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Influenza vaccine for children and adults with bronchiectasis

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the effectiveness of influenza vaccine as routine management in children and adults with bronchiectasis in (a) reducing the severity and frequency of respiratory exacerbations and (b) pulmonary decline

Background

Bronchiectasis, previously termed an 'orphan disease' is increasingly recognized as a major cause of respiratory morbidity especially in developing countries (Karadag 2005, Karakoc 2001) and in pockets of affluent countries (Callahan 2002, Edwards 2003). The underlying aetiology of bronchiectasis varies from post recurrent respiratory infections to rare immune deficiencies. However, bronchiectasis is also a common pathway for a variety of diseases. Thus, the presence of bronchiectasis is also increasingly recognised in common (e.g. chronic obstructive pulmonary disease (COPD) (Patel 2004) and uncommon respiratory diseases (e.g. bronchiolitis obliterans (Chang 1998) and sarcoidosis (Lewis 2002)) as well non primary respiratory (e.g. autoimmune) diseases. When bronchiectasis is present with another underlying disorder, it increases the morbidity and mortality of the underlying diseases (Patel 2004, Lewis 2002, Keistinen 1997). For example, in diseases like COPD the presence of bronchiectasis has been reported in 29‐50% (Patel 2004, O'Brien 2000) of cohorts and when present, increases the severity (Patel 2004) and frequency (Gursel 2006) of respiratory exacerbations. Thus, management of the symptoms and severity of bronchiectasis is important.

The dominant symptoms and signs of bronchiectasis are productive or wet cough, dyspnoea on exertion and presence of other respiratory signs (clubbing, chest wall deformity, respiratory noises such as wheeze or crepitations on auscultation). In the long term, pulmonary decline may occur (Keistinen 1997, Twiss 2006). Like patients with COPD, children and adults with bronchiectasis also suffer from recurrent acute exacerbations, some of whom require hospitalised treatment. Effective management regimes for bronchiectasis would reduce the frequency or severity of respiratory exacerbations, and/or the long term pulmonary decline. Based on Cole's 'vicious circle hypothesis', microbial colonization/infection is important in the pathophysiology of bronchiectasis as it leads to bronchial obstruction and a normal or exaggerated inflammatory response (Cole 1986). Thus treatment modalities that prevent or limit respiratory infections would prevent or reduce respiratory decline. Respiratory infections also increase morbidity and reduces quality of life in those suffering bronchiectasis (Martinez‐Garcia 2005). Therotically prevention of influenza through the use of influenza vaccine would be a useful routine management modality for children and adults with bronchiectasis. Indeed yearly influenza vaccination is recommended for patients with bronchiectasis (Chang 2002).

Both inactivated and live attenuated (LAIV) influenza vaccine are now available. Both are annually modified trivalent vaccines with reassortants for each of the major circulating influenza viruses: A (H3N2), A (H1N1) and B and administered annually (Orenstein 2005). The efficacy is directly related to the degree of concordance between the virus strains included in the vaccine and the strains circulating in the community. The inactivated vaccine contains killed viruses and is administered via intramuscular route and is recommended in those 6 months and older, in healthy individuals and those with chronic medical conditions. The newer LAIV contains live virus with potential for replication and is currently only recommended in healthy individuals aged between 5 and 49 years (Orenstein 2005), thus contraindicated in those with bronchiectasis.

Current recommendations for inactivated influenza vaccination includes adults aged 65 years and over, those in residential care and health care workers and also all adults and children with chronic illness, particularly cardiac and pulmonary diseases. Influenza vaccine has been estimated to be 70‐90% effective in preventing influenza in healthy individuals under 65 years of age, with some reduction in efficacy in the elderly (Orenstein 2005). A meta‐analysis of 20 cohort studies involving both nursing home populations and community‐dwelling elderly estimated effectiveness of 56%, 53%, 50% and 68% for preventing respiratory illness, pneumonia, hospitalisation and death, respectively. Efficacy in children is less known, though estimated to have 56% or more protection (Orenstein 2005, Fukuda 2004). In people with asthma the effect of influenza vaccine in preventing asthma exacerbations related to influenza is uncertain (Cates 2003). In another Cochrane review, Poole and colleagues concluded that influenza vaccination reduces respiratory exacerbations in patients with COPD (Poole 2006). The effect size described in the meta‐analysis of RCTs was similar to that of observational studies (Poole 2006).

In contrast to availability of data on the triggers of exacerbations for asthma and COPD, that for bronchiectasis exacerbations has not been studied. It is unknown what proportion of bronchiectasis exacerbations are triggered by an infection and if so, what infection. Thus the effectiveness of influenza vaccination for bronchiectasis may be different to that for asthma and COPD. Also, influenza vaccination may cause local and systemic adverse events and also cause a flu‐like illness (Poole 2006). A systematic review of the effectiveness of influenza for children and adults with bronchiectasis would be beneficial to guide clinical practice.

Objectives

To evaluate the effectiveness of influenza vaccine as routine management in children and adults with bronchiectasis in (a) reducing the severity and frequency of respiratory exacerbations and (b) pulmonary decline

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials using influenza vaccine in patients with bronchiectasis

Types of participants

Children or adults with bronchiectasis (defined clinically or radiologically)
Exclusion criteria: Participants with other diseases where bronchiectasis is not present

Types of interventions

All randomised controlled trials with at least one annual influenza vaccine. All types of influenza vaccines will be included.

Types of outcome measures

Attempts will be made to obtain data on at least one of the following outcome measures:

(A) for short term effectiveness (12 months or less)
a) proportions of participants who had respiratory exacerbations
b) proportions of participants who were hospitalised,
c) total numbers of days with respiratory symptoms
d) total number of hospitalised days
e) mean difference in bronchiectasis severity control (QOL, cough diary, Likert scale, visual analogue scale, level of interference of cough, cough diary, etc),
f) proportions experiencing adverse effects of the intervention, (e.g. local reaction, exacerbation immediately post vaccination, systemic effects (myalgia, fever, fatigue), Gullian‐Barre syndrome, etc)
Outcomes (a) to (e) will be examined globally as well as also specifically to proven influenza infections (from swabs or rising titres)

(B) for medium to long term outcomes (>1 year)
g) radiology scores (high resolution computed tomography scans or chest radiograph)
h) lung function
i) clinical indices of bronchiectasis severity control (QOL, cough diary, Likert scale, visual analogue scale, level of interference of cough, etc),
j) relevant airway markers of inflammation.

Search methods for identification of studies

The following topic search strategy will used to identify the relevant randomised controlled trials listed on the electronic databases:

("bronchiectasis" OR "suppurative lung disease", all as (textword) or (MeSH )) AND ("vaccin* AND "influenza"; all as (textword) or (MeSH ) )

Trials will be identified from the following sources:
1. The Cochrane Airways Group Specialised Trials Register
2. The Cochrane Central Register of Controlled Trials (CENTRAL)
3. MEDLINE (1966 to present). Topic search strategy combined with the RCT search filter as outlined in the Airways Group module.
4. OLDMEDLINE (1950 to 1965). Topic search strategy combined with the RCT search filter as outlined in the Airways Group module.
5. EMBASE (1980 to present).Topic search strategy combined with the RCT search filter as outlined in the Airways Group module.
6. The list of references in relevant publications.
7. Written communication with the authors of trials included in the review if necessary.
8. Pharmaceutical companies that manufacture influenza vaccines.

Data collection and analysis

Retrieval of studies: From the title, abstract, or descriptors, two reviewers will independently review literature searches to identify potentially relevant trials for full review. Searches of bibliographies and texts will be conducted to identify additional studies. From the full text using specific criteria, the same two reviewers will independently select trials for inclusion. Agreement will be measured using kappa statistics. Disagreement will be resolved by consensus.

Trials that satisfy the inclusion criteria will be reviewed and the following information recorded: study setting, year of study, source of funding, patient recruitment details (including number of eligible subjects), inclusion and exclusion criteria, other symptoms, randomisation and allocation concealment method, numbers of participants randomised, blinding (masking) of participants, care providers and outcome assessors, dose and type of intervention, duration of therapy, co‐interventions, numbers of patients not followed up, reasons for withdrawals from study protocol (clinical, side‐effects, refusal and other), details on side‐effects of therapy, and whether intention‐to‐treat analyses were possible. Data will be extracted on the outcomes described previously. Further information will be requested from the authors where required.

Studies included in the review will undergo quality assessment performed independently by 2 reviewers. Four components of quality will be assessed:
1. Allocation concealment. Trials will be scored as: Grade A: Adequate concealment, Grade B: Unclear, Grade C: Clearly inadequate concealment. (Grade A = high quality).
2. Blinding. Trials will be scored as: Grade A: Participant and care provider and outcome assessor blinded, Grade B: Outcome assessor blinded, Grade C: Unclear, Grade D: No blinding of outcome assessor (Grade A, B = high quality).
3. Reporting of participants by allocated group. Trials will be scored as: Grade A: The progress of all randomised children in each group described, Grade B: Unclear or no mention of withdrawals or dropouts, Grade C: The progress of all randomised children in each group clearly not described. (Grade A = high quality).
4. Follow‐up. Trials will be scored as: Grade A: Outcomes measured in >90% (where withdrawals due to complications and side‐effects are categorised as treatment failures), Grade B: Outcomes measured in 80‐90%, Grade C: Unclear, Grade D: Outcomes measured in <80%. (Grade A = high quality).
While only the allocation concealment quality assessment will be displayed in the meta‐analysis figures, all assessments will be included in the "Characteristics of included studies" table. Inter‐reviewer reliability for the identification of high quality studies for each component will be measured by the Kappa statistic.

Each study will also be assessed using a 1 to 5 scale described by Jadad et al (Jadad 1996) and summarised as follows:
Was the study described as randomised? (1=yes; 0=no)
Was the study described as double blind? (1=yes; 0=no)
Was there a description of withdrawals and dropouts? (1=yes; 0=no)
Was the method of randomisation clearly described and appropriate? (1=yes; 0=no)
Was the method of double blinding well described and appropriate? (1=yes; 0=no)

STATISTICS
For the dichotomous outcome variables of each individual study, odds ratio (OR) will be calculated using a modified intention‐to‐treat analysis. This analysis assumes that children not available for outcome assessment have not improved (and probably represents a conservative estimate of effect). An initial qualitative comparison of all the individually analysed studies of all the individually analysed studies examine whether pooling of results (meta‐analysis) is reasonable. This will take into account differences in study populations, inclusion/exclusion criteria, interventions, outcome assessment, and estimated effect size.

The results from studies that meet the inclusion criteria and reports any of the outcomes of interest will be included in the subsequent meta‐analyses. The summary weighted risk ratio and 95% confidence interval (fixed effects model) will be calculated (Cochrane statistical package, RevMan version 4.2). For cross‐over studies, mean treatment differences will be calculated from raw data, extracted or imputed and entered as fixed effects generic inverse variance (GIV) outcome, to provide summary weighted differences and 95% confidence intervals. In cross‐over trials, only data from the first arm will be included in meta analysis if data is combined with parallel studies (Elbourne 2002). Numbers needed to treat (NNT) will be calculated from the pooled OR and its 95% CI applied to a specified baseline risk using an online calculator (Cates 2003b). If studies reported outcomes using different measurement scales, the standardised mean difference will be estimated. Any heterogeneity between the study results will be described and tested to see if it reached statistical significance using a chi‐squared test. The 95% confidence interval estimated using a random effects model will be included whenever there are concerns about statistical heterogeneity.

SUB‐GROUP ANALYSIS:
An a priori sub‐group analysis is planned for
1. children (aged 18 years or less) and adults (>18 years)
2. types of influenza vaccine
3. type of control group
4. participant type (bronchiectasis as primary disease vs bronchiectasis as co‐existent disease)
5. severity of bronchiectasis (based on lung function)

Sensitivity analyses are planned to assess the impact of the potentially important factors on the overall outcomes:
a) study quality;
b) study size;
c) variation in the inclusion criteria;
d) differences in the medications used in the intervention and comparison groups;
e) differences in outcome measures;
f) analysis using random effects model;
g) analysis by "treatment received"; and
h) analysis by "intention‐to‐treat".