Inhaled non‐steroid anti‐inflammatories for children and adults with bronchiectasis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy of inhaled NSAIDs in children and adults with bronchiectasis;
(a) during stable bronchiectasis;
and for reducing
(b) the severity and frequency of acute respiratory exacerbations and
(c) long term pulmonary decline
Background
Description of the condition
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 (Chang 2008). 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) (O'Brien 2000) and uncommon respiratory diseases (e.g. bronchiolitis obliterans 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 (Lewis 2002, Keistinen 1997). For example, in diseases like COPD the presence of bronchiectasis has been reported in 29‐50% (O'Brien 2000) of cohorts and when present, increases the severity and frequency (Gursel 2006) of respiratory exacerbations.
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). Also, like patients with COPD, children and adults with bronchiectasis also suffer from recurrent acute exacerbations, some of which require hospitalised treatment (Chang 2008). Effective management regimes for bronchiectasis improves quality of life (Martinez‐Gracia 2005; Muthalithas 2008 ; Courtney 2008 ), and could reduce the frequency or severity of respiratory exacerbations ( Cymbala 2005 ), and/or the long term pulmonary decline ( Chang 2008 ). Thus, management of the symptoms and severity of bronchiectasis is important.
Description of the intervention
Non steroid anti‐inflammatory drugs (NSAIDs) are a class of medications that act as non‐selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase‐1 (COX‐1) and cyclooxygenase‐2 (COX‐2) isoenzymes. Non‐steroidal anti‐inflammatories have analgesic, antipyretic and anti‐inflammatory effects and reduce pain, fever and inflammation. NSAIDs are usually given orally but the inhaled formulation has been also utilised in people with bronchorrhoea, a feature present in many patients with bronchiectasis (Tamaoki 1992). A Cochrane review on oral NSAIDs for people with bronchiectasis did not find any suitable randomised controlled trials (Kapur 2007).
How the intervention might work
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). Anti‐inflammatory drugs may reduce the inflammatory cascade and thus ameliorate symptoms and reduce long term pulmonary decline.
As the airways of patients with bronchiectasis have intense neutrophilic inflammation (Cole 1986), the anti‐inflammatory effect of NSAIDs may have a beneficial effect for patients with bronchiectasis. "Blockade of cyclooxygenase pathway with indomethacin could decrease respiratory tract fluid and mucus by inhibiting chloride secretion and glandular secretion and by enhancing Na absorption across airway mucosa" (Tamaoki 1992). Animal studies have shown that pre‐treatment with inhaled indomethacin protects the airway to distilled water and ozone which increases lung resistance through swelling of airway epithelial cells (Mochizuki 2002).
Why it is important to do this review
Although NSAIDs may have potential benefits for those with bronchiectasis, their use can lead to adverse events. The most common side effects are nausea, vomiting, diarrhoea, constipation, decreased appetite, rash, dizziness, headache, and drowsiness. NSAIDs may also cause fluid retention, leading to edema. The most serious side effects are kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery. Some individuals are allergic to NSAIDs and may develop shortness of breath when an NSAID is administered (Behrman 2003).
In cystic fibrosis (CF), preliminary evidence suggests that NSAIDs may prevent pulmonary deterioration in people with mild lung disease due to CF (Lands 2007). However, extrapolation of treatment for CF to non‐CF bronchiectases may be harmful e.g. recombinant human DNase efficacious in CF causes harm in non CF bronchiectasis (Crockett 2001). Thus a systematic review on the efficacy of inhaled NSAIDs in the management of children and adults with bronchiectasis would help guide clinical practice.
Objectives
To evaluate the efficacy of inhaled NSAIDs in children and adults with bronchiectasis;
(a) during stable bronchiectasis;
and for reducing
(b) the severity and frequency of acute respiratory exacerbations and
(c) long term pulmonary decline
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials comparing inhaled NSAIDs to a control group (placebo or usual treatment) in patients with bronchiectasis
Types of participants
Children or adults with bronchiectasis (defined clinically or radiologically) not related to cystic fibrosis. Exclusion criteria: Participants with cystic fibrosis or with other diseases where bronchiectasis is not present.
Types of interventions
All types of inhaled NSAIDs.
Types of outcome measures
Primary outcomes
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): mean difference in bronchiectasis severity control (QOL, cough scores) )
(B) for medium to long term outcomes (>1 year): lung function data (FEV1 % predicted)
Secondary outcomes
(A) for short term effectiveness (12 months or less):
a) total numbers of days with respiratory symptoms
b) mean difference in lung function indices (spirometry, other lung volumes, airway hyper‐responsiveness)
c) proportions of participants who had respiratory exacerbations and/or hospitalisations,
d) total number of hospitalised days
e) mean difference in other objective indices (airway markers of inflammation, exhaled nitric oxide etc)
f) proportions experiencing adverse effects of the intervention, (e.g. gastritis, hematemesis, ecchymoses, etc)
g) serious adverse events (e.g. hemoptysis, bronchospasm etc)
(B) for medium to long term outcomes (>1 year):
h) radiology scores (high resolution computed tomography scans or chest radiograph)
i) clinical indices of bronchiectasis severity control (QOL, cough diary, Likert scale, visual analogue scale, level of interference of cough, etc),
j) mortality
k) proportions experiencing adverse effects of the intervention, (e.g. gastric bleeding, gastritis, hematemesis, cardiac events, etc)
l) serious adverse events (e.g. hemoptysis, bronchospasm etc)
Search methods for identification of studies
Electronic searches
The following topic search strategy will used to identify the relevant randomised controlled trials listed on the electronic databases:
("bronchiectasis" OR "suppurative lung disease" as (textword) or (MeSH )) AND ("inhaled" OR "nebulise" OR "nebulised" as (textword) or (MeSH )) AND ("anti‐inflammatory" OR "diclofenac" OR "etodolac" OR "ketorolac" OR "sulindac" OR "tolmentin" OR "diflunisal" OR "salsalate" OR "meloxicam" OR "piroxicam" OR "flurbiprofen" OR "Ibupropen" OR "ketoprofen" OR "naproxen" OR "oxaprozin" OR "indometacin" OR "COX2 inhibitors" OR "celecoxib" OR "rofecoxib" OR "valdecoxib") 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.
Searching other resources
6. The list of references in relevant publications.
7. Written communication with the authors of trials included in the review if necessary
Data collection and analysis
Selection of studies
Retrieval of studies: From the title, abstract, or descriptors, two reviewers (SP, AC) 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. Disagreement will be resolved by third party adjudication (JU).
Data extraction and management
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.
Assessment of risk of bias in included studies
In order to assess the risk of bias, two review authors will independently assess the quality of the studies included in the review according to the criteria described by Jüni (Jüni 2001).
Allocation concealment
Allocation concealment in each study will be assessed as follows:
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Adequate, if the allocation of participants involved 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;
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Unclear, if the method used to conceal the allocation was not described;
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Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised.
Generation of the allocation sequence
Each study will be graded for allocation concealment as follows:
-
Adequate, if methods of randomisation include using a random number table, computer‐generated lists or similar methods;
-
Unclear, if the trial is described as randomised, but no description of the methods used to allocate participants to treatment group was described;
-
Inadequate, if methods of randomisation include alternation; the use of case record numbers, dates of birth or day of the week, and any procedure that is entirely transparent before allocation.
Blinding (or masking)
Each study will be graded for blinding as follows:
-
blinding of clinician (person delivering treatment) to treatment allocation;
-
blinding of participant to treatment allocation;
-
blinding of outcome assessor to treatment allocation.
Follow up
Each study will be graded as to whether numbers of and reasons for dropouts and withdrawals in all intervention groups were described; or if it was specified that there were no dropouts or withdrawals.
Dealing with missing data
The authors will request further information from the primary investigators where required.
Assessment of heterogeneity
We will describe any heterogeneity between the study results and test this to see if it reached statistical significance using the chi‐squared test. We will consider heterogeneity to be significant when the P value is less than 0.10 (Higgins 2008). We also plan to use the I2 statistic, where heterogeneity is categorised such that a value of under 25% is considered low, around 50% is considered moderate and over 75% is considered a high degree of heterogeneity (Higgins 2003).
Assessment of reporting biases
If we can combine data and meta‐analysis is possible, we will assess publication bias using a funnel plot. We will try and identify and report on any selective reporting in the included trials.
Data synthesis
For the dichotomous outcome variables of each individual study, odds ratios (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 odds ratio and 95% confidence interval (fixed effects model) will be calculated (Cochrane statistical package, RevMan version 5). Only data from parallel studies will be combined.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 2003). If studies report outcomes using different measurement scales, the standardised mean difference will be estimated. Any heterogeneity between the study results will be described and explored. The 95% confidence interval estimated using a random effects model will be included whenever there are concerns about statistical heterogeneity.
Subgroup analysis and investigation of heterogeneity
The following a priori sub‐group analyses is planned:
1. children (aged 18 years or less) and adults (>18 years)
2. severity of bronchiectasis (based on FEV1: >80% classified as mild, 50‐79% classified as moderate, 30‐49% classified as severe, <30% classified as very severe).
Sensitivity analysis
Sensitivity analyses are also planned to assess the impact of the potentially important factors on the overall outcomes:
a) variation in the inclusion criteria;
b) differences in the medications used in the intervention and comparison groups;
c) differences in outcome measures;
d) analysis using random effects model;
f) analysis by "treatment received"; and
g) analysis by "intention‐to‐treat".
