Anti‐IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy and adverse effects of anti‐IgE therapy for ABPA in people with CF.
Background
Please refer to the glossary for the explanation of clinical terms (Appendix 1).
Description of the condition
Cystic fibrosis (CF), an autosomal recessive multisystem disorder, is characterized by the obstruction and infection of respiratory airways, malabsorption, and various other manifestations and complications (Rowe 2005). With an approximate prevalence of 1 in 3500 live births, CF is more frequent in northern Europe, North America, Australia and New Zealand (Rowe 2005). The mutation in the CF transmembrane regulator (CFTR) gene, with resulting dysfunction of epithelialized surfaces, is the predominant pathogenetic feature in CF. Pulmonary lesions and complications are a major cause of morbidity and mortality in people with CF. Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease caused by aspergillus‐induced hypersensitivity, which usually occurs in susceptible people with bronchial asthma and CF (Agarwal 2009; Greenberger 2002; Tillie‐Leblond 2005). The prevalence of ABPA in people with CF has been described as ranging from 2% to 15% (Becker 1996; Carneiro 2008; Geller 1999; Mastella 2000; Skov 2005; Stevens 2003; Taccetti 2000). These prevalence studies included either just adults or both adult and pediatric patients. Although, sensitization to aspergillus is not uncommon in CF patients (31% to 59% of CF patients), only a fraction of these patients develop ABPA (Hemmann 1998; Valletta 1993). The pathophysiology of ABPA is not yet clear. The aspergillus spores attach and penetrate the pre‐activated epithelium in genetically susceptible patients with CF and form hyphae (Knutsen 2011). The aspergillus antigens from hyphae activate the body’s immune response with a release of inflammatory cytokines (especially IL‐4) which cause bronchial or bronchiolar inflammation and destruction (Knutsen 2003; Knutsen 2011).
The Cystic Fibrosis Foundation Consensus Conference laid down diagnostic criteria for ABPA in CF as well as criteria for screening for ABPA in CF patients (Stevens 2003). Clinical features of ABPA in CF include acute exacerbation of symptoms, weight loss and a marked increase in productive coughing (Stevens 2003). The presence of ABPA in CF patients has been associated with a decline in lung function (Nepomuceno 1999). If untreated, ABPA may progress to bronchiectasis or pulmonary fibrosis, or both, with significant morbidity and mortality. The mainstay of treatment for ABPA includes corticosteroids and itraconazole. The treatment with corticosteroids may be required for prolonged periods or repeatedly for exacerbations of ABPA, which may lead to many adverse effects. A Cochrane review found no evidence for the use of itraconazole or other antifungal agents for ABPA in people with CF (Elphick 2000).
Description of the intervention
The monoclonal anti‐IgE antibody, omalizumab, has produced a new approach to intervene in the allergic pathway; this new approach is directed to an epitope expressed on the Cɛ3 domain of IgE that binds to high‐ and low‐affinity receptors (Shields 1995). Omalizumab has been shown to decrease circulating free IgE levels by the formation of trimeric and hexameric complexes. These complexes are then cleared by the reticuloendothelial system and there is no activation of a complement system (Corne 1997). In asthmatic patients, omalizumab inhibits early and late phases of bronchoconstriction induced by allergens, hyper‐responsiveness, and skin‐prick test results (Fahy 1997). In a randomized controlled trial, omalizumab treatment improved asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without a worsening of symptom control or an increase in rescue medication use (Holgate 2004). It has been shown to decrease eosinophil counts and also levels of interleukin (IL)‐2+ and IL‐13+ T‐lymphocytes in patients with allergic asthma (Noga 2006). Omalizumab is usually given subcutaneously and the dose is calculated by body weight and baseline total serum IgE levels (Holgate 2004; van der Ent 2007). In a Cochrane review, omalizumab had been found to be effective and safe in allergic asthma (Walker 2006).
How the intervention might work
Allergic bronchopulmonary aspergillosis is a pulmonary hypersensitivity disease induced by Aspergillus fumigatus (A. fumigatus) (Tillie‐Leblond 2005). In CF patients with ABPA, a number of immunological responses to antigens of A. fumigatus can be observed, such as peripheral blood eosinophilia, immediate cutaneous reactivity, increased levels of total serum IgE, the presence of precipitating antibodies and increased specific serum IgE and IgG antibodies to A. fumigatus (Stevens 2003). Thus, immunomodulatory drugs may be effective for treatment of ABPA. Omalizumab, an anti‐IgE antibody has been found to be effective for treating asthma with a strong allergy component. Since ABPA is also a condition resulting from hypersensitivity to specific allergens, it may be a candidate for therapy using anti‐IgE antibodies.
Why it is important to do this review
Currently, corticosteroids and antifungal therapy are the mainstay of treatment for ABPA. Corticosteroids may lead to serious side‐effects when used for prolonged periods or repeatedly for exacerbations of ABPA. Therefore, it is prudent to have a therapy for ABPA with a steroid‐sparing effect. Anti‐IgE therapy, using agents like omalizumab, may be such a potential therapy for ABPA in CF patients.
Objectives
To evaluate the efficacy and adverse effects of anti‐IgE therapy for ABPA in people with CF.
Methods
Criteria for considering studies for this review
Types of studies
Randomized or quasi‐randomized controlled trials will be included. Cross‐over and cluster‐randomized trials will be excluded.
Types of participants
People with CF and ABPA. Diagnosis of CF should be in accordance with the criteria laid down by the Cystic Fibrosis Foundation consensus report (Farrell 2008); ABPA should be diagnosed using the Rosenberg‐Patterson criteria (Rosenberg 1977), Nelson’s criteria (Nelson 1979), Greenberger’s criteria (Greenberger 2002) or the Cystic Fibrosis Foundation Consensus criteria (Stevens 2003). There will be no limit to age or disease severity for participants included in the review.
Types of interventions
Anti‐IgE therapy compared to placebo or other therapies for ABPA in CF patients. We will include all doses of anti‐IgE therapy in the review.
Types of outcome measures
Primary outcomes
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Number of patients responding to anti‐IgE therapy (as defined by a decrease in oral corticosteroid dose by 50% or more in comparison to baseline)
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Number of patients requiring rescue therapy with corticosteroids
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Adverse effects
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mild (do not lead to discontinuation of treatment)
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moderate (lead to a change in treatment)
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severe (lead to hospitalisation or are life‐threatening)
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Secondary outcomes
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Lung function
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forced expiratory volume in one second (FEV1)
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peak expiratory flow rate (PEFR)
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forced vital capacity (FVC)
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ratio of FEV1/FVC
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Time until steroid use ceases
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Number of ABPA exacerbations
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Pulmonary exacerbations requiring treatment (oral or nebulised or intravenous (IV) or combination)
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Hospitalisation
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number of admissions
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number of days in hospital
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Search methods for identification of studies
Electronic searches
We will identify relevant studies from the Group's CF Trials Register using the term: allergic bronchopulmonary aspergillosis.
The 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 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.
Searching other resources
We will also check the reference lists of any identified studies for additional potentially relevant studies. We will contact authors of included studies to find any ongoing or unpublished relevant studies. We will search the ongoing trial registry clinicaltrials.gov for any ongoing trials.
Data collection and analysis
Selection of studies
All three authors will independently assess the results of the searches for any potentially relevant studies. The authors will then retrieve and independently assess the full text of these studies for inclusion, as per the criteria listed above. The authors will list excluded studies with reasons for exclusion and resolve any disagreements by discussion.
Data extraction and management
Two review authors (KRJ and AK) will independently extract data using a standardized data collection form in accordance with chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), which will include the following data: source; eligibility; study methods; participants and settings; interventions and comparisons; outcomes; results; adverse outcomes; and miscellaneous details (e.g. funding source of the study, or potential conflicts of interest). We will resolve any disagreement which may arise by discussion.
The authors will assess all primary and secondary outcomes at ‘up to 3 months’, ‘over 3 and up to 6 months’ and ‘over 6 and up to 12 months’ of treatment. They will also consider any other time‐points that are reported.
Assessment of risk of bias in included studies
Two review authors (KRJ and AK) will independently assess the risk of bias in the included studies using the criteria described in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). The authors will assess the risk of bias for the following domains.
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Allocation sequence generation
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Concealment of allocation
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Blinding of participants and investigators
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Incomplete outcome data
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Selective outcome reporting
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Any other potential risk of bias
The authors will judge each of these criteria to have a low, high or unclear risk of bias and resolve any disagreement by discussion. They will produce figures for a 'Risk of bias graph' and 'Risk of bias summary' using Review Manager 5.1 (RevMan 2011).
Measures of treatment effect
The authors will analyse dichotomous variables by calculating the risk ratio (RR). They will express continuous variables as a mean difference (MD) or a standardized mean difference (SMD) if different scales are used for an outcome in different studies. They will analyze time‐to‐event data using the hazard ratio (HR). They will express the overall results with 95% confidence intervals (CI). They will report the numbers of ABPA exacerbations and hospital admissions as a rate ratio (Deeks 2011).
Unit of analysis issues
The authors will include only randomized and quasi‐randomized controlled parallel trials in the review; they will exclude both cross‐over and cluster‐randomized trials.
Dealing with missing data
The authors will consider taking the following steps to deal with any missing data.
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Contact study investigators to obtain missing outcome data where possible.
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Perform sensitivity analyses to assess the sensitivity of any assumptions, if made.
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Address the potential impact of missing data on the findings of the review in the 'Discussion' section.
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For missing standard deviations (SDs) of continuous outcome data, they will calculate the SD from study statistics (e.g. CIs, standard errors, T values, P values or F values). If the calculation of the SD is still not possible, then they will impute it from other studies in the meta‐analysis as per details given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). If data are still not available, the authors will generate analyses making assumptions to create the best and worst case scenarios. If this occurs, they will undertake a sensitivity analysis (see below).
Where possible, the authors will extract data to allow an intention‐to‐treat (ITT) analysis, which aims to include all participants randomized into a trial irrespective of what happened subsequently.
Assessment of heterogeneity
The authors will assess clinical and methodological heterogeneity before pooling data in a meta‐analysis. They will carry out an assessment for statistical heterogeneity initially visually and then using a Chi2 test and also using the I2 statistic. Using the Chi2 test, a low P value (P < 0.1) or a large Chi2 statistic relative to its degree of freedom will provide evidence of heterogeneity of intervention effects (i.e. the variation in effect estimates beyond chance). The authors will interpret the value of the I2 statistic as follows:
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0% to 40% ‐ might not be important;
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30% to 60% ‐ may represent moderate heterogeneity;
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50% to 90% ‐ may represent substantial heterogeneity; and
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75% to 100% ‐ considerable heterogeneity (Deeks 2011).
Assessment of reporting biases
Where the authors suspect reporting bias, they will try to contact study investigators asking them to provide missing outcome data. Where this is not possible, they will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
The authors will assess publication bias, if sufficient numbers of included studies are available, by using funnel plots in Review Manager 5.1 (RevMan 2011).
Data synthesis
The authors will perform meta‐analyses using Review Manager 5.1 (RevMan 2011). They plan to use a fixed‐effect model for pooled data analysis; however, if there is important statistical heterogeneity identified (I2 statistic is more than 50%) they will also use a random‐effects model in a sensitivity analysis among studies.
Subgroup analysis and investigation of heterogeneity
If the authors identify substantial heterogeneity (over 50%), they will explore it by performing subgroup analysis. If sufficient studies (at least 10) are available, they will conduct the following subgroup analyses:
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pediatric (up to and including 18 years of age) versus adult (over 18 years of age) patients;
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different stages of ABPA (five stages according to Patterson (Patterson 1982): (1) acute; (2) remission; (3) exacerbation; (4) corticosteroid‐dependent asthma; and (5) fibrosis (end stage).
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colonization of CF patients with Staphylococcus aureus or Pseudomonas aeruginosa or both or neither.
Sensitivity analysis
Further, the authors will perform a sensitivity analysis to explore whether the heterogeneity is a result of different risk of bias. If sufficient numbers of trials are available, (at least 10) they will undertake sensitivity analyses as follows:
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repeating meta‐analysis after exclusion of studies with a high risk of bias due to concealment of allocation;
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repeating meta‐analysis after exclusion of studies in which the outcome evaluation was not blinded;
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repeating meta‐analysis after imputing missing data as best possible and worst possible outcome; and
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comparing the difference of pooling analysis results by using a fixed‐effect model and a random‐effects model.
