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

Vitamin C supplementation for asthma (Review) Kaur B, Rowe BH, Arnold E This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 12 http://www.thecochranelibrary.com Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. T A B L E O F C O N T E N T S 1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 1 FEV1 (L) - pre-exercise challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Analysis 1.2. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 2 FEV1 (L) - post-exercise challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Analysis 1.3. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 3 FVC (L) - pre-exercise challenge. 21 Analysis 1.4. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 4 FVC (L) - post-exercise challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Analysis 1.5. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 5 PEFR (L/min) - pre-exercise challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Analysis 1.6. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 6 PEFR (L/min) - post-exercise challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Analysis 2.1. Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 1 FEV1 (% drop) post-exercise. 23 Analysis 2.2. Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 2 Symptom scores (Asthma Quality of Life Questionnnaire). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Analysis 3.1. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 1 IgE (IU/ml serum) - absolute values. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Analysis 3.2. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 2 FEV1 mL 4 months. . . . 25 Analysis 3.3. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 3 Peak Flow (L/min) 4 months. 26 Analysis 3.4. Comparison 3 Oral vitamin C vs placebo (long-term studies), Outcome 4 Geometric mean decrease in inhaled corticosteroid use (µg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 26FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iVitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Vitamin C supplementation for asthma Balvinder Kaur2, Brian H Rowe3, Elizabeth Arnold1 1Population Health Sciences & Education, St George’s, University of London, London, UK. 2Primary Care & Social Medicine, Faculty of Medicine, London, UK. 3Department of Emergency Medicine, University of Alberta, Edmonton, Canada Contact address: Elizabeth Arnold, Population Health Sciences & 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: Edited (no change to conclusions), published in Issue 12, 2010. Review content assessed as up-to-date: 28 October 2008. Citation: Kaur B, Rowe BH, Arnold E. Vitamin C supplementation for asthma. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000993. DOI: 10.1002/14651858.CD000993.pub3. Copyright © 2010 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 strategy 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. 1Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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 children with asthma. 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. 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 usingthe Cochrane methodology isneeded 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 2Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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. 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 3Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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 See: Characteristics of included studies;Characteristics of excluded 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. Table 1. Search history 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. 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 4Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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 aggregationfor 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 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. 5Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study. 6Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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. It was only possible to combine data for one outcome (FEV1). For all other outcomes, 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 reported absolute mean value postexercise, Schachter 1982 reported absolute change post-exercise and Tecklenburg 2007 was a two week intervention study rather a single dose study, and reported maximum precentage fall from baseline. Primary outcomes Lung function Single dose studies FEV1(L) - pre-exercise challenge: no significant difference (Cohen 1997,Schachter 1982) FEV1 (L) - post-exercise challenge: no significant difference (Cohen 1997,Schachter 1982) FVC (L) - pre-exercise challenge: no significant difference ( Schachter 1982) FVC (L) - post-exercise challenge: no significant difference (Schachter 1982) PEFR (L/min) - pre-exercise challenge: no significant difference (Schachter 1982) PEFR (L/min) - post-exercise challenge: no significant difference (Schachter 1982) Short term studies FEV1 (%) drop post-exercise: a significant difference was shown in favour of vitamin C: 6.5 (95% confidence interval 0.05 to 12.95), P=0.05 (Tecklenburg 2007) Long term studies FEV1 mL at four months:no significant difference (Fogarty 2003) Peak Flow L/min (morning and evening) at 4 months: no significant difference (Fogarty 2003) Symptom Scores One study (Tecklenburg 2007) reported data on symptom scores (Asthma Quality of Life Questionnaire). There was no significant difference. Secondary outcomes IgE (IU/ml serum) - absolute values at one month: no significant difference (Anderson 1983) IgE (IU/ml serum) - absolute values at three months:no significant difference (Anderson 1983) IgE (IU/ml serum) - absolute values at six months: no significant difference (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. 7Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Fogarty 2003 Methods Randomised placebo-controlled double-blind parallel group trial. Study was powered to detect a 310ml change in FEV1, a 20l/min increase in PEFR or a 1.5 fold in airway reactivity relative to placebo. Participants Patients were identified from computer records of 24 general practices in Nottingham, UK. At the start of the study there were 95 participants in the vitamin C group and 106 in the placebo group (and 99 in a third group randomised to magnesium). Vitamin C group: 37 males, mean age 42, mean daily inhaled steroids 715ug, number of long acting beta 2 agonists 20, current smokers 5, mean pack years 1.2, mean dietary vitamin C 90mg. Placebo group: 42 males, mean age 40, mean daily inhaled steroids 618ug, number of long acting beta 2 agonists 14, current smokers 4, mean pack years 1.1, mean dietary vitamin C 82mg. Interventions Parallel comparison of daily supplementation with vitamin C 1g/day and placebo. Outcomes FEV1, FVC, PD20, morning and evening PEFR, beta 2 use, symptoms. Notes Randomisation was stratified according to dose of regular corticosteroids usage. An extension to the trial provided data on the reduction in use of inhaled steroids. Ninety two of the original participants agreed to continue taking their allocated supplement for a further 10 weeks and enter a corticosteroid reduction protocol. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Yes Participants were randomly assigned using a random number generator. Allocation concealment? Yes Particpants were allocated by an individual code number. The code was broken only after the last participant left the trial. All randomisation table preparation and dispensing were carried out independently from the recruitment and assessment of participants. Blinding? All outcomes Unclear Study is described as double-blind but the appearance of the tablets is not specifically mentioned Kordansky 1979 Methods Randomised double-blind placebo controlled trial with crossover design. Participants 6 adults (2 female, 4 male) in Baltimore, USA, with ragweed sensitive asthma, defined by skinprick positivity. Tested out of the ragweed season. Asymptomatic and not on treatment. Interventions 500mg once daily vitamin C for 7 days compared to lactose placebo. 14Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Kordansky 1979 (Continued) 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 Item Authors’ judgement Description Adequate sequence generation? Unclear Method of randomisation not described Allocation concealment? Unclear Method of allocation not described Blinding? All outcomes Unclear Study described as double blind but method of blinding (e.g. identical placebo pill) not described Malo 1986 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 4different 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 Item Authors’ judgement Description Adequate sequence generation? Unclear Method of randomisation not described Allocation concealment? Yes Concealment of treatments were done using codes. The oral solutions were prepared by hospital pharmacy. Blinding? All outcomes Yes Oral solutions were described as being of similar taste 15Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. O’Sullivan 2000 Methods Randomised double-blind, cross-over placebo controlled study. 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 Item Authors’ judgement Description Adequate sequence generation? Unclear Method of randomisation not described Allocation concealment? Unclear Method of allocation not described Blinding? All outcomes Unclear Study described as double blind but method of blinding (e.g. identical placebo pill) not described Schachter 1982 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 Item Authors’ judgement Description Adequate sequence generation? Unclear Method of randomisation not described Allocation concealment? Unclear Method of allocation not described 16Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Schachter 1982 (Continued) Blinding? All outcomes Yes Identical placebo capsule Tecklenburg 2007 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 particpants 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 postexercse; sypmtom questionnaire Notes Study conducted in the USA Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear Method of randomisation not described Allocation concealment? Unclear Method of allocation concealment not described. Blinding? All outcomes Yes Matching placebo manufactured by the same company as the active treatment. 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. 17Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (Continued) 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 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). 18Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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 FEV1 (L) - pre-exercise challenge 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only 1.1 Absolute values 2 46 Mean Difference (IV, Fixed, 95% CI) 0.36 [-0.35, 1.08] 2 FEV1 (L) - post-exercise challenge 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only 2.1 Absolute values 1 22 Mean Difference (IV, Fixed, 95% CI) 0.27 [-0.39, 0.93] 2.2 Absolute change 1 24 Mean Difference (IV, Fixed, 95% CI) 0.13 [-0.05, 0.31] 3 FVC (L) - pre-exercise challenge 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.1 Absolute values 1 24 Mean Difference (IV, Fixed, 95% CI) -0.10 [-2.62, 2.42] 4 FVC (L) - post-exercise challenge 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.1 Absolute change 1 24 Mean Difference (IV, Fixed, 95% CI) 0.13 [-0.03, 0.29] 5 PEFR (L/min) - pre-exercise challenge 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 5.1 Absolute values 1 24 Mean Difference (IV, Fixed, 95% CI) -0.40 [-4.00, 3.20] 6 PEFR (L/min) - post-exercise challenge 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 6.1 Absolute change 1 24 Mean Difference (IV, Fixed, 95% CI) 0.49 [-0.07, 1.05] 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 0 Mean Difference (Fixed, 95% CI) 6.5 [0.05, 12.95] 2 Symptom scores (Asthma Quality of Life Questionnnaire) 1 0 Mean Difference (Fixed, 95% CI) 0.5 [-0.24, 1.24] 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) Subtotals only 1.1 1 month 1 16 Mean Difference (IV, Fixed, 95% CI) 4.0 [-140.42, 148.42] 1.2 3 months 1 16 Mean Difference (IV, Fixed, 95% CI) -312.0 [-628.21, 4.21] 19Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1.3 6 months 1 16 Mean Difference (IV, Fixed, 95% CI) -143.0 [-425.38, 139.38] 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) Not estimable 3.2 Evening 1 Mean difference (Fixed, 95% CI) Not estimable 4 Geometric mean decrease in inhaled corticosteroid use (µg) 1 61 Mean Difference (IV, Fixed, 95% CI) 38.0 [-20.46, 96.46] Analysis 1.1. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 1 FEV1 (L) - preexercise challenge. Review: Vitamin C supplementation for asthma Comparison: 1 Oral vitamin C vs placebo (single-dose studies) Outcome: 1 FEV1 (L) - pre-exercise challenge Study or subgroup Vitamin C group Placebo group Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 Absolute values Cohen 1997 11 2.7 (0.94) 11 2.2 (0.96) 80.5 % 0.50 [ -0.29, 1.29 ] Schachter 1982 12 2.6 (2.32) 12 2.8 (1.66) 19.5 % -0.20 [ -1.81, 1.41 ] -10 -5 0 5 10 Favours Placebo Favours Vitamin C 20Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.2. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 2 FEV1 (L) - postexercise challenge. Review: Vitamin C supplementation for asthma Comparison: 1 Oral vitamin C vs placebo (single-dose studies) Outcome: 2 FEV1 (L) - post-exercise challenge Study or subgroup Vitamin C group Placebo group Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 Absolute values Cohen 1997 11 1.93 (0.78) 11 1.66 (0.8) 100.0 % 0.27 [ -0.39, 0.93 ] Subtotal (95% CI) 11 11 100.0 % 0.27 [ -0.39, 0.93 ] Heterogeneity: not applicable Test for overall effect: Z = 0.80 (P = 0.42) 2 Absolute change Schachter 1982 12 0.21 (0.19) 12 0.08 (0.26) 100.0 % 0.13 [ -0.05, 0.31 ] Subtotal (95% CI) 12 12 100.0 % 0.13 [ -0.05, 0.31 ] Heterogeneity: not applicable Test for overall effect: Z = 1.40 (P = 0.16) Test for subgroup differences: Chi2= 0.16, df = 1 (P = 0.69), I2=0.0% -1 -0.5 0 0.5 1 Favours Placebo Favours Vitamin C Analysis 1.3. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 3 FVC (L) - preexercise challenge. Review: Vitamin C supplementation for asthma Comparison: 1 Oral vitamin C vs placebo (single-dose studies) Outcome: 3 FVC (L) - pre-exercise challenge Study or subgroup Vitamin C group Placebo group Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 Absolute values Schachter 1982 12 3.9 (2.98) 12 4 (3.32) 100.0 % -0.10 [ -2.62, 2.42 ] -10 -5 0 5 10 Favours Placebo Favours Vitamin C 21Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.4. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 4 FVC (L) - postexercise challenge. Review: Vitamin C supplementation for asthma Comparison: 1 Oral vitamin C vs placebo (single-dose studies) Outcome: 4 FVC (L) - post-exercise challenge Study or subgroup Vitamin C group Placebo group Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 Absolute change Schachter 1982 12 0.1 (0.23) 12 -0.03 (0.17) 100.0 % 0.13 [ -0.03, 0.29 ] -1 -0.5 0 0.5 1 Favours Placebo Favours Vitamin C Analysis 1.5. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 5 PEFR (L/min) - preexercise challenge. Review: Vitamin C supplementation for asthma Comparison: 1 Oral vitamin C vs placebo (single-dose studies) Outcome: 5 PEFR (L/min) - pre-exercise challenge Study or subgroup Vitamin C group Placebo group Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 Absolute values Schachter 1982 12 5.6 (4.97) 12 6 (3.98) 100.0 % -0.40 [ -4.00, 3.20 ] -10 -5 0 5 10 Favours Placebo Favours Vitamin C 22Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.6. Comparison 1 Oral vitamin C vs placebo (single-dose studies), Outcome 6 PEFR (L/min) - post-exercise challenge. Review: Vitamin C supplementation for asthma Comparison: 1 Oral vitamin C vs placebo (single-dose studies) Outcome: 6 PEFR (L/min) - post-exercise challenge Study or subgroup Vitamin C group Placebo group Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 1 Absolute change Schachter 1982 12 0.59 (0.53) 12 0.1 (0.83) 100.0 % 0.49 [ -0.07, 1.05 ] -4 -2 0 2 4 Favours Placebo Favours Vitamin C Analysis 2.1. Comparison 2 Oral vitamin C vs placebo (short term studies), Outcome 1 FEV1 (% drop) postexercise. Review: Vitamin C supplementation for asthma Comparison: 2 Oral vitamin C vs placebo (short term studies) Outcome: 1 FEV1 (% drop) post-exercise Study or subgroup Experimental Control Mean Difference (SE) Mean Difference Weight Mean Difference N N IV,Fixed,95% CI IV,Fixed,95% CI Tecklenburg 2007 0 0 6.5 (3.29) 100.0 % 6.50 [ 0.05, 12.95 ] Total (95% CI) 100.0 % 6.50 [ 0.05, 12.95 ] Heterogeneity: not applicable Test for overall effect: Z = 1.98 (P = 0.048) -100 -50 0 50 100 Favours placebo Favours vitamin C 23Vitamin C supplementation for asthma (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.