Vitamin C for asthma and exercise-induced bronchoconstriction

  • Review
  • Intervention

Authors


Abstract

Background

Dietary antioxidants, such as vitamin C, in the epithelial lining and lining fluids of the lung may be beneficial in the reduction of oxidative damage (Arab 2002). They may therefore be of benefit in reducing symptoms of inflammatory airway conditions such as asthma, and may also be beneficial in reducing exercise-induced bronchoconstriction, which is a well-recognised feature of asthma and is considered a marker of airways inflammation. However, the association between dietary antioxidants and asthma severity or exercise-induced bronchoconstriction is not fully understood.

Objectives

To examine the effects of vitamin C supplementation on exacerbations and health-related quality of life (HRQL) in adults and children with asthma or exercise-induced bronchoconstriction compared to placebo or no vitamin C.

Search methods

We identified trials from the Cochrane Airways Group's Specialised Register (CAGR). The Register contains trial reports identified through systematic searches of a number of bibliographic databases, and handsearching of journals and meeting abstracts. We also searched trial registry websites. The searches were conducted in December 2012.

Selection criteria

We included randomised controlled trials (RCTs). We included both adults and children with a diagnosis of asthma. In separate analyses we considered trials with a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). We included trials comparing vitamin C supplementation with placebo, or vitamin C supplementation with no supplementation. We included trials where the asthma management of both treatment and control groups provided similar background therapy. The primary focus of the review is on daily vitamin C supplementation to prevent exacerbations and improve HRQL. The short-term use of vitamin C at the time of exacerbations or for cold symptoms in people with asthma are outside the scope of this review.

Data collection and analysis

Two review authors independently screened the titles and abstracts of potential studies, and subsequently screened full text study reports for inclusion. We used standard methods expected by The Cochrane Collaboration.

Main results

A total of 11 trials with 419 participants met our inclusion criteria. In 10 studies the participants were adults and only one was in children. Reporting of study design was inadequate to determine risk of bias for most of the studies and poor availability of data for our key outcomes may indicate some selective outcome reporting. Four studies were parallel-group and the remainder were cross-over studies. Eight studies included people with asthma and three studies included 40 participants with exercise-induced asthma. Five studies reported results using single-dose regimes prior to bronchial challenges or exercise tests. There was marked heterogeneity in vitamin C dosage regimes used in the selected studies, compounding the difficulties in carrying out meaningful analyses.

One study on 201 adults with asthma reported no significant difference in our primary outcome, health-related quality of life (HRQL), and overall the quality of this evidence was low. There were no data available to evaluate the effects of vitamin C supplementation on our other primary outcome, exacerbations in adults. One small study reported data on asthma exacerbations in children and there were no exacerbations in either the vitamin C or placebo groups (very low quality evidence). In another study conducted in 41 adults, exacerbations were not defined according to our criteria and the data were not available in a format suitable for evaluation by our methods. Lung function and symptoms data were contributed by single studies. We rated the quality of this evidence as moderate, but further research is required to assess any clinical implications that may be related to the changes in these parameters. In each of these outcomes there was no significant difference between vitamin C and placebo. No adverse events at all were reported; again this is very low quality evidence.

Studies in exercise-induced bronchoconstriction suggested some improvement in lung function measures with vitamin C supplementation, but theses studies were few and very small, with limited data and we judged the quality of the evidence to be low.

Authors' conclusions

Currently, evidence is not available to provide a robust assessment on the use of vitamin C in the management of asthma or exercise-induced bronchoconstriction. Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the estimates. There is no indication currently that vitamin C can be recommended as a therapeutic agent in asthma. There was some indication that vitamin C was helpful in exercise-induced breathlessness in terms of lung function and symptoms; however, as these findings were provided only by small studies they are inconclusive. Most published studies to date are too small and inconsistent to provide guidance. Well-designed trials with good quality clinical endpoints, such as exacerbation rates and health-related quality of life scores, are required.

Résumé scientifique

La vitamine C pour le traitement de l'asthme et de la bronchoconstriction provoquée par l'exercice

Contexte

Les antioxydants alimentaires, tels que la vitamine C, dans la muqueuse épithélial et les liquides muqueux du poumon, pourraient être bénéfiques dans la réduction du stress oxydatif (Arab 2002). Ils peuvent donc être bénéfiques pour réduire les symptômes des affections inflammatoires des voies respiratoires telles que l'asthme et peuvent également être bénéfiques dans la réduction de la bronchoconstriction provoquée par l'exercice, qui est une caractéristique bien reconnue de l'asthme et est considérée comme un marqueur de l'inflammation des voies respiratoires. Cependant, l'association entre les antioxydants et la gravité de l'asthme ou la bronchoconstriction provoquée par l'exercice n’est pas entièrement assimilée.

Objectifs

Examiner les effets de la supplémentation en vitamine C sur les exacerbations et la qualité de vie liée à la santé (QVLS) chez les adultes et les enfants souffrant d'asthme ou de bronchoconstriction provoquée par l'exercice par rapport à un placebo ou à l'absence de vitamine C.

Stratégie de recherche documentaire

Nous avons identifié des essais dans le registre spécialisé du groupe Cochrane sur les voies respiratoires. Ce registre contient des rapports d'essais identifiés par des recherches systématiques dans plusieurs bases de données bibliographiques, des recherches manuelles dans les journaux et des résumés de conférences. Nous avons également consulté les sites Internet des registres d'essais. Les recherches ont été effectuées en décembre 2012.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés (ECR). Nous avons inclus les adultes et les enfants souffrants d’asthme. Dans des analyses séparées, nous avons pris en compte les essais présentant un diagnostic de la bronchoconstriction provoquée par l'exercice (ou l'asthme d'effort). Nous avons inclus les essais comparant la supplémentation en vitamine C à un placebo, ou la supplémentation en vitamine C à l'absence de supplémentation. Nous avons inclus les essais dans lesquels la prise en charge de l'asthme fournissait des traitements de fond similaires, ceci dans les groupes de traitement et les groupes témoins. Le principal objectif de cette revue porte sur la prise quotidienne de la supplémentation en vitamine C pour prévenir les exacerbations et améliorer la QVLS. L'utilisation à court terme de la vitamine C au moment d'exacerbations ou pour les symptômes du rhume banal chez les personnes atteintes d'asthme ne figurent pas dans cette revue.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment passé au crible les titres et résumés des études potentiellement pertinentes et examiné les textes des rapports d'étude pour l'inclusion. Nous avons utilisé la méthode standard prévue par la Collaboration Cochrane.

Résultats principaux

Onze essais, comportant 419 participants, répondaient à nos critères d'inclusion. Dans 10 études, les participants étaient des adultes et une seule portait sur les enfants. Dans la plupart des études, le rapport des plans d'étude n'était pas suffisant pour déterminer le risque de biais. De plus, la faible disponibilité des données pour nos résultats principaux peut indiquer un rapport sélectif des résultats. Quatre études étaient en groupes parallèles et les autres étaient des études croisées. Huit études incluaient des personnes asthmatiques et trois études totalisaient 40 participants atteints d'asthme d'effort. Cinq études rapportaient des résultats en utilisant des doses uniques avant des défis bronchiques ou des tests d'exercice. Il y avait une hétérogénéité marquée dans les dosages de vitamine C utilisés dans les études sélectionnées, provoquant des difficultés à réaliser des analyses.

Une étude sur 201 adultes asthmatiques ne rapportait aucune différence significative dans notre critère de jugement principal, la qualité de vie liée à la santé (QVLS) et la qualité globale de ces preuves étaient faible. Aucune donnée n’était disponible pour évaluer les effets de la supplémentation en vitamine C avec nos autres résultats primaires, les exacerbations chez les adultes. Une étude de petite taille a rapporté des données sur les crises d'asthme chez les enfants et il n'y avait ni exacerbation de vitamine C, ni groupe sous placebo (preuves de très faible qualité). Dans une autre étude menée sur 41 adultes, les exacerbations n’étaient pas définies conformément à nos critères d'inclusion et les données n'étaient pas disponibles dans un format éligible par notre méthode pour l'évaluation. Les données correspondant à la fonction pulmonaire et aux symptômes ont été fournies par des études individuelles. La qualité de ces preuves était modérée, mais des recherches supplémentaires sont nécessaires pour évaluer les implications cliniques qui peuvent être liées aux changements dans ces paramètres. Dans chacun de ces critères de jugement, il n'y avait aucune différence significative entre la vitamine C et un placebo. Aucun événement indésirable n’a été rapporté, les preuves sont également de très faible qualité.

Les études portant sur la bronchoconstriction provoquée par l'exercice suggéraient une certaine amélioration de la fonction pulmonaire avec la supplémentation en vitamine C, mais les études étaient peu nombreuses et de petite taille, avec des données limitées et des preuves de faible qualité.

Conclusions des auteurs

Les preuves ne sont actuellement pas disponibles pour fournir une évaluation solide sur l'utilisation de la vitamine C dans la prise en charge de l'asthme ou de la bronchoconstriction provoquée par l'exercice. D'autres recherches sont très susceptibles d'avoir un impact important sur notre confiance dans les estimations de l'effet et sont susceptibles de modifier les estimations. À ce jour, aucune donnée n’indique que la vitamine C peut être recommandée en tant qu'agent thérapeutique dans le traitement de l'asthme. Certaines données indiquaient que la vitamine C était utile dans le traitement de la dyspnée provoquée par l'exercice pour la fonction pulmonaire et les symptômes; toutefois, étant donné que ces résultats ont été fournis uniquement par des études de petite taille, ils ne sont pas concluants. La plupart des études publiées à ce jour sont trop petites et trop contradictoires pour fournir des informations supplémentaires. Des essais bien planifiés, avec des critères de jugement cliniques de bonne qualité, tels que les taux d'exacerbation et les résultats portant sur la qualité de vie liée à la santé, sont nécessaires.

アブストラクト

喘息および運動誘発性気管支収縮に対するビタミンC

背景

肺の上皮層および上粘液においてビタミンCのような食物抗酸化剤は、酸化的損傷の減少に有益である可能性がある(Arab 2002)。http://Arab 2002したがって喘息などの炎症性気道疾患の症状緩和に利益がある可能性があり、喘息の良く知られた特徴であり気道炎症のマーカーと考えられる運動誘発性気管支収縮を減少させるのに有益である可能性もある。しかし食物抗酸化剤と喘息の重度または運動誘発性気管支収縮との関係は十分に分かっていない。

目的

喘息または運動誘発性気管支収縮の成人および小児での憎悪および健康に関するQOL(HRQL)におけるビタミンC補充の効果を、プラセボまたは無ビタミンCと比較し検討すること。

検索戦略

Cochrane Airways Group’s Specialised Register (CAGR)の試験を同定した。Registerには、多くの書誌データベースをシステマティックに検索して同定した試験報告とジャーナルおよび会議のアブストラクトのハンドサーチが含まれている。また試験登録ウェブサイトも検索した。 2012年12月に検索を実施した。

選択基準

ランダム化比較試験(RCT)を選択した。喘息と診断された成人および小児を選択した。個別分析には、運動誘発性気管支収縮(または運動誘発性喘息)と診断された試験を対象とした。ビタミンC補充とプラセボまたはビタミンC補充と無補充を比較した試験を選択した。治療およびコントロール群の喘息管理において同等の治療経歴のある試験を選択した。レビューの主要論点は、憎悪予防およびHRQL改善のための日常ビタミンC補充である。喘息患者における憎悪期間時または風邪症状のための短期ビタミンC使用は、本レビューから除外した。

データ収集と分析

2名のレビュー著者が独立して該当すると考えられるタイトルおよびアブストラクトを選び、その後研究レポートの全文を検査し選択した。コクラン共同計画より想定できる標準方法を使用した。

主な結果

参加者419例の11試験が選択基準に適合した。10件の研究で参加者が成人であり、1件だけが小児におけるものであった。研究デザインの報告は大部分の研究に対するバイアスのリスクを確定するのに不十分であり、主要アウトカムに対するデータ入手の不備がある種の選択的アウトカム報告を示している可能性がある。4件の研究が並列群で、それ以外はクロスオーバー試験であった。8件の研究で喘息患者を選択し、3件で運動誘発性喘息の参加者40例を選択した。5件の研究で、気管支検査または運動テストの前に単回投与養生法を用いた報告があった。選択した研究で用いられたビタミンC投与には顕著な異質性があり、有意な分析を実施するには困難であった。

201名の成人喘息患者に関する1件の研究では、主要アウトカムである健康に関連するQOL(HRQL)に有意差の報告はなく、本エビデンスの質は総体的に低かった。その他の主要アウトカムである成人における憎悪にかんするビタミンCの効果を評価するデータは、入手不可能であった。1件の小規模研究で小児の喘息憎悪に関するデータの報告があったが、ビタミンCまたはプラセボ群とも憎悪は見られなかった(エビデンスの質は極めて低い)。もう1件の41例の成人患者の試験では本基準による憎悪は確認できず、本方法による評価に適したフォーマットでデータを入手することは不可能であった。肺機能および症状データは、単回研究によるものであった。本エビデンスの質を中程度としたが、これらのパラメータにおける変化に関連する可能性のある臨床上の意義を評価するにはさらなる研究が必要である。これらのアウトカムすべてでビタミンCとプラセボ間に有意差は認められなかった。有害事象は全く報告されなかったが、このエビデンスの質も極めて低い。

運動誘発性気管支収縮の研究では、ビタミンC供給の肺機能測定において何らかの改善を示唆しているが、これらの研究の件数は少なく小規模でデータも限定的なことから、エビデンスの質は低いと判断した。

著者の結論

現在、喘息または運動誘発性気管支収縮の管理におけるビタミンCの使用に関して確固たる評価をしているエビデンスは入手不可能である。効果の推測に十分に自信を与えるさらなる研究が必要であり、その推測は変わる可能性がある。現在ビタミンCが喘息の治療剤として推薦できることを示しているものは何もない。ビタミンCが運動誘発性息切れの症状および肺機能に対して有効であるということを示すものはあるが、これらの結果は決定的でない小規模の研究によってのみもたらされるものであった。今までに公表された研究はほとんどが小規模で一貫性がなく助言に値しない。増悪率や健康に関するQOLなどの良好な質の臨床的エンドポイントのあるデザインの良い試験が必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.10]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Vitamin C for asthma and exercise-induced breathlessness

Review question

This review considered the question of whether vitamin C may be helpful for people with asthma or exercise-induced breathlessness.

Background

Asthma is an inflammatory lung condition characterised by the narrowing of airways and is associated with wheezing, breathlessness, cough and chest tightness. Vitamin C has been suggested as a possible treatment for asthma.

Study characteristics

Eleven studies on 419 people with asthma or exercise-induced breathlessness were included in this review comparing vitamin C compared to placebo (no vitamin C). Most studies were in adults and one small study was in children. The small number of studies available for review and their different designs meant that we were only able to describe individual studies, rather than pooling the results together to get an average from the trials. The study design was not well described in most study reports and therefore it was impossible to determine risk of bias for most of the studies. There was very little data available in the trials for our key outcomes and this may indicate some selective outcome reporting.

Key results

There was no indication of benefit from the studies that considered vitamin C in relation to asthma. However, it is not possible to form any clear conclusions on the basis of those studies at this stage. The review concludes that there is insufficient evidence currently available to evaluate the use of vitamin C as a treatment in asthma. Larger, well-designed research is needed to provide clearer guidance. There was some indication that vitamin C was helpful in exercise-induced breathlessness in terms of how easily people breathe and their symptoms; however, as these findings were provided by only very small studies they do not provide complete answers to guide treatment.

Quality of the evidence

Details of the way patients were allocated to receive vitamin C or not were not clearly described in 10 of the 11 studies and we considered this carefully in the review in relation to our level of uncertainty in interpreting the results. Taking this into account, together with the imprecision of the results, we judged the estimates of the usefulness of vitamin C as a treatment to be of either low or moderate quality in relation to asthma.

Additionally, for exercise-induced breathlessness the three studies providing data to the review were small and we are mindful of the need to draw very cautious conclusions about the results.

This plain language summary is current as of December 2012.

Résumé simplifié

La vitamine C pour le traitement de l'asthme et de la dyspnée provoquée par l'exercice

Question de la revue

Cette revue a cherché à savoir si la vitamine C pourrait être utile pour les personnes souffrant d'asthme ou de dyspnée provoquée par l'exercice.

Contexte

L’asthme est une affection pulmonaire inflammatoire qui se caractérise par le rétrécissement des voies respiratoires et est associé à une respiration sifflante, un essoufflement, de la toux et une sensation d'oppression. La vitamine C a été proposée comme traitement possible de l'asthme.

Les caractéristiques de l'étude

Onze études totalisant 419 personnes souffrants d'asthme ou de dyspnée provoquée par l'exercice ont été inclues dans cette revue comparant la vitamine C au placebo (absence de vitamine C). La plupart des études portaient sur les adultes et une petite étude portait sur les enfants. Du fait du petit nombre d'études disponibles pour la revue et de leurs différents plans d’étude, nous n’avons pu décrire que les études individuelles, plutôt que de regrouper les résultats pour obtenir une moyenne des essais. Le plan d'étude n'était pas correctement décrit dans la plupart des rapports d'étude et par conséquent, il était impossible de déterminer le risque de biais pour la plupart des études. Très peu de données étaient disponibles dans les essais pour nos principaux critères de jugement et cela pourrait signifier des rapports sélectifs de résultats.

Les principaux résultats

Aucune étude n’indiquait de bénéfice de la vitamine C en tant que traitement de l'asthme. Cependant, à ce stade, il n'est pas possible d'établir de conclusions claires sur la base de ces études. Cette revue conclut qu'il n'existe pas suffisamment de preuves actuellement disponibles pour évaluer l'utilisation de la vitamine C en tant que traitement de l'asthme. Des recherches supplémentaires plus larges et bien planifiées sont nécessaires pour fournir des conseils plus clairs. Certaines données indiquaient que la vitamine C a été utile en tant que traitement de la dyspnée provoquée par l'exercice en termes de symptômes et de facilité à respirer. Toutefois, étant donné que ces résultats ont été fournis par de très petites études, ils ne fournissent pas de réponses complètes pour orienter le traitement.

Qualité des preuves

La manière dont les patients étaient assignés à recevoir de la vitamine C ou non n'était pas clairement décrite dans 10 des 11 études et nous avons considéré ceci de façon approfondie dans la revue en termes de notre niveau d'incertitude dans l'interprétation des résultats. Du fait de cette prise en compte et de l'imprécision des résultats, nous avons jugé que les estimations de l'utilité de la vitamine C en tant que traitement pour l’asthme étaient d'une qualité faible à modérée.

De plus, pour la dyspnée provoquée par l'exercice, les trois études fournissant des données pour la revue étaient de petite taille et nous sommes conscients de la nécessité à être très prudents pour tirer des conclusions concernant les résultats.

Ce résumé simplifié est à jour en décembre 2012.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

平易な要約

喘息および運動誘発性息切れに対するビタミンC 

レビューの論点

このレビューでは喘息または運動誘発性気管支収縮患者にビタミンCが有効である可能性があるかどうかについて検討した。

背景

喘息は気道収縮が特徴の炎症性肺疾患で、喘鳴、息切れ、咳および胸部緊張の症状がある。ビタミンCは喘息の治療法となる可能性が示唆されてきた。

研究の特性

喘息または運動誘発性気管支収縮におけるビタミンCとプラセボ(無ビタミンC)を比較した419例の11件の試験を選択した。大部分の研究が成人においてであったが、1件の小規模研究は小児におけるものであった。このレビューに対して入手可能な研究数が少なかったのと異なる研究デザインであったことから、個々の研究を記述することだけが可能であり、試験の平均値を得るためにそれぞれの結果をプールすることは不可能であった。研究デザインは多くの研究報告であまりきちんと記述されておらず、多くの研究のバイアスのリスクを確定することは不可能であった。主要アウトカムに対して入手可能である試験データが極めて少なかったが、このことは何らかの選択的アウトカム報告を示している可能性がある。

主な結果

ビタミンCを喘息と関連付けて考える研究からは何の利益を指し示すものではなかった。しかし、この段階でこれらの研究に基づいて確かな結論を出すことは不可能である。このレビューでは、喘息治療としてビタミンCを使うことを評価するエビデンスについて現在は不十分であると結論付けている。より明確な助言をするにはより規模の大きい良いデザインの研究が必要である。ビタミンCが運動誘発性気管支収縮において患者の呼吸し易さおよび症状の点で有効であるという示唆があるが、これらの結論は極めて小規模の研究だけによるもので、治療を指導するための完璧な答えとは言い難い。

エビデンスの質

どのようにしてビタミンCを摂取するかしないかに患者を割りつけたかは11件中10件で詳しくはっきりと記述されていなかったが、このレビューでは結果を解釈する時にこれを不確実性のレベルと結びつけて慎重に考えた。これを結果の不正確さと共に考慮して、ビタミンCの喘息治療での有効性はその質が低くも中等度でもないと推測した。

さらに運動誘発性気管支収縮に対してはこのレビューにデータを提供した3件の研究が小規模であったので、その結果に関しては極めて注意する必要がある。

この平易な要約は2012年12月現在のものである。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.10]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Summary of findings(Explanation)

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

Vitamin C supplementation compared with placebo for asthma

Patient or population: adults and children with asthma

Settings: community

Intervention: vitamin C supplementation

Comparison: placebo

OutcomesAnalyses in study reportNo of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Health-related quality of life (HRQL)There was no evidence of a difference in HRQL between the groups after 16 weeks treatment as measured by the available SF-36 data201 adults (1 study)⊕⊕⊝⊝
low
1, 2
Authors' note: "SF-36 data on physical functioning were incomplete and this section was excluded from analysis"
Asthma exacerbationsNo exacerbations in either group16 children (1 study)⊕⊝⊝⊝
very low1,3
 
Lung function: FEV1 (ml) (change from 0 to 16 weeks)MD -11 (95% CI -92 to 70)201 adults (1 study)⊕⊕⊕⊝
moderate1
The 95% CI excludes a clinically important mean difference in FEV1, so the outcome was not downgraded for imprecision
Asthma symptoms (change from 0 to 16 weeks)MD 0 (95% CI -0.2 to 0.1)201 adults (1 study)⊕⊕⊕⊝
moderate1
 
Adverse eventsNo adverse events in either group41 adults (1 study)⊕⊝⊝⊝
very low1,3
 

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

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

Summary of findings 2 Summary of findings: Vitamin C supplementation compared with placebo for exercise -induced bronchoconstriction/asthma

Summary of findings 2. Summary of findings: Vitamin C supplementation compared with placebo for exercise -induced bronchoconstriction/asthma
  1. 1One point deducted for selective reporting as data provided by only one small trial.
    2One point deducted to reflect the 'Risk of bias' assessment for this trial (unclear randomisation).

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

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

Settings: community

Intervention: vitamin C supplementation

Comparison: placebo

OutcomesAnalyses in study reportNo of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Health-related quality of life (HRQL)See commentSee commentSee commentNo between-group data reported
Asthma exacerbationsSee commentSee commentSee commentNot reported

Lung function: FEV1 % drop

Postexercise

Reported that the maximum percentage drop in FEV1 postexercise on the vitamin C diet was -6.4% (95% CI -12.0% to -0.8%; the effect size using omega-squared (ES) was 0.40) which is indicative of an attenuated EIB response. This was significantly different (P < 0.05) from the maximum drop of -12.9% (95% CI -18.6% to -12.3%) on placebo8 adults (1 study)⊕⊕⊝⊝
low1,2
Cross-over study
Asthma symptomsReported that a significant improvement (P < 0.05) in mean asthma symptom scores was observed (6.3; 95% CI 5.8 to 6.8) on the vitamin C diet compared to the placebo diet (5.8; 95% CI 5.1 to 6.2)8 adults (1 study)⊕⊕⊝⊝
low1,2
Cross-over study
Adverse eventsSee commentSee commentSee commentNot reported

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

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

Background

Description of the condition

Asthma is a chronic inflammatory airways disease that is associated with episodic symptoms of breathlessness, wheeze and chest tightness. The spectrum of severity of this condition is wide, ranging from no or minimal symptoms to it being disabling or life-threatening. It can affect all age groups although it often starts in children. It is estimated that 300 million people suffer from asthma worldwide and it is predicted that this number will increase to 400 million by 2025 (WHO 2007). Between 2001 and 2009 the number of people in the US with asthma increased by five million, from 20 to 25 million (CDC 2012; CDCP 2011); during 2008 to 2010 there were higher asthma prevalence rates among Alaska Native (9.4%), American Indian (also 9.4%), black (11.2%) and multiple-race (14.1%) people than white people (7.7%), and for Asian people the rate was 5.2% (CDCP 2011). Prevalence rates are slightly higher among children (10%) than adults (8%) in the US (CDCP 2011).

There are quality of life (Clayton 2005) and financial (Wu 2007) implications for many people with asthma. Over 65,000 hospital admissions for asthma were recorded In the period between 2005 and 2006 in the UK (NHS 2011) and in the US approximately 10 million people experience asthma exacerbations each year (Krishnan 2006).

National (e.g. BTS/SIGN 2011; NIH 2007) and international (e.g. GINA 2011) guidelines have been produced for the management of asthma.

Exercise-induced bronchoconstriction describes narrowing of airways during or following exercise and is associated with exercise-induced symptoms of breathlessness, wheeze and cough. It is a common symptom in asthma and is a marker of the presence of airways inflammation. However, up to 20% of individuals with exercise-induced bronchoconstriction do not have a diagnosis of asthma (Parsons 2013) and therefore may represent a discreet clinical entity.

Description of the intervention

There is some evidence that a lower level of fruit consumption is associated with paediatric wheezing (Chatzi 2007; Okoko 2007). Benefits of fruit intake to adults with asthma have also been reported, suggesting that this aspect of diet may be a modifiable risk factor for asthma symptoms (Patel 2006).

In the UK consumption of fresh fruit and vegetables declined between the 1950s and early 1990s (Seaton 1994). In the US fruit and vegetable consumption remained at the same level between 1994 and 2005 (Blanck 2008), and there are numerous recent examples of national initiatives to promote consumption of fresh fruit and vegetables both in Europe (EUFIC 2012) and worldwide (WHO 2012). It has been hypothesised that this reduction in fruit intake in a 'western diet' is associated with the increase in prevalence of asthma and its severity in the developed countries (Misso 2005; Patel 2006). This association may be related to a reduction in intake of the dietary antioxidants, including vitamin C, and hence vitamin C supplementation may ameliorate some of the symptoms of asthma.

How the intervention might work

Vitamin C is a recognised dietary antioxidant and it has been suggested that dietary antioxidants in the epithelial lining and lining fluids of the lung may be beneficial in the reduction of oxidative damage (Arab 2002). A reduction in the intake of naturally occurring antioxidants, such as vitamin C, may result in greater exposure to reactive oxygen species and hence result in inflammation. This may be implicated in the aetiology of asthma or in its severity. Misso 2005 reported particularly low vitamin C intake in males with severe asthma, and noted the need for more research to assess the benefits of vitamin C supplementation in patients with severe asthma. However, the association of dietary antioxidants with asthma severity is not fully understood. Misso 2005 noted, for example, that whilst there was some indication of an association between vitamin C intake and asthma severity in men, data from women, who had a significantly higher vitamin C intake than men in the sample, did not indicate a similar pattern. Alternative mechanisms for the potential action of vitamin C in asthma are its effects on the arachidonic acid pathway (Cohen 1997) or its antiviral properties (Anah 1980).

Why it is important to do this review

This review aims to establish whether vitamin C supplementation may have a positive role in the management of asthma in children and adults.

Objectives

To examine the effects of vitamin C supplementation on exacerbations and health-related quality of life (HRQL) in adults and children with asthma or exercise-induced bronchoconstriction compared to placebo or no vitamin C.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs). We planned to include studies reported in full text, those published as an abstract only and also unpublished data.

Types of participants

We included both adults and children with a diagnosis of asthma. In separate analyses we considered trials with a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma).

Types of interventions

We included trials comparing vitamin C supplementation with placebo, or vitamin C supplementation with no supplementation. The primary focus of the review is on daily vitamin C supplementation to prevent exacerbations and improve HRQL. The short-term use of vitamin C at the time of exacerbations or for cold symptoms in people with asthma are outside the scope of this review and we planned to exclude clinical trials addressing these issues if they were identified in our searches.

Types of outcome measures

Primary outcomes
  1. Health-related quality of life.

  2. Asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids.

Secondary outcomes
  1. Measures of lung function: forced expiratory flow in one second (FEV1), peak expiratory flow rate (PEFR) including changes related to exercise.

  2. Asthma symptoms.

  3. Adverse events reported to be related to vitamin C supplementation.

Reporting one or more of the outcomes listed here in the trial was not an inclusion criterion for the review.

In the separate analysis of patients with a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma) we focused on measures of lung function: FEV1, PEFR.

Search methods for identification of studies

Electronic searches

We identified trials from the Cochrane Airways Group's Specialised Register (CAGR), which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through 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 Appendix 1 for further details). We searched all records in the CAGR using the search strategy in Appendix 2.

We also conducted a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the WHO trials portal (www.who.int/ictrp/en/) using search terms based on those in Appendix 2. We searched all databases from their inception up to December 2012, with no restriction on language of publication.

Searching other resources

We checked reference lists of all primary studies and review articles for additional references, and we searched for errata or retractions from included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed). We reported the date this was done within the review.

Data collection and analysis

Selection of studies

Two review authors (SJM and AH) independently screened the titles and abstracts of all the potential studies we identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We included trials where the asthma management of both treatment and control groups provided similar background therapy. We retrieved the full-text study reports/publication and two review authors (SJM and AH) independently screened the full text, identified studies for inclusion and identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreement through discussion and consulted a third member of the author team (MW). We identified and excluded duplicates and collated multiple reports of the same study so that each included study rather than each report was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Figure 1) and 'Characteristics of excluded studies' table.

Figure 1.

Study flow diagram.

Data extraction and management

We used a data collection form for study characteristics and outcome data which we piloted on one study in the review. Two review authors (SJM and AH) extracted study characteristics from the included studies. We extracted the following study characteristics.

  1. Methods: study design, total duration of study, details of any 'run-in' period, number of study centres and location, study setting, withdrawals and date of study.

  2. Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria and exclusion criteria.

  3. Interventions: intervention, comparison, concomitant medications and excluded medications.

  4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

  5. Notes: funding for trial and notable conflicts of interest of trial authors.

Two review authors (SJM and AH) independently extracted outcome data from the included studies. We have noted in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We resolved disagreements by consensus or by involving a third author (MW). One review author (SJM) transferred data into the Review Manager (RevMan) file. We double-checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (AH) spot-checked study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (SJM and AH) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements by discussion or by involving another author (MW). We assessed the risk of bias according to the following domains:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessment;

  5. incomplete outcome data;

  6. selective outcome reporting;

  7. other bias.

We graded each potential source of bias as high, low or unclear and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarised the 'Risk of bias' judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all-cause mortality may be very different than for a patient-reported pain scale). Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the 'Risk of bias' table.

When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to a published protocol and would have reported any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We analysed dichotomous data as odds ratio and continuous data as mean difference or standardised mean difference. We entered data presented as a scale with a consistent direction of effect.

We undertook meta-analyses only where this was meaningful, i.e. if the treatments, participants and the underlying clinical question were similar enough for pooling to make sense.

We planned to describe skewed data reported as medians and interquartile ranges narratively. The issue did not arise in the included trials.

Where multiple trial arms were reported in a single trial, we included only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) had been combined in the same meta-analysis, we planned to halve the control group to avoid double-counting. The issue did not arise in our evaluation of the included trials.

Unit of analysis issues

In all studies the unit of analysis was the patient. In repeated measures studies (cross-over trials) we have reported within-patient differences. As no statistical aggregation of studies was possible in this review we have reported results as presented in the trial reports.

Dealing with missing data

We planned to contact investigators or study sponsors in order to verify key study characteristics and to obtain missing numerical outcome data where possible (e.g. when a study was identified as abstract only). Where this was not possible, and the missing data were thought to introduce serious bias, we planned to explore the impact of including such studies in the overall assessment of results by a sensitivity analysis; however this issue did not arise.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis. If we had identified substantial heterogeneity we planned to report it and explore possible causes by prespecified subgroup analysis. This was, however, not an issue as there were no opportunities to aggregate studies statistically.

Assessment of reporting biases

If we had been able to pool more than 10 trials, we would have created and examined a funnel plot to explore possible small study biases. However, this was not an issue in this review.

Data synthesis

We planned to use a fixed-effect model and perform a sensitivity analysis with a random-effects model. However, these concerns did not arise with the included studies. We planned to analyse dichotomous outcomes using odds ratio and continuous data as mean difference; however, there was no opportunity for statistical aggregation of studies and the results reported in the review were obtained directly from the trial reports.

'Summary of findings' table

We created two 'Summary of findings' tables using the following outcomes:

  1. health-related quality of life;

  2. asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids;

  3. measures of lung function: FEV1, PEFR;

  4. asthma symptoms;

  5. adverse events.

We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence as it relates to the studies which contributed data to the review for the prespecified outcomes. We used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the GRADEpro software. We have justified all decisions to downgrade or upgrade the quality of studies using footnotes and we have included comments to aid the reader's understanding of the review where necessary.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses:

  1. age (children under 12 years of age versus adults and adolescents);

  2. severity (requirement for regular preventative treatment or not).

We planned to use the following outcomes in subgroup analyses:

  1. health-related quality of life;

  2. asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids;

  3. measures of lung function: FEV1, PEFR;

  4. asthma symptoms;

  5. adverse events.

There was, however, no opportunity to pursue these planned analyses as studies could not be aggregated.

We planned to use the formal test for subgroup interactions in Review Manager (Review Manager (RevMan)) if the requirement to do so had arisen.

Sensitivity analysis

We planned to carry out the following sensitivity analyses:

  1. study quality as defined by standard Cochrane 'Risk of bias' criteria;

  2. use of random-effects meta-analysis instead of fixed-effect.

However, the need to do this did not arise as it was not possible to combine data from different trials in any single analysis.

Reaching conclusions

We based our conclusions only on findings from the quantitative or narrative synthesis of the included studies in this review. We avoided making recommendations for practice and our implications for research suggests priorities for future research and outlines uncertainties in the area.

Results

Description of studies

Results of the search

We identified 99 records through Cochrane Airways Group database searches and a further 24 from other sources. Further details are provided in Figure 1.

Included studies

Eleven studies met our inclusion criteria (Anah 1980; Anderson 1983; Cohen 1997; Fogarty 2003; Kordansky 1979; Malo 1986; O'Sullivan 2000; Nadi 2012; Schachter 1982; Schertling 1990; Tecklenburg 2007). Eight of these (Anah 1980; Anderson 1983; Fogarty 2003; Kordansky 1979; Malo 1986; O'Sullivan 2000; Nadi 2012; Schertling 1990) focused on asthma and three (Cohen 1997; Schachter 1982; Tecklenburg 2007) on exercise-induced bronchoconstriction. In total there were 419 participants (379 for asthma and 40 for exercise-induced bronchoconstriction).

In 10 studies the participants were adults and only one (Anderson 1983) focused on a paediatric group (16 children). Four of the 11 studies were parallel-group in design (Anah 1980; Anderson 1983; Fogarty 2003; Nadi 2012) (318 participants in total), and the remainder (Kordansky 1979; Malo 1986; O'Sullivan 2000; Schachter 1982; Schertling 1990; Tecklenburg 2007) were cross-over design studies (101 participants in total).

However, only six of the 11 studies on 338 participants provided data that could be included in our analyses (Anah 1980; Anderson 1983; Fogarty 2003; Nadi 2012; Schachter 1982; Tecklenburg 2007). The majority were parallel-group in design (Anah 1980; Anderson 1983; Fogarty 2003; Nadi 2012 (318 participants in total)) and the remaining two cross-over studies (Schachter 1982; Tecklenburg 2007) contributed eight and 12 participants respectively. These two cross-over trials (Schachter 1982; Tecklenburg 2007) contributed to the exercise-induced asthma/bronchoconstriction analyses reported in Table 1. The four parallel-group studies contributed to the analysis of asthma outcomes reported in Table 2.

Table 1. Outcomes: chronic asthma
  1. *Authors note: "SF-36 data on physical functioning were incomplete and this section was excluded from analysis".

    FEV1: forced expiratory volume in one second
    HRQL: health-related quality of life
    PEFR: peak expiratory flow rate

Vitamin C supplementation versus control (asthma)
OutcomeStudiesNAgeStudy IDStudy reported result
Health-related quality of life1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference in HRQL between the groups after 16 weeks treatment as measured by the available SF-36 data*
Asthma exacerbations116 children
Vitamin C: 7
No treatment: 9
Vitamin C mean: 9.3 years (± 2.4)
Control mean: 9.2 years (± 1.9)
Anderson 1983No exacerbations in either group
FEV1 (L) (at one month)160 participants
Vitamin C: 30
Placebo: 30
Vitamin C mean: 48.38 years (± 9.03)
Placebo mean: 40.53 years (± 10.48)
Nadi 2012No direct comparison between vitamin C and placebo reported. Before versus after treatment comparison in vitamin C (P = 0.65) and in placebo (P = 0.044)
FEV1 (ml) (change from 0 to 16 weeks)1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD -11 (95% CI -92 to 70), P = 0.78
FEV1 (% predicted)110 participants (cross-over design)Very limited details in trial report (conference abstract) O'Sullivan 2000No significant change in FEV1 after vitamin C administration (95 ± 2.7% versus 94.2 ± 3.2%)
PEFR (L/min) (change from 0 to 16 weeks) AM1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD 0.9 (95% CI -11.8 to 13.5), P = 0.89
PEFR (L/min) (change from 0 to 16 weeks) PM1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD 2.2 (95% CI -10.0 to 14.3), P = 0.73
Asthma symptoms (change from 0 to 16 weeks)1201 participants randomised
Vitamin C: 95 (72 completed (76%))
Placebo: 106 (82 completed (77%))
Vitamin C mean: 42 years
Placebo mean: 40 years
Fogarty 2003No significant difference between vitamin C and placebo: MD 0 (95% CI -0.2 to 0.1), P = 0.33
Adverse events141 participants
Vitamin C: 22
Placebo: 19
Vitamin C mean: 26.5 years (range 15 to 42)
Placebo mean: 27.8 years (range 15 to 46)
Anah 1980No adverse events in either group
Table 2. Outcomes: exercise-induced bronchoconstriction/asthma
  1. *Tecklenburg 2007 used Asthma Quality of Life Questionnaire symptom score component. These data are reported in the table under symptoms.

    CI: confidence interval
    FEV1: forced expiratory volume in one second
    NS: non-significant
    SE: standard error

Vitamin C supplementation versus placebo (exercise-induced bronchoconstriction/asthma)
OutcomeStudiesNAgeStudy IDStudy reported result

Health-related quality of life

 

00

Asthma exacerbations

 

00 — — —

FEV1 (L) (change scores)

 

Immediately after exercise112 participants (cross-over design)

Mean age 26 years (± 5)

 

Schachter 1982No significant difference between vitamin C and placebo
Vitamin C: mean +0.21 (standard error (SE) ± 0.06)
Placebo mean +0.08 (SE ± 0.08)
t = 1.46 (P = 0.18)
5 minutes after exercise112 participants (cross-over design)Mean age 26 years (± 5) Schachter 1982No significant difference between vitamin C and placebo
Vitamin C: mean - 0.24 (SE ± 0.06)
Placebo mean: -0.44 (SE ± 0.14)
t = 2.13 (P = 0.057)
Post-bronchodilator112 participants (cross-over design)Mean age 26 years (± 5) Schachter 1982Post-bronchodilator scores significantly better on vitamin C
Vitamin C: mean + 0.43 (SE ± 0.12)
Placebo mean + 0.22 (SE ± 0.10)
t = 3.42 (P < 0.01)

FEV1 % drop postexercise

 

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

PEF (change scores)

 

Immediately after exercise112 participants (cross-over design)Mean age 26 years (± 5) Schachter 1982A significant advantage in favour of vitamin C
Vitamin C: mean +0.59 (SE ± 0.16)
Placebo mean +0.10 (SE ± 0.25)
t = 2.3 (P < 0.05)
5 minutes after exercise112 participants (cross-over design)Mean age 26 years (± 5) Schachter 1982No significant difference between vitamin C and placebo
Vitamin C: mean -0.73 (SE ± 0.28)
Placebo mean -0.95 (SE ± 0.40)
t = 0.90 (NS)
Post-bronchodilator112 participants (cross-over design)Mean age 26 years (± 5) Schachter 1982A significant advantage in favour of vitamin C
Vitamin C: mean +0.83 (SE ± 0.26)
Placebo mean +0.39 (SE ± 0.29)
t = 2.69 (P < 0.05)

Asthma symptoms

 

1

8 participants (cross-over design)

 

Mean age: 24.5 years (4.8)

 

Tecklenburg 2007

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

 

Adverse events00 — — —

There was marked heterogeneity in vitamin C dosage regimes used in the selected studies.

Six studies used regular regimes with differing dosages varying from 1 g (Anah 1980; Anderson 1983; Fogarty 2003; Nadi 2012) and 1.5 g (Tecklenburg 2007) to 5 g once daily (Schertling 1990). Duration of treatment was also very variable, ranging from two weeks to six months.

Five studies (Cohen 1997; Kordansky 1979; Malo 1986; O'Sullivan 2000; Schachter 1982) reported results using single-dose regimes prior to bronchial challenges or exercise tests. The dosages varied from 500 mg (Kordansky 1979; Schachter 1982) to 2 g (Cohen 1997; Malo 1986; O'Sullivan 2000).

Anah 1980 was funded by the Research Grant Committee of the College of Medical Sciences, University of Benin. Fogarty 2003 was funded by the NHS National Research and Development Programme on Asthma Management administered by the National Asthma Campaign. Kordansky 1979 was funded by the National Institute of Allergy and Infectious Diseases and Tecklenburg 2007 was funded, in part, by the Gatorade Sports Science Institute (Gatorade is a sports drinks). The source of funding was unspecified in the trial reports for Anderson 1983; Cohen 1997; Malo 1986; Nadi 2012; O'Sullivan 2000; Schachter 1982 and Schertling 1990

Excluded studies

We excluded 83 references for the following reasons: 77 (93%) did not compare vitamin C with placebo or no treatment; three (4%) were non-randomised, one (1%) was not focused on participants with asthma, one (1%) was a summary of an excluded study and the remaining study (1%) was retracted by the authors following publication. Full details can be found in Characteristics of excluded studies.

Risk of bias in included studies

Full details of our 'Risk of bias' judgements can be found in Characteristics of included studies and an overview of our judgements can be seen in Figure 2.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We judged only one trial as low risk with regard to random sequence generation (Fogarty 2003) and assessed the remainder as unclear in this respect. We evaluated two trials as low risk in terms of allocation concealment (Anah 1980; Fogarty 2003) with the remaining nine in the unclear category.

Blinding

We assessed five studies as low risk with regard to performance bias (Anah 1980; Fogarty 2003; Malo 1986; Schachter 1982; Tecklenburg 2007). We judged five to be in the unclear category (Cohen 1997; Kordansky 1979; Nadi 2012; O'Sullivan 2000; Schertling 1990) and one (the only paediatric study in the review) was in the high risk of bias category (Anderson 1983). Our assessment of detection bias led to similar judgements as in the performance bias although two studies (Fogarty 2003; Malo 1986) were placed in the unclear rather than the low category and there were, therefore, only three studies in the low risk of bias category, seven in unclear and one which we assessed as high risk of bias.

Incomplete outcome data

We judged six studies to be at low risk of bias (Anderson 1983; Cohen 1997; Fogarty 2003; Kordansky 1979; Malo 1986; Schachter 1982). One study (Schertling 1990) was in the high risk of bias category, and we rated the remaining four as unclear in terms of attrition bias.

Selective reporting

We rated all studies as unclear in terms of reporting bias, but we had concerns about the SF-36 data from Fogarty 2003, as SF-36 data on physical functioning were noted by the authors to be incomplete and this section was excluded from the analysis.

Effects of interventions

See: Summary of findings for the main comparison Summary of findings: Vitamin C supplementation compared with placebo for asthma; Summary of findings 2 Summary of findings: Vitamin C supplementation compared with placebo for exercise -induced bronchoconstriction/asthma

Asthma

Health-related quality of life

We found no health-related quality of life (HRQL) data in the included studies that could be included in our analyses. However, Fogarty 2003 narratively reported no evidence of a difference in HRQL between the vitamin C and placebo groups after 16 weeks of treatment in terms of the available SF-36 data; we rated the quality of this evidence as low (Summary of findings for the main comparison). Details of data reported in the included trials relevant to our prespecified outcomes are included in Table 1. No mean difference or confidence interval is reported in the paper.

Asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids

Only one small study, involving 16 children, reported data for asthma exacerbations (as defined by hospital admissions or treatment with a course of oral corticosteroids) and there were no events in either the vitamin C or control group (Anderson 1983); we rated the quality of this evidence as very low (Summary of findings for the main comparison). Although data on exacerbations were provided for 22 adults on vitamin C and 19 adults on placebo in Anah 1980, the data were not reported in a format consistent with our prespecified criteria (defined by hospital admissions or treatment with a course of oral corticosteroids). Anah 1980 reported nine asthma attacks in the vitamin C group and 35 asthma attacks in the placebo group; these data include mild, moderate and severe asthma attacks as defined by the authors. There were two severe asthma attacks in the vitamin C group and eight in the placebo group, one moderate asthma attack in the vitamin C group and 16 in the placebo group, and six mild attacks in the vitamin C group and 11 in the placebo group. It is unclear how many asthma attacks were experienced by each participant.

Measures of lung function: FEV1, PEFR

In five studies there was no significant difference between vitamin C and placebo in FEV1 outcomes (Fogarty 2003; Kordansky 1979; Malo 1986; Nadi 2012; O'Sullivan 2000).

  • FEV1 (L) at one month was reported in one study with 60 participants (Nadi 2012) and based on within-group analyses (paired t-tests). A slight but significant advantage was reported for change in FEV1 in the placebo group (before 1.63 ± 0.68, after 1.82 ± 0.78, P = 0.044) but not in the vitamin C group (before 1.40 ± 0.56, after 1.44 ± 0.59, P = 0.65). Data were not reported in a form that enabled us to do an appropriate between-group analysis, given pretreatment imbalances for this outcome.

  • Change in FEV1 (ml) from zero to 16 weeks was reported in one study with 201 participants(Fogarty 2003). There was no significant difference between placebo and vitamin C (MD 11 ml; 95% CI -70 to 92); we rated the quality of this evidence as moderate, as the confidence interval excluded a clinically important change in FEV1 on vitamin C (Santanello 1999; Summary of findings for the main comparison).

  • FEV1 outcomes were recorded in Kordansky 1979. However, they could not be included in our analysis as the data were not reported; there is an indication in the trial report that no significant difference was detected for this outcome between vitamin C and placebo.

  • FEV1 data were also collected in Malo 1986. The data were not reported in a format that we could transfer to a meta-analysis, however it is indicated in the trial report that there was no significant difference between vitamin C and placebo for this outcome.

  • FEV1 % predicted was reported in O'Sullivan 2000 (a conference abstract) but insufficient details were reported to transfer to a meta-analysis. The authors reported that "There was no significant change in FEV1 after vitamin C administration (95 ± 2.7% versus 94.2 ± 3.2%)".

In Fogarty 2003 and Schertling 1990, the only two studies reporting PEFR outcomes, there was no significant difference between vitamin C and placebo.

  • PEFR data collected at both AM and PM were reported by one study with 201 participants (Fogarty 2003). There was no significant difference between vitamin C and placebo with respect to AM (MD 0.90 L/min; 95% CI -11.8 to 13.5) or PM scores (MD 2.20 L/min; 95% CI -10.0 to 14.3). This study has a narrow confidence interval and therefore implies no clinically important change in PEFR with vitamin C.

  • In relation to PEFR, Schertling 1990 reported that there were no statistically significant differences, or clinically relevant differences, between vitamin C and placebo. Insufficient details were reported to transfer to a meta-analysis.

Asthma symptoms

Data were provided by one study with 201 participants (Fogarty 2003) regarding the change in symptom scores between zero and 16 weeks. There was no significant difference between vitamin C and placebo (MD 0.0; 95% CI -0.2 to 0.1); we rated the quality of this evidence as moderate (Summary of findings for the main comparison).

With regard to asthma symptoms, Schertling 1990 reported that there were no statistically significant differences, or clinically relevant differences, between vitamin C and placebo

Adverse events

Only one parallel-group study (Anah 1980) with 41 participants explicitly reported adverse event data. There were no adverse events in either in the vitamin C or the placebo groups; we rated the quality of this evidence as very low (Summary of findings for the main comparison).

In Schertling 1990, a cross-over trial with 29 participants, one patient reported nausea during the ascorbic acid period, and a few patients noted other mild symptoms during the study, but the authors report "no relevant differences for occurrences between two groups / testing periods".

Withdrawals

Only one study specifically reported withdrawals. Fogarty 2003 documented a withdrawal rate of 24%, mostly for non-medical reasons with a small number withdrawing due to asthma deterioration or "other medical reasons" which were not specified.

Exercise-induced asthma/bronchoconstriction

Health-related quality of life

None of the three included studies reported between-group differences in HRQL in relation to exercise-induced asthma/bronchoconstriction. Tecklenburg 2007 provided data from the symptoms component of the Asthma Quality of Life Questionnaire (AQLQ), reporting a significant improvement on the vitamin C diet (mean score 6.3; 95% CI 5.8 to 6.8) versus placebo (mean score 5.8; 95% CI 5.1 to 6.2) (P < 0.05). However, we are mindful that this measure may be more relevant to asthma studies considering the effects of vitamin C supplementation over longer periods and arguably of less relevance in short-term studies investigating more immediate outcomes. Data reported in the included trials relevant to our prespecified outcomes are included in Table 2.

Asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids

This outcome, in relation to exercise-induced asthma/bronchoconstriction, was not reported in the included studies. Again this outcome is of particular importance in asthma trials measuring the effects of vitamin C supplementation over longer periods and less relevant in contexts where more immediate outcomes are informative.

Measures of lung function: FEV1, PEFR

The change in FEV1 (L) following exercise, compared with FEV1 (L) before exercise, was reported in a small cross-over study with 12 participants (Schachter 1982). The comparison of vitamin C versus placebo change scores was recorded immediately following exercise (MD 0.13; vitamin C 0.21 (standard error (SE) 0.06) versus placebo 0.08 (SE 0.08), P = 0.18), at five minutes after exercise (MD 0.20; vitamin C -0.24 (SE 0.06) versus placebo -0.44 (SE 0.14), P = 0.057) and following postexercise bronchodilator (MD 0.21; vitamin C 0.43 (SE 0.12) versus placebo 0.22 (SE 0.10), P < 0.01). The authors report significantly greater increases in post-bronchodilator pulmonary function in patients on vitamin C compared with placebo).

The maximum % drop in FEV1 scores following exercise was reported in a very small cross-over study with eight participants (Tecklenburg 2007). The authors reported that the maximum percentage drop in FEV1 postexercise on the vitamin C diet was 6.4% (95% CI 12.0% to 0.8%; effect size using omega-squared (ES) 0.40), which is indicative of an attenuated exercise-induced bronchoconstriction response. We rated the quality of this evidence as low (Summary of findings for the main comparison). This was significantly different (P < 0.05) from the maximum drop of 12.9% (95% CI 18.6% to 12.3%) on the placebo diet. There are uncertainties regarding the reported CI for the placebo diet and the data were not reported in a form that enabled us to do a between-group analysis

Categorical outcomes relating to FEV1 were reported in Cohen 1997, a cross-over trial. In the vitamin C group 11 of the 20 participants demonstrated less deterioration in their postexercise change scores (with a % fall in FEV1 no greater than 15%), however in the placebo group all participants had a % fall greater than 15%. These data suggest a protective effect of vitamin C in exercise-induced asthma.

Postexercise change in PEFR was also reported by Schachter 1982. In a comparison of vitamin C versus placebo change scores recorded immediately following exercise there was a significant difference favouring vitamin C (MD 0.49 L/second; vitamin C 0.59 (SE0.16) versus placebo 0.10 (SE 0.25), P < 0.05). However, at five minutes after exercise this difference was not significant (MD 0.22; vitamin C -0.73 (SE 0.28) versus placebo -0.95 (SE 0.40), non-significant). Following postexercise bronchodilator there was a significant difference favouring vitamin C (MD 0.44 L/second; vitamin C 0.83 (SE 0.26) versus placebo 0.39 (SE 0.29), P < 0.05).

Asthma symptoms

One very small cross-over study with eight participants (Tecklenburg 2007) reported asthma symptom data using the AQLQ and showed a significant improvement in patients on the vitamin C diet (MD .6.3; 95% CI 5.8 to 6.80) versus the placebo diet (MD 5.8; 95% CI 5.1 to 6.2, P < 0.05); we rated the quality of this evidence as low (Summary of findings for the main comparison). The minimally important difference on this scale is regarded as 0.5 units.

Adverse events

None of the included studies explicitly reported adverse event data.

Withdrawals

No study specifically reported withdrawals.

Discussion

Summary of main results

Eleven studies were identified as meeting the inclusion criteria for this review: vitamin C versus no vitamin C supplementation. All but one of the studies were in adults, and the studies varied considerably with respect to severity (Characteristics of included studies). The small number of studies available for review and their disparate designs meant that only descriptions of the individual studies were possible with no prospect of aggregating the current studies available. We are also mindful that only three of the 11 included studies were published in the last 10 years (Fogarty 2003; Nadi 2012; Tecklenburg 2007) and the management context for the most of the studies may not be comparable to the treatment patients receive today

Given the significant impact exacerbations of asthma may have on lung function and quality of life, this is an important endpoint for studies in this condition. None of the studies provided robust evidence of vitamin C supplementation influencing asthma exacerbations or health-related quality of life. Only one study (Anah 1980) used exacerbation rate as a primary outcome, but the data could not be included in our review as the definition of exacerbation did not meet our inclusion criteria and there was a lack of statistical analysis. This study reported a reduction in the numbers of severe exacerbations, defined as asthma attacks requiring hospital admission. However, no statistical analysis was presented to allow comparison of the number of participants with one or more exacerbations in each group, or the exacerbation rates between groups.

Fogarty 2003 was the largest included trial with 201 participants and looked at changes in symptom scores in patients with a clinical diagnosis of asthma taking supplements of vitamin C, magnesium or placebo. No significant difference in symptom scores was demonstrated during the period of this study, either as an individual outcome or in combination with others.

The fundamental importance of considering the impact of exacerbations (Fitzgerald 2006) and health-related quality of life (Wilson 2012) in relation to asthma has been well appreciated for several years, and these outcomes are commonly assessed in clinical trials of asthma. It is therefore particularly disappointing that there is very little information in the trials relating to these outcomes.

Nine studies used lung function (including FEV1, PEFR or measures of bronchial hyperreactivity) as their primary outcome measures. There was some evidence from very small studies of improved lung function but it would be necessary to replicate these findings in larger trials for any robust conclusions to be drawn. The largest study (Fogarty 2003), which was at lowest risk of bias, reported narrow confidence intervals for FEV1 and PEFR; this implies no clinically important effect of vitamin C on these measures of lung function.

Table 1 clarifies the data available from the trials including our prespecified primary and secondary outcomes for asthma. There was a paucity of data for our primary outcomes (health-related quality of life and asthma exacerbations) and the available data for measures of lung function and symptoms scores reported in the table do not indicate a significant benefit of vitamin C supplementation. The strength of the evidence is generally low (Summary of findings for the main comparison) and most of the studies contributing data are very small, with disparate approaches. It is therefore not feasible to draw firm conclusions either for or against the use of supplementary vitamin C in the management of asthma. In summary, we would suggest that currently there is insufficient robust evidence from the available trials to evaluate the benefits of vitamin C supplementation and that such judgements should be reserved until data are available from further adequately powered studies.

Our concerns about the available data for the impact of vitamin C supplementation on exercise-induced bronchoconstriction/asthma are similar. The data are tabulated in Table 2. There is some evidence of a significant benefit in post-bronchodilator FEV1 and PEFR; however, in each case these data are contributed only by a single small study. There is also suggestive evidence of a benefit in symptoms scores, but these data are drawn from only one small study. As with the primary and secondary outcomes for asthma, the strength of evidence is of a low order (Summary of findings 2). In summary, there is a need for additional adequately powered studies, with appropriate outcome measures, to bring more clarity to the assessment of the role of vitamin C supplementation in exercise-induced bronchoconstriction/asthma.

Overall completeness and applicability of evidence

The primary outcomes chosen, exacerbation rates and health-related quality of life, are important in assessing asthma control and the impact of treatment. Data for these clinically significant endpoints were lacking, with no studies reporting complete health-related quality of life data and only one using exacerbations as a primary endpoint.

Measures of lung function were used more frequently, including exercise-induced changes in lung function or bronchial challenge tests. However, the studies were small and disparate in design and it is not possible to draw conclusions about overall clinical effectiveness from the results.

One of the two studies identified in our searches, but for which data are currently not posted (IRCT138904224359N1a), may meet our inclusion criteria in the update of this review. However, we note that it will not contribute to our primary outcomes as it does not focus on health-related quality of life or asthma exacerbations. We also note that the other ongoing trial (NCT01057615a) may well not meet our inclusion criteria as the comparison appears to be essentially between vitamin C supplementation and fish oil, rather than vitamin C supplementation versus placebo, and the trial specifically focuses on exercise-induced bronchoconstriction. However, a more adequate assessment will be possible when the full details of the trial are reported

There is currently only a single small study in children (Anderson 1983 including 16 children), so we currently have very limited evidence to assess the impact of vitamin C on asthma in children.

Quality of the evidence

Only one of the 11 trials meeting our inclusion criteria included over 100 participants (Fogarty 2003) and on average the sample size per trial was just 38. In the remaining 10 included studies the sample sizes ranged from six to 60 and the average per trial was just 22. Only six of the 11 studies provided data that could be included in our tables (Table 1; Table 2) and for each outcome we could include data from only one study in each case. There is, therefore, a worrying paucity of data available for this review and there is a substantial risk that there may have been reporting bias. With respect to the quality of the included research, in terms of our 'Risk of bias' assessment using Cochrane criteria, we categorised only one trial as low risk with regard to random sequence generation (Fogarty 2003) and we evaluated the remainder as unclear. In terms of allocation concealment we evaluated three trials as low risk of bias (Anah 1980; Fogarty 2003; Schertling 1990) with the remaining eight assessed as unclear. In terms of both the quantity and quality of available data, with respect to our 'Risk of bias' assessment relating to randomisation procedures, it is clear that any robust interpretation of these data would be inappropriate and this conclusion is supported by our assessment of performance bias where we judged only five studies (Anah 1980; Fogarty 2003; Schachter 1982; Schertling 1990; Tecklenburg 2007) to be low risk of bias. We judged five to be in the unclear category (Cohen 1997; Kordansky 1979; Malo 1986; O'Sullivan 2000; Nadi 2012) with the remaining trial in the high risk of bias category (Anderson 1983). The evaluation of detection bias was consistent with our assessment of performance bias, apart from Schertling 1990 which we judged in this context as unclear rather than low risk of bias.

We primarily downgraded for risk of bias due to the inadequate description of study design across the included studies and the risk of selective reporting as noted above. For a number of outcomes we also downgraded for imprecision as the results came from small trials or were otherwise indeterminate. The notable exception to this was FEV1, where the estimated effect excludes a clinically meaningful difference of 120mL (Summary of findings for the main comparison).

Potential biases in the review process

A possibility of publication bias in this review is acknowledged, whereby a potential failure to identify unpublished negative trials could conceivably lead to the positive effects of vitamin C supplementation being overestimated and, similarly, any failure to identify unpublished positive trials may have led to a conservative assessment of the treatment benefits. These issues are present in most systematic reviews and we believe that a very significant proportion of the research addressing this clinical question has been identified through the Cochrane Airways Group's comprehensive systematic database searches, in the identification of both published and unpublished trials meeting our inclusion criteria.

We also acknowledge the possibility of study selection bias. We endeavoured to minimise this risk by two review authors independently evaluating all identified studies, and we are confident that trials judged as failing to meet our inclusion criteria were assessed on a consistent basis.

Agreements and disagreements with other studies or reviews

Our conclusions are very similar to a previous Cochrane review on vitamin C for asthma (Kaur 2009). However, in Kaur 2009 the primary outcomes were lung function and symptom scores as opposed to exacerbations and health-related quality of life in this review. Two additional studies meeting the inclusion criteria were identified in this review (Nadi 2012; Schertling 1990). However, our conclusions are consistent with those drawn in the 2009 review where the authors argue that "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". We hope that such research will be conducted and that particular emphasis will be given to the assessment of efficacy with respect to any impact on asthma exacerbations and health-related quality of life.

Authors' conclusions

Implications for practice

The studies of vitamin C supplementation in asthma included in this review provide only very limited evidence with which to evaluate the use of vitamin C in stable asthma or exercise-induced bronchoconstriction/asthma. There is currently no indication that vitamin C can be recommended as a therapeutic agent in asthma or in the prevention of exercise-induced bronchoconstriction. The studies are generally too small to provide clinical recommendations. In addition, clinically important endpoints such as exacerbation rates and health-related quality of life scores are lacking.

Implications for research

Our conclusions are in line with a previous Cochrane review considering the use of vitamin C in stable asthma (Kaur 2009). We agree that larger, more robust research is required to clarify the use of this supplement.

Well-designed and adequately powered double-blind, placebo-controlled trials are required in both adults and children. These trials should include clinically meaningful endpoints including exacerbation rates, health-related quality of life measures, robust symptom scores and the use of rescue medications. In addition changes to lung function parameters, including markers of bronchial hyperreactivity and spirometric changes, should be examined and their clinical implications reported.

We concur with Hemila 2013 that more research would be helpful with respect to exercise-induced asthma. More specific trials are required to examine the inconclusive evidence reported for the use of vitamin C in exercise-induced asthma and to clarify its influence on bronchial hyperreactivity.

Future studies should report adverse effects of vitamin C, which to date have not been adequately reported.

Acknowledgements

We would particularly like to acknowledge the excellent support and assistance from Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane Airways Review Group, together with the greatly appreciated guidance from Chris Cates (Cochrane Airways Review Group Co-ordinating Editor). We are also most grateful to Uwe Wollina, Katja Boehm, Dariusz Wozniak, Alieksei Seniukovich and Zhirajr Mokini Poturljan for the translation of non-English studies; and to Professor Peter Barnes and Dr Al Biltagi who provided helpful feedback on two trials. The support provided by librarians Judith Scammel, Jane Appleton and Hilary Garrett at St George's University, London, is also greatly appreciated.

Milo Puhan was the Editor for this review and commented critically on the review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
CENTRAL (The Cochrane Library)Monthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly
CINAHL (EBSCO)Monthly
AMED (EBSCO)Monthly

 

Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

Appendix 2. Search strategy for Cochrane Airways Group Register

#1 AST:MISC1

#2 MeSH DESCRIPTOR Asthma Explode All

#3 asthma*:ti,ab

#4 #1 or #2 or #3

#5 MeSH DESCRIPTOR Ascorbic Acid

#6 ascorbic* near acid*

#7 vitamin* NEAR C

#8 antioxidant*

#9 #5 or #6 or #7 or #8

#10 #4 and #9

[In search line #1, MISC1 denotes the field in the reference record where the record has been coded for condition, in this case, asthma.]

Contributions of authors

SJM drafted the protocol, with input from AH and MW. SJM and AH independently selected studies for inclusion, with support from MW, and independently extracted the data for inclusion in the meta-analyses. SJM and AH independently evaluated each included study for risk of bias. SJM and AH completed the analyses and results sections. MW completed the discussion and conclusions with input from SJM and AH. SJM and AH assessed the quality of evidence for the 'Summary of findings' tables with input from Milo Puhan and Chris Cates.

Declarations of interest

None known.

Sources of support

Internal sources

  • SJM, UK.

    NIHR and St George's University of London

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anah 1980

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

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

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

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

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

The trial was conducted in Benin City, Nigeria

Interventions

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

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

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

14-week trial

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

Effervescent tablets were provided by Roche (Nig.) Limited

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot specified
Allocation concealment (selection bias)Low riskCoded allocation to A (vitamin C group) or B (placebo group) which was decoded on completion of the trial
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. 2 identical effervescent tablets were provided for the trial by Roche (Nig.) Limited
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. 2 identical effervescent tablets were provided for the trial by Roche (Nig.) Limited
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo indication of withdrawals
Selective reporting (reporting bias)Unclear riskSome outcomes not reported (genotype, stool microscopy and eosinophil count data not reported as the authors judged the data to be unreliable)

Anderson 1983

MethodsRandomised controlled trial, parallel-group design
Participants

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

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

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

Exclusion criteria: none specified in trial report

Paediatric Respiratory Clinic H F Verwoerd Hospital, Pretoria

Interventions

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

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

OutcomesExacerbations (requiring glucocorticoids or hospitalisation), IgE (serum), antibodies to streptolysin 0 (ASO), polymorphonuclear leucocyte (PMNL) migration, secretory immunoglobulin A (IgA), serum immunoglobulin and total haemolytic complement levels
NotesFunding source not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
High riskThe study compared ascorbic acid to no intervention and therefore the trial was unblinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskNo statement that assessors were unblinded or any attempt so to do, but measurements objective
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete data
Selective reporting (reporting bias)Unclear riskNo stated primary objective; some outcomes not reported

Cohen 1997

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

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

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

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

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

The setting was a university hospital in Israel

InterventionsReported as: 2 g of oral ascorbic acid versus placebo 1 hour before a 7-minute treadmill exercise session. 8 minutes after exercise pulmonary function tests were performed. 1 week later participants received the alternative intervention
OutcomesDevelopment of exercise-induced asthma (EIA), FEV1 (L) and FEV1 (% predicted)
Notes

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

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

Funding source not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as double-blind but method of blinding (whether it was a matched placebo) is unclear in trial report
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as double-blind but method of blinding (whether it was a matched placebo) is unclear in trial report
Incomplete outcome data (attrition bias)
All outcomes
Low riskInformation included in trial report from all 20 participants
Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Fogarty 2003

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

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

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

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

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

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

Patients recruited from 24 GP practices, Nottingham, UK

Interventions

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

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

Outcomes

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

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

Notes

16-week trial

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were assigned using a random number generator, in blocks also stratified by a regular corticosteroid dose, defined as low or high
Allocation concealment (selection bias)Low riskAllocation by an individual code number, decoded after the last participant completed the trial. Randomisation and dispensing performed independently from the recruitment of trial participants
Blinding of participants and personnel (performance bias)
All outcomes
Low riskRandomised to vitamin C 1 g/day (5.6 mmol) plus magnesium placebo, magnesium amino chelate (Lamberts Health Care, Tunbridge Wells, UK) 450 mg/day (27.6 mmol) plus vitamin C placebo, or double-matched placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear in trial report
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for withdrawal listed in study report. Loss to follow-up, but taken into account. ITT analysis and as treated analysis reported: precise details of ITT imputation not given: "assuming deterioration in all outcomes in participants who withdrew".  66/300 withdrew (some from magnesium group not included in this review)
Selective reporting (reporting bias)Unclear riskPrimary outcome measure reported, but secondary outcomes not all reported and incomplete reporting of SF-36 data

Kordansky 1979

MethodsRandomised controlled trial, cross-over design
Participants

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

Inclusion criteria: ragweed-sensitive asthmatics

Trial conducted in Baltimore, USA

Interventions

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

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

Outcomes

PD20 to ragweed extract challenge FEV1, PD35 SGaw, tested on day 7, 3 hours after dose of placebo/vitamin C

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

Notes

7-day cross-over trial

Funded by the National Institute of Allergy and Infectious Diseases

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy described as double-blind but details of blinding (whether an identical placebo pill was used) were not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStudy described as double-blind but details of blinding (whether an identical placebo pill was used) were not described
Incomplete outcome data (attrition bias)
All outcomes
Low risk6 participants completed both periods of the cross-over. No information on withdrawals included in trial report
Selective reporting (reporting bias)Unclear riskNot all outcomes summarised. Sample dose-response curves given. No tables of summary statistics

Malo 1986

MethodsRandomised controlled trial, cross-over design
Participants

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

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

Interventions

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

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

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

Outcomes

FEV1, FVC, PC20 during histamine challenge

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

NotesFunding source not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised according to a 4.3.1 two-treatment cross-over design, but details of random sequence generation were not included in trial report
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy described as double-blind and details of blinding are provided as "The active and placebo medications consisted of 250 mL of a transparent and odourless sweet liquid in which was dissolved or not, respectively, 2 gm of ascorbic acid. These solutions of similar taste were prepared and coded by the hospital pharmacy"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low risk16 participants completed both periods of the cross-over. No information on withdrawals included in trial report
Selective reporting (reporting bias)Unclear riskTrial report does not include complete details of outcomes

Nadi 2012

MethodsRandomised, double-blind trial, parallel-group design
Participants

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

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

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

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

Participants recruited from Ekbatan hospital in Hamadan (Iran)

Interventions

1000 mg vitamin C daily versus placebo

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

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

1-month trial

Funding source not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not described. Participants were randomly divided into 2 groups, A and B (including 30 patients in each group), and were matched according to their age, weight, height, gender, BMI and drug consumption
Allocation concealment (selection bias)Unclear riskDescribed as "Both patients and physician were unaware of details of patient’s distributions", however no further details available in trial report
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blind – however details of the placebo (whether it was matched to the intervention) are not included in trial report
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDouble-blind – however details of the placebo (whether it was matched to the intervention) are not included in trial report
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details of withdrawals in trial report
Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

O'Sullivan 2000

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

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

Location of trial not included in abstract

InterventionsEach participant completed 2 treatment periods with ingestion of either 2 g of ascorbic acid or placebo 45 minutes prior histamine broncho-provocation
OutcomesFEV1 and bronchial hyper-responsiveness to inhaled histamine
NotesFunding source not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy described as double-blind but unclear whether an identical placebo was used
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo indication of withdrawals
Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Schachter 1982

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

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

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

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

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

Trial conducted in New Haven, Connecticut, USA

Interventions

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

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

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

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

Funding source not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. Vitamin C and placebo in identical capsules
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Vitamin C and placebo in identical capsules
Incomplete outcome data (attrition bias)
All outcomes
Low riskData provided for 12 participants
Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Schertling 1990

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

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

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

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

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

Interventions

2-week run-in period

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

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

The order of the test periods was chosen randomly

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

2 weeks on daily oral ascorbic acid or placebo

Funding source not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe sequence of testing periods was chosen randomly. Details of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskInsufficient details in trial report
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient details in trial report
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information included in trial report about masking for data collectors/analysers
Incomplete outcome data (attrition bias)
All outcomes
High riskData provided on 23 or 24 participants
Selective reporting (reporting bias)Unclear riskNone apparent

Tecklenburg 2007

  1. a

    Abbreviations

    ASO: antibodies to streptolysin O
    BMI: body mass index
    EIA: exercise-induced asthma
    EIB: exercise-induced bronchoconstriction
    FEV1: forced expiratory volume in one second
    FVC: forced vital capacity
    IgA: immunoglobulin A
    ITT: intention-to-treat
    MEF: maximal expiratory flow
    MEF40%(P): maximal expiratory flow at 40% of the vital capacity below total lung capacity on the partial expiratory flow-volume curve
    MEFR: mid-expiratory flow rate
    mmol: millimoles
    MMEFR: resting maximal mid-expiratory flow rate
    PC20: histamine provocative concentration causing a 20% drop in FEV1
    PCV: packed cell volume
    PEFR: peak expiratory flow rate
    PD35 sGaw: a 35% reduction in specific airway conductance
    PMNL: polymorphonuclear leucocyte
    WBC: white blood cell count

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

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

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

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

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

Inclusion criteria: exercise-induced bronchoconstriction

Participants: university students and the local community
Indiana, USA

Interventions

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

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

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

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

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskMatching placebo manufactured by the same company as the active treatment
Blinding of outcome assessment (detection bias)
All outcomes
Low riskMatching placebo manufactured by the same company as the active treatment
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo indication of withdrawals
Selective reporting (reporting bias)Unclear riskNo indication of reporting bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Al-Biltagi

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

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

Aliyali 2010Study did not compare vitamin C to placebo/no treatment
Bagnato 1999Study did not compare vitamin C to placebo/no treatment
Baumann 2005Study did not compare vitamin C to placebo/no treatment
Bede 2008Study did not compare vitamin C to placebo/no treatment
Belousova 2006Study did not compare vitamin C to placebo/no treatment
Bernorio 1996Study did not compare vitamin C to placebo/no treatment
Bime 2012Not a trial of vitamin C
Cakmak 2004AStudy did not compare vitamin C to placebo/no treatment
Carlsten 2011Study did not compare vitamin C to placebo/no treatment
Carlsten 2011aStudy did not compare vitamin C to placebo/no treatment
Chazan 1981Study not randomised
Covar 2010Study did not compare vitamin C to placebo/no treatment
Cristofalo 1999Study did not compare vitamin C to placebo/no treatment: combination intervention as vitamin C given with N-acetylcysteine
Cuomo 2004Study did not compare vitamin C to placebo/no treatment: intervention was a mixture of antioxidants
Daniliak 1995Study did not compare vitamin C to placebo/no treatment
Dauletbaev 2001Study did not compare vitamin C to placebo/no treatment; not randomised
De Lucia 1991Study did not compare vitamin C to placebo/no treatment
Dunstan 2007Study did not compare vitamin C to placebo/no treatment: combination intervention
Echazarreta 2000Study did not compare vitamin C to placebo/no treatment
Echazarreta 2005Study did not compare vitamin C to placebo/no treatment
Ensom 2003Study did not compare vitamin C to placebo/no treatment
Falk 2005Study did not compare vitamin C to placebo/no treatment
Greenough 2010Participants not diagnosed with asthma; a prophylactic study
Gvozdjakova 2005Study did not compare vitamin C to placebo/no treatment
Gvozdjakova 2005bStudy did not compare vitamin C to placebo/no treatment: combination intervention
Gvozdjakova 2006Study did not compare vitamin C to placebo/no treatment: combination intervention
Hernandez 2009Study did not compare vitamin C to placebo/no treatment: combination intervention
Hosseini 2001Study did not compare vitamin C to placebo/no treatment
Houdard 1969Study did not compare vitamin C to placebo/no treatment
Jabbari 2005Study did not compare vitamin C to placebo/no treatment
Jahnova 2002Study did not compare vitamin C to placebo/no treatment
Kiss 2000Study did not compare vitamin C to placebo/no treatment: combination intervention
Kligler 2011Study did not compare vitamin C to placebo/no treatment
Kolpakova 2007Study did not compare vitamin C to placebo/no treatment
Kongerud 2003Study did not compare vitamin C to placebo/no treatment
Kriukov 2003Study not focused on participants with asthma: evaluation of antioxidants in the prophylaxis of respiratory diseases in young servicemen
Kurth 2008Study did not compare vitamin C to placebo/no treatment
Labhe 2001Study did not compare vitamin C to placebo/no treatment
Lau 2004Study did not compare vitamin C to placebo/no treatment
Lipman, 1964Study did not compare vitamin C to placebo/no treatment
Lisitsa 2007Study did not compare vitamin C to placebo/no treatment
Liu 2003Study did not compare vitamin C to placebo/no treatment: intervention was a combination of vitamins C and E
Ma 2013Study did not compare vitamin C to placebo/no treatment: intervention was enhanced diet and antioxidants
Medvedeva 2002Study did not compare vitamin C to placebo/no treatment
Mohsenin 1983Not a randomised controlled trial
Murphy 2002Study did not compare vitamin C to placebo/no treatment
Neuman 1999Study did not compare vitamin C to placebo/no treatment
Neuman 2000Study did not compare vitamin C to placebo/no treatment
Nikitin 1993Study did not compare vitamin C to placebo/no treatment.
Olekhnovich 1982Study did not compare vitamin C to placebo/no treatment: the comparison was between vitamin E (intramuscular or orally) and lecithin versus lecithin, and there is no indication of randomisation
Onur 2011Study did not compare vitamin C to placebo/no treatment
Panahi 2012Study did not compare vitamin C to placebo/no treatment
Panina 2002Study did not compare vitamin C to placebo/no treatment
Pearson 2004Study did not compare vitamin C to placebo/no treatment
Peden 2005Study did not compare vitamin C to placebo/no treatment
Pennings 1999Study did not compare vitamin C to placebo/no treatment
Peters 2001Study did not compare vitamin C to placebo/no treatment
Prieto 1988Study did not compare vitamin C to placebo/no treatment
Ratanamaneechat 2010Study did not compare vitamin C to placebo/no treatment
Romieu 1998Study did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2001Study did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2002Study did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2002aStudy did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2003Study did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2003aStudy did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2004Study did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2004aStudy did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2004bStudy did not compare vitamin C to placebo/no treatment: combination intervention
Romieu 2004cStudy did not compare vitamin C to placebo/no treatment: combination intervention
Shaheen 2007Study did not compare vitamin C to placebo/no treatment
Shimizu 1996Study did not compare vitamin C to placebo/no treatment
Smith 2004Study did not compare vitamin C to placebo/no treatment
Szlagatys 2005Study did not compare vitamin C to placebo/no treatment
Ting 1983Not a randomised controlled trial
Trenca 2001Study did not compare vitamin C to placebo/no treatment: combination intervention
Tug 2007Study did not compare vitamin C to placebo/no treatment
Tunnicliffe 2003Study did not compare vitamin C to placebo/no treatment
Varshavskii 2003Study did not compare vitamin C to placebo/no treatment
Vazquez-Armenta 2012Not a trial of vitamin C, but of alpha-lipoic acid
Voelker 1997A summary report of a trial (almost certainly Trenca 2001) using a combination intervention
Voitsekhovskaia 2007Study did not compare vitamin C to placebo/no treatment
Wood 2007Study did not compare vitamin C to placebo/no treatment
Wood 2008Study did not compare vitamin C to placebo/no treatment
Wood 2012Study did not compare vitamin C to placebo/no treatment
Wood 2012aStudy did not compare vitamin C to placebo/no treatment
Yamamoto 2013Not a trial of vitamin C, but of N-acetylcysteine supplementation to people exposed to diesel exhaust

Characteristics of ongoing studies [ordered by study ID]

IRCT138904224359N1

Trial name or titleEffect of Vitamin E and C supplements on improving asthma
MethodsRandomised controlled trial
ParticipantsHistory of at least 1 year asthma, age 18 to 50 years
Exclusion criteria: suffering from diseases other than asthma, smoking, consumption of contraceptive pills
Interventions800 mg of vitamin C daily for 12 weeks versus placebo (study also includes a vitamin E condition and a vitamin E + vitamin C condition)
OutcomesAsthma severity and serum levels
Starting dateNovember 2010
Contact information

Dr Hesamodin Nabavi Zadeh

Yasuj University of Medical Sciences

Notes

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

Study results not posted at time of completion of this review

NCT01057615

Trial name or titleEffect of Fish Oil and Vitamin C on Exercise-Induced Bronchoconstriction and Airway Inflammation in Asthma
MethodsRandomised controlled trial
ParticipantsDiagnosis of asthma, based on medication use as well as history and symptoms as outlined in the NHLBI Guidelines for the Diagnosis and Management of Asthma
InterventionsFish oil versus vitamin C versus fish oil + vitamin C
OutcomesPulmonary function and exhaled nitric oxide to measure airway inflammation
Starting dateJanuary 2010
Contact information

Timothy D Mickleborough, PhD

Indiana University

Notes

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

Study results not posted at time of completion of this review

Ancillary