Omega-3 fatty acids for cystic fibrosis

  • Review
  • Intervention

Authors


Abstract

Background

Studies suggest that a diet rich in omega-3 essential fatty acids may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis.

Objectives

To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality and to identify any adverse events associated with supplementation.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Authors and persons interested in the subject of the review were contacted.

Date of last search: 08 July 2013.

Selection criteria

Randomised controlled trials in people with cystic fibrosis comparing omega-3 fatty acid supplements with placebo.

Data collection and analysis

Two authors independently selected studies for inclusion, extracted data and assessed the risk of bias of the studies.

Main results

The searches identified 14 studies; four studies with 91 participants were included. Two studies were judged to be at low risk of bias based on adequate randomisation but this was unclear in the other two studies. Three of the studies adequately blinded patients, however, the risk of bias was unclear in all studies with regards to allocation concealment and selective reporting.

Two studies compared omega-3 fatty acids to olive oil for six weeks. One study compared a liquid dietary supplement containing omega-3 fatty acids to one without for six months. One study compared omega-3 fatty acids and omega-6 fatty acids to a control (capsules with customised fatty acid blends) for three months. Only one short-term study (19 participants) comparing omega-3 to placebo reported a significant improvement in lung function and Shwachman score and a reduction in sputum volume in the omega-3 group. Another study (43 participants) demonstrated a significant increase in serum phospholipid essential fatty acid content and a significant drop in the n-6/n-3 fatty acid ratio following omega-3 fatty acid supplementation compared to control. The longer-term study (17 participants) demonstrated a significant increase in essential fatty acid content in neutrophil membranes and a significant decrease in the leukotriene B4 to leukotriene B5 ratio in participants taking omega-3 supplements compared to placebo.

Authors' conclusions

This review found that regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although evidence is insufficient to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. This review has highlighted the lack of data for many outcomes meaningful to people with or making treatment decisions about cystic fibrosis. A large, long-term, multicentre, randomised controlled study is needed to determine any significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Résumé scientifique

Acides gras Oméga 3 pour la mucoviscidose

Contexte

Les études suggèrent qu'un régime riche en acides gras essentiels Oméga 3 pourrait avoir des effets anti-inflammatoires bénéfiques pour les affections chroniques telles que la mucoviscidose.

Objectifs

Déterminer s’il existe des preuves que la supplémentation en acides gras polyinsaturés Oméga 3 réduit la morbidité et la mortalité et identifier tous les effets indésirables associés à la supplémentation.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d’essais du groupe Cochrane sur la mucoviscidose et les maladies génétiques comprenant des références identifiées lors de recherches exhaustives dans des bases de données électroniques. Nous avons également recherché manuellement des revues appropriées et des résumés d'actes de conférence. Les auteurs et les personnes pertinents pour le sujet de cette revue ont été contactés.

Date de la dernière recherche : 8 juillet 2013.

Critères de sélection

Essais contrôlés randomisés chez les patients atteints de mucoviscidose comparant la supplémentation en acides gras Oméga 3 à un placebo.

Recueil et analyse des données

Deux auteurs ont indépendamment sélectionné les études à inclure, extrait les données et évalué le risque de biais des études.

Résultats principaux

Les recherches ont identifié 14 études; quatre études portant sur 91 participants ont été inclues. Deux études ont été considérées comme présentant un faible risque de biais sur la base d'une randomisation adéquate, mais les deux autres études présentaient des risques de biais incertains. Trois des études ont convenablement évalué des patients en aveugle. Cependant, dans toutes les études, le risque de biais était incertain en ce qui concerne l'assignation secrète et le compte-rendu sélectif.

Deux études comparaient des acides gras Oméga 3 à l'huile d'olive pendant six semaines. Une étude comparait des compléments alimentaires liquides avec ou sans acides gras Oméga 3 pendant six mois. Une étude comparait des acides gras Oméga 3 et des acides gras Oméga 6 à un groupe témoin (sous gélules avec des mélanges d’acides gras) pendant trois mois. Seule une étude à court terme (19 participants) comparant des Oméga 3 à un placebo a rapporté des améliorations significatives de la fonction pulmonaire et du score Shwachman et une réduction du volume d'expectorations dans le groupe Oméga 3. Une autre étude (43 participants) montrait une augmentation significative dans le sérum phospholipide d’acide gras essentiel et une baisse significative du rapport des acides gras Oméga 3 et 6 à la suite d’une supplémentation en acides gras Oméga 3 par rapport au groupe témoin. L'étude à plus long terme (17 participants) montrait une augmentation significative des acides gras essentiels contenus dans les membranes neutrophiles et une baisse significative du rapport du leucotriène B4 au leucotriène B5 chez les participants prenant des suppléments riches en Oméga 3 par rapport à un placebo.

Conclusions des auteurs

Cette revue a découvert que la prise régulière de suppléments riches en Oméga 3 pourrait apporter certains bénéfices chez les patients atteints de mucoviscidose avec relativement peu d'effets indésirables, bien que les preuves soient insuffisantes pour apporter des conclusions définitives ou recommander l'utilisation systématique de ces suppléments chez les patients atteints de mucoviscidose. Cette revue a mis en évidence le manque de données pour de nombreux critères de jugement importants chez les patients atteints de mucoviscidose ou pour prendre des décisions sur le traitement à suivre lors de mucoviscidose. Une étude à grande échelle, à long terme, multicentrique et randomisée est nécessaire afin de déterminer l'effet thérapeutique significatif et d’évaluer l'impact de la gravité de la maladie, le dosage et la durée du traitement. Des chercheurs devraient évaluer la nécessité d'enzymes pancréatiques supplémentaires.

アブストラクト

囊胞性線維症に対するオメガ-3脂肪酸

背景

複数の研究で、オメガ-3必須脂肪酸を多く含む食事には、囊胞性線維症などの慢性疾患に対して有効な抗炎症効果を有する可能性があることを示唆している。

目的

オメガ-3多価不飽和脂肪酸の補充が罹病率および死亡率を減少させるとするエビデンスの有無を検討し、補充に伴うあらゆる有害事象を同定すること。

検索戦略

包括的な電子データベース検索で特定した参考文献リストからなるCochrane Cystic Fibrosis and Genetic Disorders Group’s Trials Registerを検索し、さらに関連性のある雑誌や会議議事録の抄録をハンドサーチした。本レビューの主題に関係のある著者等には連絡を取った。

最終検索日:2013年7月8日

選択基準

囊胞性線維症患者を対象としてオメガ-3脂肪酸の補充とプラセボを比較したランダム化比較試験(RCT)。

データ収集と分析

2名の著者が独立して研究を選択し、データを抽出し、研究のバイアスのリスクを評価した。

主な結果

本調査では14件の研究を同定し、このうち4件の91例を対象とした。 2件の研究は適切なランダム化によりバイアスのリスクが低いと判断したが、他の2件はリスク不明とした。 3件の研究では患者を適切に盲検化していたが、割りつけのコンシールメント(隠蔵化)、および 選択的な報告に関するバイアスのリスクが不明であった。

2件の研究では、オメガ-3脂肪酸とオリーブオイルを6週間にわたって比較した。 1件の研究では、オメガ-3脂肪酸を含有する液体栄養剤と含有しない液体栄養剤を6カ月間にわたって比較した。 1件の研究では、オメガ-3脂肪酸およびオメガ-6脂肪酸を、3カ月間にわたってコントロール(特製の脂肪酸混合物カプセル)と比較した。 オメガ-3とプラセボを比較した1件の短期研究(19例)のみが、omega-3 群における肺機能とShwachmanのスコアの有意な改善、および痰の減少を報告した。 もう1件の研究(43例)では、オメガ-3脂肪酸の補充とコントロールを比較して、血清リン脂質の必須脂肪酸量の有意な増加、およびn-6/n-3脂肪酸比の有意な減少を明らかにした。 長期研究(17例)では、オメガ-3の補充とプラセボを比較して、好中球膜の必須脂肪酸量の有意な増加、およびロイコトリエンB5に対するロイコトリエンB4の比率の有意な減少を明らかにした。

著者の結論

本レビューでは、オメガ-3の定期的な補充は有害作用が比較的少なく、囊胞性線維症患者に利益がある可能性を見出したが、確固たる結論を出したり、囊胞性線維症患者に日常的なサプリメントの摂取を推奨したりするにはエビデンスが不十分である。 本レビューでは、囊胞性線維症患者やそれを治療すると決めた人にとって重大な多くのアウトカムに関するデータが不足していることを明らかにした。 あらゆる有意な治療効果を検討し、疾患の重症度への影響、用量、および治療期間を評価するには、大規模で長期の多施設共同ランダム化比較試験が必要である。 将来的には、膵酵素を追加する必要性について検討すべきである。

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/)[2015.12.20]  《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

The use of omega-3 supplements in people with cystic fibrosis

Cycles of infection and inflammation are believed to worsen lung function in people with cystic fibrosis. Studies suggest that omega-3 fatty acids, such as those derived from fish oils, may be anti-inflammatory and may benefit many chronic inflammatory diseases including cystic fibrosis. This review includes four small studies with a total of 91 participants which compare omega-3 supplements to placebo. It was not clear if these studies had any risk of bias to the results. One short-term study reported that lung function and clinical status improved when taking omega-3 supplements. Patients also produced less sputum when taking omega-3 supplements. Two longer studies showed significant increases in essential fatty acid content of white blood cell membranes and serum phospholipids in people taking omega-3 supplements. Few adverse effects were reported in any of the studies. We conclude that regular omega-3 supplements may benefit people with cystic fibrosis with few adverse effects. However, there is not enough evidence from the four small studies included in this review to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. Larger and longer trials are needed to assess the clinical benefit of omega-3 supplementation and to determine the appropriate dosage.

Résumé simplifié

L'utilisation de suppléments riches en Oméga 3 chez les patients atteints de mucoviscidose

Les cycles d'infection et d'inflammation semblent aggraver la fonction pulmonaire chez les patients atteints de mucoviscidose. Des études suggèrent que les acides gras Oméga 3, tels que ceux provenant des huiles de poisson, pourraient être des anti-inflammatoires et pourraient être bénéfiques à de nombreuses maladies inflammatoires chroniques, notamment la mucoviscidose. Cette revue comprend quatre études de petite taille, avec un total de 91 participants qui ont comparé les suppléments riches en Oméga 3 à un placebo. Le risque de biais pour les résultats de ces études était incertain. Une étude à court terme a rapporté que la fonction pulmonaire et l'état clinique s’amélioraient lors d’une prise de suppléments riches en Oméga 3. Les patients produisaient également moins de glaires lors d’une prise de suppléments riches en Oméga 3. Deux études plus larges rapportaient une augmentation significative en acide gras essentiels des membranes cellulaires de globules blancs et des phospholipides sériques chez les patients prenant des suppléments riches en Oméga 3. Peu d'effets indésirables étaient rapportés dans les études. Nous avons conclu qu’une prise régulière de suppléments riches en Oméga 3 pourrait être bénéfique chez les patients atteints de mucoviscidose et avec peu d'effets indésirables. Cependant, les preuves, issues des quatre petites études incluses dans cette revue, sont insuffisantes pour pouvoir apporter des conclusions définitives ou recommander l'utilisation systématique de ces suppléments chez les patients atteints de mucoviscidose. Des essais plus larges et sur une plus longue durée sont nécessaires pour évaluer les effets bénéfiques cliniques de la supplémentation en Oméga 3 et déterminer la posologie appropriée.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Minist�re Fran�ais des Affaires sociales et de la Sant�, 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

Laički sažetak

Upotreba omega-3 masne kiseline kod oboljelih od cistične fibroze

Smatra se da ciklusi infekcija i upala pogoršavaju funkciju pluća u ljudi s cističnom fibrozom. Studije pokazuju da omega-3 masne kiseline, kao što su one izolirane iz ribljeg ulja, djeluju protuupalno i mogu pomoći u mnogim kroničnim upalnim bolestima uključujući i cističnu fibrozu. Ovaj Cochrane sustavni pregled uključio je četiri male studije s ukupno 91 ispitanika, a koje uspoređuju učinak dodataka s omega-3 masnim kiselinama i placeba. Nije jasno je li u tim studijama bilo opasnosti od pristranosti u dobivenim rezultatima. Jedna kratka studija tvrdi da su funkcija pluća i klinička slika poboljšane prilikom primjene dodataka s omega-3 masnim kiselinama. Pacijenti su također izlučivali manju količinu sputuma (ispljuvak). Dvije dulje studije pokazale su značajno povećanje količine esencijalnih masnih kiselina u membranama bijelih krvnih stanica i u serumskim fosfolipidima u ljudi koji su uzimali omega-3 dodatke. U svim je studijama zabilježen mali broj negativnih popratnih pojava. Zaključujemo da redovita primjena dodataka s omega-3 masnim kiselinama može pomoći ljudima s dijagnozom cistične fibroze uz mali broj nuspojava. Međutim, dokazi dobiveni iz četiri male studije, uključene u ovaj pregled, nisu dovoljni da bismo izveli čvrste zaključke ili preporuke o načinu korištenja ovih dodataka u ljudi s dijagnozom cistične fibroze. Za procjenu kliničke koristi te za određivanje odgovarajuće doze dodataka s omega-3 masnim kiselinama potrebne su veće i dulje studije.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Nikolina Gabelica
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

平易な要約

囊胞性線維症患者におけるオメガ-3サプリメントの使用

囊胞性線維症患者は、感染と炎症をくりかえすごとに肺機能が悪化すると考えられている。 複数の研究が、魚油などに含まれるオメガ-3脂肪酸には抗炎症作用があり、囊胞性線維症などの多くの慢性炎症性疾患に利益がある可能性を示している。 本レビューでは、オメガ-3サプリメントとプラセボを比較した、総計91例を対象とする4件の小規模研究について検討している。 これらの研究の結果にバイアスのリスクがあるかについては不明であった。 1件の短期研究では、omega-3サプリメントを摂取すると肺機能および臨床状態が改善すると報告した。 また、omega-3サプリメントを摂取すると、患者の痰の産生が減少した。 2件の長期研究では、omega-3サプリメントを摂取した人で、白血球細胞膜および血清リン脂質の必須脂肪酸量が有意に増加することを示した。 有害作用を報告した研究はほとんどなかった。 オメガ-3の定期的な補充には有害作用がほとんどなく、囊胞性線維症患者に利益がある可能性があると結論づける。 しかし、本レビューで対象とした4件の小規模研究では、確固たる結論を出したり、囊胞性線維症患者に日常的なサプリメントの摂取を推奨したりするにはエビデンスが不十分である。 オメガ-3の補充に関する臨床的利益を評価し、適切な用量を決定するためには、大規模な長期試験が必要である。

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/)[2015.12.20]  《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。

Background

Description of the condition

Cystic fibrosis (CF) is the most common life-threatening genetically inherited disease in the Caucasian population, affecting approximately one in 2500 births (CF Trust 2006). Pulmonary inflammation is believed responsible for the progressive loss of lung function that is the major cause of morbidity and mortality in CF (Konstan 1996). In response to lung infections, with organisms such as Pseudomonas aeruginosa, neutrophils (white blood cells) accumulate within the airways, producing proteolytic enzymes and oxidants which mediate the inflammatory response (Wilmott 2000). These neutrophils contribute to the thick and viscous secretions characteristic of CF, leading to mucus plugging of the smaller airways and further cycles of infection and inflammation. Treatment with anti-inflammatory drugs, including corticosteroids (Cheng 1999) and non-steroidal anti-inflammatory agents (Lands 2007) have been shown to have some benefit.

Description of the intervention

Mucus may also prevent pancreatic enzymes reaching the intestine and lead to malabsorption (especially fat malabsorption), diarrhoea and failure to thrive (Hunt 1985; Imrie 1975). The importance of growth and nutrition on survival in CF is well established (Corey 1998; Dodge 1988; Gaskin 1982). Dietary strategies concentrate upon providing a high energy and high protein diet, together with pancreatic enzyme replacement therapy. Despite this, however, there are many people with CF with sub-optimal nutritional absorption who continue to require fat soluble vitamins on a daily basis (Benabdeslam 1998).

How the intervention might work

It has been hypothesised that essential fatty acid deficiency may contribute to the development of respiratory disease in infants, even before clinical signs become apparent (Lloyd-Still 1996). Furthermore, animal models suggest that phenotypic changes in the CF-affected organs of lung, pancreas and intestine may be due to a defect in essential polyunsaturated fatty acid metabolism (Freedman 1999).

In humans, the polyunsaturated fatty acids (PUFA) linoleic acid (18:2 omega-6, or n-6) and alpha-linolenic (18:3 omega-3, or n-3) are 'essential' for normal growth and function; the only source is dietary. The nomenclature refers to their chemical structure.

Research into the omega-3 series of essential polyunsaturated fatty acids stems from the observation that the native Inuit (Eskimo) of Greenland (who consume a traditional diet rich in fish oils) have a very low incidence of some of the chronic inflammatory immune-based disorders commonly found in Europe and North America (Corcoran 1937; Osterud 1995). Fish oils are the richest dietary source of the metabolically active omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); however alternative and novel sources are currently being researched. Omega-3 fatty acids have been shown to play an important role in the integrity of cellular membranes, where they exert a profoundly anti-inflammatory response. Some of the beneficial effects of omega-3 fatty acids on inflammatory disease can be explained by a decrease in the production of pro-inflammatory metabolites from the omega-6 fatty acid family and an increase in the biologically less-active omega-3 end products (Gaszo 1989). Studies suggest that these fatty acids can exert anti-inflammatory effects which may benefit a range of chronic inflammatory diseases, including CF.

Why it is important to do this review

As has been discussed above, the absorption of fatty acids may be impaired in people with CF for a number of reasons and it is therefore possible that supplementation with omega-3 fatty acids may prove to be an effective treatment although details of dosage and administration remain to be elucidated. This is an update of previous versions of this review (Beckles-Willson 2002; Oliver 2010; Oliver 2011).

Objectives

To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality. To identify any adverse events associated with omega-3 polyunsaturated fatty acid supplementation.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), quasi-randomised trials, and cross-over trials.

Types of participants

People with CF, of any age and severity, diagnosed clinically and by sweat or genetic testing.

Types of interventions

Dietary supplementation of omega-3 essential fatty acids of any dosage, frequency and duration compared with placebo in people with CF. The supplements contain omega-3 fatty acids in the form of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or both. Studies were included if they compared the effect of this intervention with a placebo with low omega-3 or omega-6 fatty acid content, such as olive oil.

Types of outcome measures

Primary outcomes
  1. Number of respiratory exacerbations including:

    1. hospitalisations

    2. number of courses of antibiotics given (oral and intravenous) (moved from secondary outcomes in a post hoc change)

  2. Adverse events and dropouts

  3. Lung function including

    1. per cent predicted forced expiratory volume in one second (FEV1)

    2. forced vital capacity (FVC)

Secondary outcomes
  1. Quality of life

  2. Number of deaths

  3. Clinical variables including indices of growth or nutrition

  4. Bronchial responsiveness as measured by any provocation testing

  5. Biochemical markers of essential fatty acid status including plasma, platelet and erythrocyte (red blood cell) levels of EPA or DHA or both, plus omega-3 to omega-6 fatty acid ratio

Search methods for identification of studies

Electronic searches

Relevant studies were identified from the Group's cystic fibrosis trials register using the terms: omega-3 fatty acids.

The Group's Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching through the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.

In addition, the original review team performed electronic searches of CINAHL and EMBASE (from 1995 to April 2007) (Appendix 1). When the current review team took on this review, these searches were no longer run.

Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 08 July 2013.

Searching other resources

The reference lists of all studies identified have also been checked. The first author of each paper, and others with a known interest in the subject of the review, were contacted and invited to identify any other published or unpublished studies that might be relevant.

Data collection and analysis

Selection of studies

For the current version of the review, two authors (CO, HW) independently selected studies to be included in the review. If there had been any disagreement, they would have resolved this by discussion.

Data extraction and management

The two authors (CO, HW - originally TN'D and for the 2011 update NJ)) independently extracted data onto data acquisition forms. Authors discussed all stages of data extraction and interpretation and there were no disagreements to resolve.

They grouped outcome data into those measured at six and twelve weeks and at six months from baseline. For future updates of this review, if data are reported at any other time periods, they will consider reporting these as well.

Since hospitalisations are often used as a marker for respiratory exacerbations, if the authors include a study which reports hospitalisations in addition to or instead of exacerbations, they will include this information in the review under the first primary outcome ‘Number of respiratory exacerbations’.

Assessment of risk of bias in included studies

Two authors (CO, HW) assessed each trial using the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011).

The authors assessed the following domains as low risk of bias, unclear risk of bias or high risk of bias:

  1. randomisation (low risk - random number table, computer-generated lists or similar methods; unclear risk - described as randomised, but no details given; high risk - e.g. alternation, the use of case record numbers, and dates of birth or day of the week).

  2. concealment of allocation (low risk - e.g. list from a central independent unit, on-site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed opaque envelopes; unclear risk - not described; high risk - if allocation sequence was known to, or could be deciphered by the investigators who assigned participants or if the trial was quasi-randomised).

  3. blinding (of participants, personnel and outcome assessors) (low risk - e.g. there was no blinding, but we judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding, or at least outcome assessors were blinded; unclear risk - not described; high risk - e.g. no or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding, or blinding was attempted, but likely to have been broken).

  4. incomplete outcome data (Whether investigators used an intention-to-treat analysis) (low risk - e.g. no missing data, or missing data have been imputed using appropriate methods; unclear risk - e.g. insufficient reporting of attrition/exclusions; high risk - e.g. reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups).

  5. selective outcome reporting (low risk - e.g. the study protocol is available and all of the studies pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; unclear risk - e.g. insufficient information to permit judgement; high risk - e.g. not all of the study's pre-specified primary outcomes have been reported).

  6. other potential sources of bias (low risk - the study appears to be free of other sources of bias; unclear risk - e.g. insufficient information to assess whether an important risk of bias exists; high risk - e.g. had a potential source of bias related to the specific study design used, or had extreme baseline imbalance).

The authors compared assessments and resolved any inconsistencies by discussion.

Measures of treatment effect

For binary outcomes, the authors have calculated a pooled estimate of the treatment effect for each outcome across studies using the odds ratio (OR) (the odds of an outcome among treatment allocated participants to the corresponding odds among controls) and 95% confidence intervals (CIs). For continuous outcomes, they recorded either mean change from baseline for each group or mean post-treatment or intervention values and standard deviations for each group. Then, where appropriate, they have calculated a pooled estimate of treatment effect by calculating the mean difference (MD) and 95% CIs.

Unit of analysis issues

When conducting a meta-analysis combining results from cross-over studies the authors planned to use the methods recommended by Elbourne (Elbourne 2002). Limited availability of data would mean, we would only able to either use only the first-arm data or to treat the cross-over studies as if they are parallel studies. Elbourne states that this approach will produce conservative results as it does not take into account within-patient correlation (Elbourne 2002). Also each participant will appear in both the treatment and control group, so the two groups will not be independent. For the cross-over study included in the review, the authors were not able to access the first-arm data, and so they have treated the study as if it were parallel. If they are able to obtain a correlation co-efficient for future updates of this review, they will analyse the data more appropriately.

Dealing with missing data

For future updates of the review, in order to allow an intention-to-treat analysis, the authors will seek data on the number of participants by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow up.

The review authors have requested missing data from the primary investigators of two studies on several occasions (Koletzko 2000; Romano 1997); however, up until 2007 there was no response. They have therefore excluded these studies and do not plan to contact the authors of them again in the future.

Assessment of heterogeneity

For future updates of the review, if the authors are able to present combined data from a sufficient number of studies (at least four), they will test for heterogeneity between study results using the I2 statistic (Higgins 2003). For this measure of consistency of results across studies values range from 0% to 100%. They plan to categorise heterogeneity in a simple way such that if the I2 value is around 25% or below, they consider heterogeneity to be low; if the value is around 50%, they will consider it moderate; if the value is around 75% or above, they will consider it high.

Assessment of reporting biases

The review authors checked that the study investigators reported on all the outcomes they stated they planned to measure in the full publications of their studies. When the authors include a sufficient number of studies, they will attempt to assess whether this review is subject to publication bias by using a funnel plot. If they detect asymmetry, they will explore causes other than publication bias.

The review authors also checked for selective outcome reporting by comparing the protocols of the included studies (where available) to the final paper to ensure that the investigators reported all outcomes measured. If the study protocols were not available, the review authors compared the 'Methods' section to the 'Results' section in the final published paper.

Data synthesis

The review authors have analysed their data using a fixed-effect model. However, if for future updates they identify moderate or high degrees of heterogeneity, they will analyse the data using a random-effects model.

Subgroup analysis and investigation of heterogeneity

If the authors identify moderate or high degrees of heterogeneity and they are able to included sufficient studies in the review (at least four), they plan to investigate this by performing subgroup analyses (e.g. children versus adults and severity of existing lung disease).

Sensitivity analysis

If the authors identify moderate or high degrees of heterogeneity and they are able to include sufficient studies in the review, they also plan a sensitivity analysis comparing trials with or without cross-over design.

Results

Description of studies

Results of the search

The literature searches identified 14 studies. Four studies involving 91 participants with CF met the inclusion criteria (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006). One further paper has been published in abstract form at a conference and appears to meet our inclusion criteria (O'Sullivan 2011). The authors will be contacted for further information and for now the study has been listed under Studies awaiting classification. One study previously listed as ongoing has been completed and published; however on closer consideration this study was not eligible for inclusion in the review (Alicandro 2013). For one study, we did not have sufficient information to include it in past reviews and had contacted the authors for further information; no response was received therefore the study has been excluded (Starling 1988). Thus, a total of nine studies were excluded in this version of the review (Alicandro 2013; Christophe 1992; Katz 1996; Koletzko 2000; Kurlandsky 1994; Lloyd-Still 2006; Romano 1997; Starling 1988; van Biervliet 2008). Please also see the PRISMA diagram generated for this process (Figure 1).

Figure 1.

Study flow diagram.

Included studies

Trial characteristics

All four included trials were randomised controlled trials (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006). Trial duration varied from six weeks (Henderson 1994) to six months (Panchaud 2006). Likewise the number of participants varied from 12 (Henderson 1994) to 43 (Keen 2010).

Two studies were of parallel design (Henderson 1994; Keen 2010). Henderson split participants into four groups, two of which were in people without CF, we did not consider information from the groups without CF, as this was not an objective of the review. The two groups of participants with CF received either active supplement or placebo. We required additional data to analyse comparisons between the two CF groups; however, a reply from the author has not been received (Henderson 1994). Keen randomised participants to three groups: one group received a high omega-3 fatty acid blend (EPA and DHA); one group received a fatty acid blend containing predominantly omega-6 fatty acids (linoleic acid (LA), arachidonic acid (AA)); the control group received a high saturated fatty acid (SFA) blend. Only results of 35 participants who completed the study were used. We did not consider results from the group receiving the omega-6 fatty acid intervention as this was not an objective of the review (Keen 2010).

Two studies were of cross-over design (Lawrence 1993; Panchaud 2006). Lawrence found a carry-over effect despite a 12-week washout period, therefore, only the results from the 16 participants who completed the first six-week period of the study were used (Lawrence 1993). Panchaud did not include a washout period (Panchaud 2006).

Participants

All four studies included both children and adults (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006), although only one study included older adults, where the age range was stated as up to 41 years (Keen 2010). None of the studies were very large; the number of participants in each trial ranged from 12 (Henderson 1994) to 43 (Keen 2010). There were more males in three of the studies (Henderson 1994; Lawrence 1993; Panchaud 2006), but one more female than males in the Keen study (Keen 2010).

Three studies described participants as having pancreatic insufficiency (Henderson 1994; Keen 2010; Panchaud 2006). Two studies stated that participants were chronically infected with Pseudomonas aeruginosa (Keen 2010; Lawrence 1993). Keen additionally described participants as having severe mutations (Keen 2010).

Interventions

Two studies compared omega-3 fatty acids to olive oil control for a six-week treatment period (Henderson 1994; Lawrence 1993). One study compared omega-3 fatty acids to placebo control for a six-month treatment period (Panchaud 2006). Another study compared essential fatty acid supplementation to a placebo for a three-month treatment period (Keen 2010).

The dose and form of omega-3 fatty acids differed between the studies. Henderson used four 1 g capsules of fish oil, twice daily (containing a daily dose of 3.2 g eicosapentaenoic acid (EPA) and 2.2 g docosahexaenoic acid (DHA)) (Henderson 1994). Lawrence used fish oil capsules containing a daily total of 2.7 g EPA (Lawrence 1993). Panchaud used a liquid PUFA mixture containing 0.2 g EPA and 0.1 g DHA per 200 ml (Panchaud 2006). The volume of supplementation was determined according to participant's weight; intake ranged from 200 mg to 600 mg EPA and 100 mg to 300 mg DHA per day. Keen used a customised fatty acid blend containing 21.27 % mmol EPA and 6.99 % mmol DHA and participants received 50 mg per kg body weight per day (Keen 2010).

Outcomes

All four studies reported on adverse events (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006) and three on deaths (Henderson 1994; Lawrence 1993; Panchaud 2006). Two studies reported on changes in haematological indices (Henderson 1994; Lawrence 1993). Two studies presented data on serum fatty acid content (Henderson 1994; Keen 2010) and two on changes in in-vitro neutrophil chemotaxis (Lawrence 1993; Panchaud 2006). Two studies reported responses to inflammatory markers and nutritional indices (Keen 2010; Panchaud 2006); both Keen and Lawrence reported on lung function (Keen 2010; Lawrence 1993).

Excluded studies

Seven studies were excluded in the previous version of the review (Christophe 1992; Lloyd-Still 2006; Katz 1996; Kurlandsky 1994; Koletzko 2000; Romano 1997; van Biervliet 2008). One study used parenteral (via blood stream), not enteral (oral) supplementation with omega-3 fatty acids (Katz 1996). Four studies compared omega-3 supplementation with a large omega-6 fatty acid source, rather than a neutral placebo that contains relatively little omega-3 or omega-6 fatty acid such as olive oil. One study compared omega-3 supplementation with borache oil (Christophe 1992), two studies with sunflower oil (Kurlandsky 1994; van Biervliet 2008) and one study with corn/soy oil as placebo (Lloyd-Still 2006). Two studies were excluded on the basis of insufficient information and a lack of response from the studies' authors (Koletzko 2000; Romano 1997). For this review, a further two studies have been excluded (Alicandro 2013; Starling 1988). One study compared omega-3 supplementation with a large omega-6 fatty acid source (germ oil) rather than a neutral placebo containing relatively little omega-3 or omega-6 (Alicandro 2013). One study was excluded due to insufficient information and a lack of response from the author (Starling 1988).

Risk of bias in included studies

Please see the risk of bias summary presented in the figures (Figure 2).

Figure 2.

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

Allocation

Generation of randomisation sequence

All four studies were described as randomised but only two of them gave any details of the randomisation process. The Henderson study was randomised using a stratified randomised block design, whilst the Keen study was randomised using a random number generator (Henderson 1994; Keen 2010). We graded these studies as having a low risk of bias. The other two studies did not state the randomisation technique, so were graded as having an unclear risk of bias (Lawrence 1993; Panchaud 2006).

Concealment of allocation

Allocation concealment was graded as having an unclear risk of bias for all four studies as no details were provided in the primary papers (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006).

Blinding

All four studies were described as double blind, details were provided as follows. While the capsules in the Henderson study were also not described as identical, it was stated that the placebo olive oil capsules were flavoured to obtain a slight fish taste which the review authors agreed would be sufficient to blind participants (Henderson 1994). In the Lawrence study the treatment was administered as "identical olive oil capsules" (Lawrence 1993). In the third study the placebo treatment was not stated to be identical but it was described as the same liquid dietary supplement as the intervention but without the PUFA mixture (Panchaud 2006). We therefore attributed a low risk of bias to each of these three studies. In the Keen study, the appearance of the capsules was not described and 2 of 12 participants complained of a fish smell in the omega-3 treatment group, therefore the risk of bias in this study is unclear (Keen 2010).

Incomplete outcome data

In all four studies, withdrawals from the study were discussed with explanations (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006). Further details of these withdrawals are given in the Characteristics of included studies tables. Only one study included all participants in the data analysis, which was performed according to the intention-to-treat principle (Henderson 1994). This study was judged to have a low risk of bias. The other three studies did not employ this approach, but did describe withdrawals from the study (Lawrence 1993; Panchaud 2006; Keen 2010). In one study, some of the data from baseline and end of treatment in the placebo and treatment groups were excluded from analysis due to "technical reasons" which were not defined (Panchaud 2006). More than 15% of participants entering the trial were excluded from data analysis in one study (Keen 2010). We therefore assessed the Lawrence study as having a low risk of bias, but the Panchaud and Keen studies as having an unclear risk of bias.

Selective reporting

We have not been able to determine any selective reporting from the final publication of any of the included studies; however, we have not been able to compare the full study reports to the original study protocols (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006).

Other potential sources of bias

We have not been able to determine any other potential sources of bias in three of the included studies and judge there to be a low risk of bias (Henderson 1994; Lawrence 1993; Panchaud 2006). There is a potential source of bias in one of the studies that did not describe the actual dose of EPA and DHA given (Keen 2010).

Effects of interventions

Many of the protocol-defined outcomes in our review were not reported in any of the studies (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006); those clinical outcomes that were reported in one trial, published medians and ranges, which cannot be entered into the data tables and therefore these outcomes were not formally analysed within our review (Lawrence 1993).

Primary outcomes

1. Number of respiratory exacerbations

One study reported no difference in antibiotic use during the study compared with a similar time period in the previous year (Keen 2010). This outcome was not measured in three of the studies (Henderson 1994; Lawrence 1993; Panchaud 2006).

2. Adverse events and dropouts
a. Steatorrhoea

Two studies reported the need for participants in both the study and placebo groups, to increase their daily dose of pancreatic enzymes to prevent steatorrhoea (Henderson 1994; Lawrence 1993). This was not reported in the other two studies (Keen 2010; Panchaud 2006).

b. Diarrhoea

Two out of seven participants in the Henderson study stopped fish oil supplements because of diarrhoea; the same symptoms caused two out of five participants in the placebo group with CF to withdraw. There was no significant difference between the groups, odds ratio (OR) 0.60 (95% confidence interval (CI) 0.05 to 6.80) (Henderson 1994). Diarrhoea was not reported in the remaining three studies (Lawrence 1993; Panchaud 2006; Keen 2010).

c. Asthma

Only Lawrence reported this event; 3 out of 19 participants had an asthma exacerbation requiring corticosteroid therapy. These were excluded from analysis. The authors argued that corticosteroids affect essential fatty acid metabolism. One of the three participants was taking the active treatment (Lawrence 1993).

d. Stomach pains

Only Keen reported the incidence of stomach pains; five participants (treatment group not specified) of the 35 who completed the study complained of stomach pains (Keen 2010).

3. Lung function

Lawrence reported a significant increase in FEV1 in the EPA group (median 0.25 L, range 0.1 L to 0.85 L) compared with the placebo group (median -0.1 L, range -1.15 L to 0.24 L), P = 0.006. There was also a significant rise in FVC in the EPA group (median 0.6 L, range -0.1 L to 0.75 L) as compared with placebo (median 0 L, range -0.15 L to 0.35 L), P = 0.011 (Lawrence 1993). There were no significant differences in lung function reported in the Panchaud study, mean difference (MD) 2.00 (95% CI -19.11 to 23.11) (Analysis 1.2) (Panchaud 2006). No change in lung function was reported in the Keen study (Keen 2010); lung function was not measured in the Henderson study (Henderson 1994).

Secondary outcomes

1. Quality of life

This outcome was not measured in any of the studies.

2. Number of deaths

None occurred in any of the studies (Henderson 1994; Keen 2010; Lawrence 1993; Panchaud 2006)..

3. Clinical variables

Lawrence reported a significant fall in daily sputum volumes in the EPA group (median fall -10 ml, range -50 ml to 5 ml) compared with the placebo group (median fall 0 ml, range 0 ml to 10 ml), P = 0.015 (Lawrence 1993).

The Shwachman score is an overall clinical scoring system in CF, when an increase in the score indicates improvement in clinical conditions (Shwachman 1958). A significant increase in Shwachman score was also reported in the EPA group (median rise 5%, range -10% to 20%) compared with the placebo group (median rise 0%, range -10% to 0%), P = 0.034 (Lawrence 1993).

Clinical parameters were recorded in two studies as exploratory outcomes. No significant differences were found in anthropometric parameters in one study (Panchaud 2006). Panchaud reported a body mass index (BMI) SD score using the nine centiles for BMI in British girls and boys as normal value, and their associated co-efficient of variation. There was no significant difference between the PUFA group and the placebo group, MD 0.00 (95% CI -0.64 to 0.64) (Panchaud 2006). Significant weight gain was reported in the omega-3 fatty acid group and placebo group from baseline (Keen 2010). Only medians and ranges were reported which did not allow us to include the data in a meta-analysis; median difference (range) 1.75 kg (0.0 to 3.5, P = 0.001) and 1.0 kg (-2.0 to 5.5, P = 0.004) in the omega-3 fatty acid group and placebo group respectively (Keen 2010).

4. Bronchial responsiveness

This outcome was not measured in any of the studies.

5. Biochemical markers of essential fatty acid status

Panchaud reported a significant increase in EPA content of the neutrophil membrane in the omega-3 PUFA-supplemented group compared to the placebo group (mean (SD) 0.7 (0.6) compared to 1.6 (0.6) μmol %, P < 0.01) (Panchaud 2006). This is also significant in our analysis, MD 0.90 (95% CI 0.46 to 1.34). However, no significant differences were observed in DHA membrane concentration between the study groups, MD 0.10 (95% CI -0.45 to 0.65) (Panchaud 2006) (Analysis 1.4). The leukotriene B4 to leukotriene B5 ratio decreased significantly more in the omega-3 PUFA-supplemented group compared to placebo, MD -48.00 (95% CI -61.06 to -34.94) (Panchaud 2006) (Analysis 1.5).

Keen reported means and standard errors (which we converted to SDs to allow analysis in RevMan) on the EPA and DHA content of serum phospholipids and the n6 to n3 ratio (Keen 2010). There was a significant increase from baseline in EPA content of serum phospholipids in the omega-3 supplemented group compared to placebo, MD 0.70 (95% CI 0.42 to 0.98) (Keen 2010) (Analysis 1.5). Similarly, there was a significant increase in DHA content of serum phospholipids in the treatment group compared to placebo, MD 1.10 (95% CI 0.39 to 1.81) (Keen 2010) (Analysis 1.5). There was also a significant decrease in n-6/n-3 ratio in the omega-3 group compared to placebo MD -1.42 (95% CI -2.30 to -0.54) (Keen 2010) (Analysis 1.6). Further biochemical marker data were reported by Keen, but these were reported as medians and ranges which we were not able to analyse in RevMan. A significant decrease in the inflammatory markers, ESR and IL-8 was reported in the omega-3 fatty acid supplemented group. In the omega-3 fatty acid supplemented group, ESR decreased from a median (range) of 7 mm/h (3 to 26) at baseline to 6 mm/h (3 to 25) after three months (P=0.05). After supplementation with omega-3 fatty acids, IL-8 decreased significantly from a median of 17.5 pg/ml (<0.8 to 35) to 9.3 pg/ml (0.8 to 22) (P = 0.0017) after three months (Keen 2010).

Discussion

The most notable feature highlighted by this review was the lack of data for many of the outcomes likely to be meaningful to people with or making treatment decisions about CF. Information was limited on a number of the primary outcomes that we would have expected to find in a randomised controlled trial. One short-term study with 16 participants reported benefits from omega-3 supplementation with improved FEV1, FVC and Schwachman score (Lawrence 1993). Another, longer-term study with 17 participants found omega-3 supplementation improved fatty acid status within cellular membranes, which may exert anti-inflammatory effects (Panchaud 2006). The Lawrence study also indicated an improvement in sputum volumes with omega-3 supplements, although it should be noted that the treatment group had a higher median sputum volume at baseline and therefore had more scope for improvement (Lawrence 1993). The Keen study also showed that short-term supplementation with omega-3 fatty acids favourably influences serum phospholipid fatty acid pattern and inflammatory markers in people with CF (Keen 2010).

The risks of bias varied across studies and domains. Two of the four included studies had a low risk of bias from sequence generation, but for the remaining two this was unclear; all of the studies had an unclear risk of bias due to allocation concealment. The authors judged all but one of the studies to have adequately blinded patients by giving control oils that were sufficiently similar to the active fish oils that no difference could be observed. Two of the four studies had a low risk of bias from incomplete outcome data as either all patients were included in the analysis or withdrawals clearly accounted for; the remaining two studies had an unclear risk of bias for this domain. All studies were judged to have an unclear risk of bias due to selective reporting as the original study protocols were not accessible. Finally, one study was judged to be at high risk of bias as it did not report the actual doses of treatment or control oils given.

On a practical point, two of the studies reported that people with CF needed to increase their intake of pancreatic enzymes in order to control symptoms of steatorrhoea (Henderson 1994; Lawrence 1993). The authors attributed this to the increased fat intake of both the fish oil and the placebo, olive oil (Henderson 1994; Lawrence 1993). Future researchers should note the need for additional pancreatic enzymes. Panchaud reported that participants did not increase pancreatic enzyme dose, which was most likely due to the lower level of omega-3 supplementation relative to the other two studies (200 mg to 600 mg EPA compared to 2.7 g and 3.2 g EPA in the Lawrence and Henderson studies respectively) (Panchaud 2006). Participants in the Keen study did increase their pancreatic enzyme supplements for the trial period. No side effects of diarrhoea or steatorrhoea were reported, although stomach pains were reported (Keen 2010).

There is no information available about the distribution of the data in any of the studies. These data may be highly skewed because of the small number of participants and so the results are not generalisable to other people with CF.

At present, we are unaware of any published data available about the effects of long-term supplementation or appropriate dosage of omega-3 fatty acids.

Authors' conclusions

Implications for practice

We conclude that the limited evidence from these four small studies is not adequate to support any change in clinical practice. The reported benefits, from the use of omega-3 fatty acid supplements, are from small studies in which the risk of bias is unclear and hence cannot be used to make recommendations for practice (Henderson 1994; Lawrence 1993; Panchaud 2006; Keen 2010).

There is little evidence to recommend that people with CF supplement or modify their dietary intake of fish oil in order to improve their CF control. Equally, there is an absence of evidence that they are at risk if they do so. Although the data are sparse, it would seem prudent for people with CF taking fish oil supplements to take no more than the recommended dose and to increase their pancreatic enzymes.

Implications for research

Further large, long-term, multicentre, randomised, controlled studies are needed in order to determine if there is a significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Acknowledgements

We gratefully acknowledge the assistance of Sheffield Children's Hospital Appeal funding, which has supported the undertaking of the initial version of this review.

We acknowledge the considerable input into the production of the protocol and initial review of the former lead author, Naomi Beckles-Wilson, and co-authors Dr Mark Everard and Tracy N'Diaye.

Data and analyses

Download statistical data

Comparison 1. Omega-3 fatty acids versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Adverse events1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 Diarrhoea and eructation1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Lung function1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 FEV1 % predicted1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 FVC % predicted1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Clinical variables1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Change in body mass index1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Biochemical markers of essential fatty acid status (EPA & DHA content)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Change in EPA % content of neutrophil membrane1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Change in DHA % content of neutrophil membrane1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Biochemical markers of essential fatty acid status (B4/B5 ratio)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Leukotriene B4 to leukotriene B5 ratio1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Biochemical markers of essential fatty acid status (EPA & DHA content)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Change in EPA content of serum phospholipids1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Change in DHA content of serum phospholipids1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Biochemical markers of essential fatty acid status (n6/n3)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Change in n6/n3 ratio content of serum phospholipids1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 1 Adverse events.

Analysis 1.2.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 2 Lung function.

Analysis 1.3.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 3 Clinical variables.

Analysis 1.4.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 4 Biochemical markers of essential fatty acid status (EPA & DHA content).

Analysis 1.5.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 5 Biochemical markers of essential fatty acid status (B4/B5 ratio).

Analysis 1.6.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 6 Biochemical markers of essential fatty acid status (EPA & DHA content).

Analysis 1.7.

Comparison 1 Omega-3 fatty acids versus placebo, Outcome 7 Biochemical markers of essential fatty acid status (n6/n3).

Appendices

Appendix 1. Search strategies: EMBASE & CINAHL (1995 to April 2007)

Search terms
1. cystic fibrosis
2. essential fatty acids
3. diet
4. nutrition
5. fish oil
6. omega-3 fatty acid
7. n-3 fatty acid
8. eicosapentaenoic acid
9. epa
10.docosahexaenoic acid
11. dha

What's new

DateEventDescription
26 November 2013New citation required but conclusions have not changed

Nikki Jahnke has stepped down as co-author and Helen Watson is the new co-author on this review.

No new studies were included in this update of the review, therefore our conclusions remain the same.

26 November 2013New search has been performedA search of the Cystic Fibrosis & Genetic Disorders Group's Cystic Fibrosis Trials Register identified four new references. Three of these related to a study previously listed as ongoing, including the full paper (Alicandro 2013); and the fourth was a reference to an abstract of a new study. We have excluded the Alicandro study and the new abstract by O'Sullivan is listed as awaiting classification until we can obtain further information to allow us to include or exclude the study (O'Sullivan 2011).

History

Protocol first published: Issue 3, 2000
Review first published: Issue 3, 2002

DateEventDescription
10 March 2011New search has been performedA search of the Cystic Fibrosis Trials Register identified eleven new references to six trials which were potentially eligible for inclusion in the review. Three of these studies were excluded (Christophe 1992; Lloyd-Still 2006; van Biervliet 2008). One study was listed as awaiting assessment (Starling 1988). One study was listed as ongoing (Alicandro 2013). One study was included in the review (Keen 2010).
10 March 2011New citation required but conclusions have not changed

The title of the review has been amended removing 'from fish oils' and hence expanding the different potential sources of omega-3 fatty acids to be considered for this review.

One of the authors, Dr Mark Everard, has stepped down from the review team. A new author, Nikki Jahnke, joined the team for this update. Another author, Tracy N'Diaye, has not been actively involved in this update of the review and is currently not listed on the citation.

11 November 2009AmendedContact details updated.
12 August 2009AmendedContact details updated.
13 June 2008New search has been performedA search of the Group's Cystic Fibrosis Trials Register did not identify any studies potentially eligible for inclusion in the review.
2 June 2008AmendedConverted to new review format.
22 August 2007New search has been performedOne new study has been included in the review (Panchaud 2006) and the methodological quality of the study was assessed using the criteria suggested by Jüni (Jüni 2001).
22 August 2007AmendedThe methodological quality of the two previously included studies were also re-assessed using the criteria described by Jüni (Jüni 2001).

Two studies previously listed as 'Awaiting assessment' have been excluded from the review on the basis of insufficient information and lack of response from the primary investigators.

The previous 'Synopsis' has been replaced by a 'Plain Language Summary'.

The outcome measures have been re-ordered, a number of these have been moved from primary outcomes to secondary outcomes.

Given that the review has been substantively updated and following the death of the previous lead author, Naomi Beckles-Wilson, her name has been removed from the byline of this review and her contribution recognised in the 'Acknowledgements' section.
22 August 2007New citation required and conclusions have changedSubstantive amendment
10 November 2004New search has been performedNo new references were found in the latest search of the Group's trials register.
26 November 2003New search has been performedNo new references were found in the latest search of the Group's trials register.
1 March 2002New search has been performedHandsearching of several ASPEN/ESPEN and BAPEN conference proceedings were carried out by a contributor to the Group for another review. This search was not thorough. However, some RCTs were identified, including one of the references included in this review (Manner 1993), identified from the ASPEN proceedings.

Contributions of authors

Original review
NBW formulated the question, was primarily responsible for development of the protocol and writing the original review. NBW and TN'D selected the studies, graded the quality and extracted the data.

ME was consulted at all stages of the review, providing advice and support when needed.

Updates from 2007
Following the death of the lead author NBW, CO has taken on the lead and acts as guarantor of the review from 2007. The methodological quality of the included studies was re-assessed by CO using the criteria described by Jüni (Jüni 2001) and then again to reflect the current Cochrane guidelines with regards to risk of bias.

At the update in 2011, ME stepped down from the review team and a new author, NJ joined the team. For this update also, TN'D has not been actively involved and her name does not currently appear on the citation.

At the update in 2013, NJ stepped down from the review team and a new author, HW, joined the team.

Declarations of interest

None known.

Sources of support

Internal sources

  • Sheffield Children's Hospital Appeal, UK.

External sources

  • No sources of support supplied

Differences between protocol and review

The former secondary outcome "number of courses of antibiotics given (oral and intravenous)" has been moved to a sub-outcome of the primary outcome "Number of respiratory exacerbations" as often respiratory exacerbations are defined by the courses of antibiotics prescribed.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Henderson 1994

Methods6-week, parallel design trial with 4 arms. Randomised using stratified randomised block design.
Participants

12 children and young adults diagnosed with CF and pancreatic insufficiency (mean (SD) age 12.2 (5.4) years) on genotype or sweat test and able to complete the spirometric tests. Also pancreatic insufficient and plasma vitamin A and E levels within the normal range.

13 gender and age-matched people, without CF (mean (SD) age 13.4 (6.3) years), 7 male, 6 female.

Interventions8 x 1 g capsules fish oil (4 capsules twice daily) (3.19 g EPA and 2.21 g DHA) compared with olive oil placebo capsules flavoured to obtain a slight fish taste, over 6 weeks.
OutcomesOutcomes included in this review:
number of people experiencing adverse events;
number of deaths;
changes in haematological indices;
changes in plasma and erythrocyte levels of EPA and DHA and EPA/AA ratio.
NotesSignificantly lower plasma n-6 fatty acids (linoleic acid and arachidonic acid) noted at baseline in participants with CF compared with the group who did not have CF.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised using a stratified randomised block design.
Allocation concealment (selection bias)Unclear riskNot discussed in paper.
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blind - while the capsules were not described as identical, it was stated that the placebo olive oil capsules were flavoured to obtain a slight fish taste which we agreed would be sufficient to blind participants.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals from the study were discussed with explanations (20 out of 25 randomised participants completed the study). Study included all participants in the data analysis, which was performed according to the intention-to-treat principle.
Selective reporting (reporting bias)Unclear riskProtocol not available for comparison, so unable to definitely eliminate selective reporting.
Other biasLow riskNo additional bias identified.

Keen 2010

Methods3-month, parallel design trial. Randomised using random number generator.
Participants43 children and adults with "severe" CF mutations (age range 7 to 41 years); 35 participants completed the study; 18 female, 17 males. 20 participants were chronically infected with Pseudomonas aeruginosa. 8 participants discontinued the study and the inclusion parameters of these patients did not differ from those who completed the study.
Interventions50 mg/kg per day of 1 of 3 fatty acid blend capsules over 3 months; group A capsules contained predominantly EPA and DHA, group C contained high proportion of linoleic acid and arachidonic acid and group B (placebo) contained predominantly saturated fatty acids. Participants increased their pancreatic enzymes by 10% to 20% to maintain normal stools.
OutcomesOutcomes included in this review:
changes in serum phospholipid essential fatty acid content;
changes in inflammatory markers;
adverse effects;
BMI and weight;
lung function;
medical treatment.
NotesActual dose of EPA and DHA administered not described.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised using random number generator.
Allocation concealment (selection bias)Unclear riskNot discussed in paper.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind; treatment was assumed to be administered as identical capsules; however, 2 participants complained of fish smell in group A.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk45 participants were initially randomised, but 2 were excluded due to acute exacerbations and therefore did not enter the study. Withdrawls from study were described: 35 participants completed the study; 8 discontinued because of low compliance (n = 4), stomach pains (n = 2) and weight gain (n = 2). Study did not include all participants in the data analysis, therefore data was not analysed as 'intention to treat'.
Selective reporting (reporting bias)Unclear riskProtocol not available for comparison, so unable to definitely eliminate selective reporting.
Other biasHigh riskThe lack of information on dosage is a potential risk of bias.

Lawrence 1993

Methods6-week cross-over study planned. However, significant carry-over effect of treatment noted at end of study, therefore analysis restricted to the first 6-week treatment period.
Participants19 adolescents and adults diagnosed with CF on genotype, sweat test, or clinically (median age 17 years, age range 12 years to 26 years), 11 male, 5 female.
3 participants excluded due to requiring a course of corticosteroids for asthma attacks.
All were recruited within 4 weeks of hospitalisation for acute respiratory infection and judged to be in optimum condition for disease stage. All were Pseudomonas aeruginosa colonised and produced at least 5 ml sputum daily.
Initial randomisation gave groups with comparable baseline characteristics except for age. The treatment group also had significantly greater weight, peripheral blood leucocyte and neutrophil counts.
Interventions2.7 g EPA daily compared with identical olive oil placebo capsules, over 6 weeks.
OutcomesOutcomes included in this review:
number of people experiencing adverse events;
number of deaths;
changes in haematological and growth indices;
changes in lung function;
changes in in-vitro neutrophil chemotaxis.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDid not state the randomisation technique.
Allocation concealment (selection bias)Unclear riskNo details were provided in the primary paper.
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blind, treatment was administered as 'identical olive oil capsules'.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOf the 19 participants recruited, 3 participants were excluded from the study before analysis due to corticosteroid treatment during the first treatment period.
Selective reporting (reporting bias)Unclear riskProtocol not available for comparison, so unable to definitely eliminate selective reporting.
Other biasLow riskNo additional bias identified.

Panchaud 2006

  1. a

    AA: arachidonic acid
    CF: cystic fibrosis
    DHA: docosahexaenoic acid
    EPA: eicosapentaenoic acid
    GLA: gamma-linolenic acid
    PUFA: polyunsaturated fatty acids
    SD: standard deviation
    STA: stearidonic acid

Methods2 x 6-month period, cross-over trial with no washout period.
Participants17 children and young adults with CF and pancreatic insufficiency (mean (SD) age 18 (9) years)), 10 male and 7 female. 1 participant discontinued study after 8 months for personal convenience.
InterventionsLiquid dietary supplement containing PUFA mixture (EPA, DHA, GLA and STA) compared with liquid dietary supplement without PUFA mixture over 6 months. Volume of supplementation was determined according to participant's weight; intake ranged from 100 mg - 300 mg DHA and 200 mg - 600 mg EPA per day.
OutcomesOutcomes included in this review:
number of people experiencing adverse events;
number of deaths;
changes in peripheral blood neutrophil membrane composition;
in vitro neutrophilic response to inflammatory stimuli;
changes in in-vitro neutrophil chemotaxis.
NotesRelatively low daily dose EPA and DHA compared to previous clinical trials.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDid not state the randomisation technique.
Allocation concealment (selection bias)Unclear riskNo details were provided in the primary paper.
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blind, placebo treatment was not stated to be identical but it was described as the same liquid dietary supplement as the intervention but without the PUFA mixture.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk17 participants were randomised; 16 completed the study and one discontinued after 8 months for personal convenience.
Due to technical reasons, data could not be analysed for several participants' samples at baseline (4 participants), after treatment with omega-3 supplements (1) and after placebo (2).
High possibility of attrition bias since the analysis of the final cohort differed from the original cohort.
Selective reporting (reporting bias)Unclear riskProtocol not available for comparison, so unable to definitely eliminate selective reporting.
Other biasLow riskNo additional bias identified.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Alicandro 2013Omega 3 supplementation compared with large omega-6 fatty acid source (germ oil) rather than a neutral placebo that contains relatively little omega-3 or omega-6 fatty acid (olive oil).
Christophe 1992Omega-3 supplementation compared with large omega-6 fatty acid source (borache oil) rather than a neutral placebo that contains relatively little omega-3 or omega-6 fatty acid (olive oil).
Katz 1996Parenteral (via blood stream), not enteral (oral) supplementation with omega-3 fatty acids.
Koletzko 2000Eligibility unclear, attempts made to contact author for further information, but no response received.
Kurlandsky 1994Omega-3 supplementation compared with large omega-6 fatty acid source (sunflower oil) rather than a neutral placebo that contains relatively little omega-3 or omega-6 fatty acid (olive oil).
Lloyd-Still 2006Omega-3 supplementation compared with large omega-6 fatty acid source (corn/soy) rather than a neutral placebo that contains relatively little omega-3 or omega-6 fatty acid (olive oil).
Romano 1997Eligibility unclear, attempts made to contact author for further information, but no response received.
Starling 1988Eligibility unclear, attempts made to contact author for further information, but no response received.
van Biervliet 2008Omega-3 supplementation compared with large omega-6 fatty acid source (sunflower oil) rather than a neutral placebo that contains relatively little omega-3 or omega-6 fatty acid (olive oil).

Characteristics of studies awaiting assessment [ordered by study ID]

O'Sullivan 2011

  1. a

    AA: arachidonic acid
    CF: cystic fibrosis
    CXR: chest x-ray
    DHA: docosahexaenoic acid
    IRT: immunoreactive trypsin

Methods12-month parallel trial.
Participants83 infants diagnosed with CF in the first 2 months of life who were exclusively bottle fed.
InterventionsInfant formula containing DHA and AA compared to standard infant formula containing no DHA or AA over 12 months.
Outcomes

Weight and height at 1 year of age;

Serum DHA and AA levels, IRT and alpha feto-protein levels;

Brasfield CXR score.

NotesFecal elastase measured at screening and then monthly for the study duration.

Ancillary