants who had benefit of vitamin C (Cohen 1997 Table 2). Furthermore, the review presents the average of post-exercise FEV1 values and not the pre-post-exercise difference in FEV1 in analysis 1.2. The post-exercise averages for Cohen's Table 2 are 1.66 (SD 0.80) litres/s in the placebo period and 1.93 (SD 0.78) litres/s in the vitamin C period (P = 0.42). However, given that the EIB is defined by the pre-post change in FEV1, the measurement of the effect on EIB should be based on the pre-post-exercise difference in FEV1 (Rundell 2009). Furthermore, the relative effect calculated by Cohen (Table 2; in %units) is a better measure than the absolute value (in litres/s) because the relative effect adjusts for the great variation in baseline FEV1; the relative decrease in FEV1 is also used in guidelines (Rundell 2009). Cohen reports that the average relative fall in FEV1 is 25% in the placebo period and 5% in the vitamin C period (Cohen 1997 table 2). Because the observations are paired, the paired t-test should be used. The average of the differences is 20% (SD 12%, SE 3.7%), which gives t = 5.57, corresponding to P[1-tail] = 0.00012. Thus, although the review presented only the 11 participants in which vitamin C was beneficial, the calculation suggests that even in this subgroup vitamin C was without effect (P = 0.42), whereas a correct calculation gives a much smaller P-value. In their EIB trial, Tecklenburg 2007 studied 8 participants who were administered vitamin C and placebo at different times. They measured post-exercise FEV1 at 1, 5, 10, 15, 20, and 30 min after the exercise. Tecklenburg 2007 reported that the decrease in FEV1 in the vitamin C period was 6.4% (SE 2.4%) and decrease in the placebo period was 12.9% (SE 2.4%). Tecklenburg did not publish the paired comparison, nor original data so that the paired t-test could be calculated. Nevertheless, these averages give unpaired t = 1.91, corresponding to P[1tail] = 0.038, which is conservative, the paired test P-value would be smaller. Thus, three trials included in the review found benefit of vitamin C supplementation against EIB at 5 and 8 minutes after the exercise (Cohen 1997; Schachter 1982), or at the time of maximum fall in FEV1 (Tecklenburg 2007). The three P-values calculated above (0.028, 0.0005, 0.038) can be combined by using the Fisher method (Fisher 1948). The combined P[1-tail] = 0.00007 provides evidence that the effects of vitamin C on EIB in these three trials are not explained by random fluctuations. Analyses 1.1, 1.3 and 1.5 present baseline data of two EIB trials discussed above (Cohen 1997; Schachter 1982). However, when a trial specifically examines the effect of vitamin C on EIB, the relevant outcome is the difference between the baseline and the 5-10 minutes postexercise FEV1 values (the pre-post change), and not the baseline FEV1 value alone. Finally, diagnosis of EIB by the change in FEV1 is well established (Rundell 2009) and the authors should have considered whether there is any benefit for readers from making additional analyses of the FVC and PEFR values of the oldest trial by Schachter 1982. The more recent trials by Cohen 1997and Tecklenburg 2007 did not report changes in FVC and PEFR." Reply This comment on the trials relating to exercise induced bronchoconstriction (EIB) was submitted in March 2009 and published alongside the review in November 2010. We thank Dr Hemilä for the feedback, but do not think that the technical issues raised over the analysis of data from the three small crossover trials (including a total of 40 participants), substantively alter the strength or direction of the results, the quality of the evidence, or the conclusions of the review. We agree that crossover trials are best analysed using paired t-tests, but do not agree with the presentation of one-tail P values above. A two-tailed paired t-test did not show a statistically significant difference in change in FEV1 either immediately after exercise (shown in analysis 1.2) or five minutes later in Schachter 1982 (P = 0.18 and 0.057 from Table II and Table III respectively). Therefore the author's choice not to include the latter observation does not mislead the reader in our opinion. We agree that the mean differences in FEV1 reported from only 11 of the 20 participants in Cohen 1997 should not be included in the review, and this has been removed from the analyses. The authors entered data for the fall in FEV1 from Tecklenburg 2007, using a standard error derived from a conservative estimate of the P value based on the paired t-test (reported in the paper as P < 0.05). We see no compelling reason to overturn this approach since the average effect is unaltered and the data come from a study of only eight participants. We agree that the baseline lung function is not a useful outcome for this review and have removed the pre-exercise outcomes. We do not agree with the suggested approach of combining P values from Cohen 1997, Schachter 1982 and Tecklenburg 2007 in view of the clinical heterogeneity between the studies and outcomes under consideration. Such an approach focuses attention on whether any effect Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews observed is attributable to chance. This is itself potentially misleading since it does not take account of the magnitude of effect across the studies. The analyses presented in the review have now been amended so that only mean differences and confidence intervals for the studies are presented, and not associated P values. We are content for readers to consider the comment from Dr Hemilä alongside our response, and to make up their own minds regarding the authors' approach to the analysis of data and the conclusions of the review. Posted by Emma Welsh, Mangaging Editor of the Cochrane Airways Group, on behalf of the author and editorial teams. Contributors Harri Hemilä, Department of Public Health, University of Helsinki, Helsinki, Finland W H A T ' S  N E W  Date Event Description 13 June 2012 Amended Feedback incorporated, We are aware of a new relevant study, this has been added to studies awaiting classification. 13 June 2012 Feedback has been incorporated In light of the feedback, we have removed three instances of reporting of baseline lung function values and deleted statistical data from a trial who only reported data on participants who benefited from treatment. These changes have not altered the conclusions of the review and we do not believe the review will mislead the reader. 13 June 2012 Review declared as stable The methods used in the review are somewhat outdated and therefore a new review is required in this topic. Applications to register this title will be subject to our prioritisation procedure.  H I S T O R Y Protocol first published: Issue 3, 1996 Review first published: Issue 1, 1999  Date Event Description 5 November 2010 Amended Feedback has been published alongside the original text of the review. 1 December 2008 Amended Contact details of B Kaur altered 29 October 2008 New citation required but conclusions have not changed One new included study, one extension to a previously included study (Fogarty 2003) and five excluded studies were identified. Conclusions remain unchanged. Change in authorship. 29 August 2008 New search has been performed New search. 14 August 2008 Amended Converted to new review format. 1 April 2004 New citation required and conclusions have changed Substantive amendment Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 22 Cochrane Library Trusted evidence. Informed decisions. Better health.   Cochrane Database of Systematic Reviews  C O N T R I B U T I O N S  O F  A U T H O R S Felix Ram and BK conducted the original version of this review in 2001. BR was the assigned editor contributing to the protocol and review editing. FR updated the review in April 2004. ES updated the review in August 2008. D E C L A R A T I O N S  O F  I N T E R E S T There are no known conflicts of interest. S O U R C E S  O F  S U P P O R T Internal sources •St George's, University of London, UK. External sources •No sources of support supplied I N D E X  T E R M S Medical Subject Headings (MeSH) *Dietary Supplements; Antioxidants [*therapeutic use]; Ascorbic Acid [*therapeutic use]; Asthma [*drug therapy]; Randomized Controlled Trials as Topic MeSH check words Humans Vitamin C supplementation for asthma (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 23