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Immunosuppressive drug therapy for preventing rejection following lung transplantation in cystic fibrosis

  1. Ian J Saldanha1,*,
  2. Oluwaseun Akinyede2,
  3. Naomi A Mckoy3,
  4. Karen A Robinson2

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 9 DEC 2013

Assessed as up-to-date: 27 NOV 2013

DOI: 10.1002/14651858.CD009421.pub2


How to Cite

Saldanha IJ, Akinyede O, Mckoy NA, Robinson KA. Immunosuppressive drug therapy for preventing rejection following lung transplantation in cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD009421. DOI: 10.1002/14651858.CD009421.pub2.

Author Information

  1. 1

    Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD, USA

  2. 2

    Johns Hopkins University, Department of Medicine, Baltimore, MD, USA

  3. 3

    GlaxoSmithKline, SSM Microbial Upstream Common Use Production, Rockville, Maryland, USA

*Ian J Saldanha, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Room E6014, Baltimore, MD, 21204, USA. isaldanh@jhsph.edu.

Publication History

  1. Publication Status: New
  2. Published Online: 9 DEC 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms
 

Description of the condition

Cystic fibrosis (CF) is a common autosomal recessive multi-system disorder, occurring in approximately 1 in every 2500 live births (Ratjen 2003). In the USA, CF affects approximately 30,000 individuals and worldwide affects approximately 70,000 (Cystic Fibrosis Foundation 2013). It predominantly affects the lungs, pancreas, liver, and intestines. The main genetic defect is a mutation of the CF transmembrane conductance regulator (CFTR) gene, a gene responsible for a chloride channel that transports salt across the cell membrane (Rowe 2005). The abnormal salt transport, caused by the CF gene defect, results in viscous mucus. The increased viscosity of mucus makes it difficult for airway cilia to propel mucus out of the airways. Retention of this mucus leads to pulmonary colonisation of pathogenic bacteria. Recurrent colonisation and inflammation lead to chronic airway disease. Pulmonary disease accounts for most of the morbidity and mortality in people with CF (90% of fatalities) (Ramsey 1996).

For patients with advanced pulmonary damage, lung transplantation is an available and viable option (Jaramillo 2005). Although more patients consider it, between 1990 and 2008 in the USA on average about 140 patients with CF per year received lung transplants (Cystic Fibrosis Foundation 2011). Since May 2005 in the USA, eligible lung transplant candidates across indications are prioritised using the lung allocation score (LAS) system (Yusen 2010). The LAS system is based on a combination of medical urgency and expected post-transplant outcomes for patients. In patients 12 years of age and older, prioritisation is based on the LAS, in addition to ABO blood group and distance from the donor hospital. In patients under 12 years of age, prioritisation is based on time on lung transplant waiting list, ABO compatibility, and distance from the donor hospital (Yusen 2010).

The indication for between 14% and 17% of all lung transplants, both in the USA and around the world, was CF (Christie 2011; Yusen 2010). In paediatric patients (under 18 years of age), CF, with its associated bronchiectasis and obstructive lung disease, was the indication in about 70% of lung transplants both in the USA and around the world (Aurora 2009; Yusen 2010). Most of these paediatric transplants occurred in adolescents (aged between 6 and 18 years of age).

The overall 1-year, 5-year, and 10-year unadjusted mean survival rates after lung transplantation in the USA have been reported to be approximately 83%, 54%, and 29% respectively (OPTN 2009). Among patients with CF or immunodeficiency disorders, these rates were reported to be approximately 87%, 57%, and 38% respectively. Similar rates have been reported around the world (Christie 2011). Among the various indications for transplantation, CF has been associated with the highest rates of post-lung transplant survival (Christie 2011; Yusen 2010).

Bilateral lung transplants have been associated with higher unadjusted survival rates at 5-years and 10-years post-transplant compared to single lung transplants (Christie 2011; OPTN 2009). However, differences in rates of survival by procedure type need to be interpreted with caution because survival is influenced by multiple clinical factors that inform the decision to perform a particular procedure type (Christie 2011). Lung transplants can also be classified based on whether the donor is living or deceased. Deceased donors can be further classified as donation after brain death (DBD) donors or donation after cardiac death (DCD) donors. It is extremely rare that DCD donor lungs are used (1% in 2008) (OPTN 2009).

Whatever the type of lung transplant, graft rejection is an important potential consequence. Graft rejection has been classified into the following three clinically and histologically distinct categories (King-Biggs 1997).

 

Hyperacute rejection

This usually arises within minutes after perfusion of the newly grafted organ is established (King-Biggs 1997). It is an antibody-mediated reaction in response to blood group antigens, human leukocyte antigens (HLA), and other antigens that cause cell-mediated injury. Widespread testing for compatibility of donors and recipients in terms of blood group antigens, HLA, and other antigens has virtually led to the elimination of this complication (King-Biggs 1997).

 

Acute rejection

This is a cell-mediated inflammatory response in the recipient due to HLA antigens of the donor (King-Biggs 1997). The major effector cells are T-cells. The classical clinical picture of acute rejection includes symptoms such as dyspnoea, fatigue, and dry cough; and signs such as low-grade fever, a drop in oxygenation greater than 10 mm Hg from baseline, development of new or changing radiographic infiltrates, and a decrease in forced expiratory volume in one second (FEV1) greater than 10% from baseline. The most common differential diagnosis in the early post-operative period is infection (King-Biggs 1997). One out of every four acute rejection episodes occurs in the first month after transplant surgery. However, acute rejection remains an ongoing risk during the life of the transplanted organ (Hopkins 2002). Although currently available immunosuppressive agents adequately control episodes of acute rejection once they occur (Hopkins 2008), almost 80% of lung transplant recipients have been reported to suffer at least one acute rejection episode in the first month after surgery (Hopkins 2002).

 

Chronic rejection (obliterative bronchitis or bronchiolitis obliterans syndrome (BOS))

This usually occurs months to years after transplantation (King-Biggs 1997). It is characterised by progressive airflow obstruction that is often disabling (Paradis 1993). Chronic rejection occurs due to a complex immuno-pathogenic process, possibly involving sustained T-cell activation by donor major histocompatibility complex (MHC) and other antigens (Hopkins 2008) as well as non-immune factors. Current immunosuppressive protocols have not been sufficient to adequately prevent and treat this complication. It remains the major cause of late graft rejection following lung transplantation (Hopkins 2008).

It is worth noting that the terms acute and chronic rejection refer to the immunological process and not their period of occurrence (Hopkins 2008). Graft rejection and non-cytomegalovirus (non-CMV) infections have been reported to be the predominant causes of significant death among transplant recipients (Christie 2011).

 

Description of the intervention

Immunosuppressive therapy is needed to prevent episodes of graft rejection and thus significantly reduces morbidity and mortality in all patients with lung transplantation.

Immunosuppressive therapy has been defined as therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection (National Cancer Institute 2010). There are a number of classes of these drugs acting on different components of the immune system. The main classes of immunosuppressive drugs currently being used during and after lung transplantation are listed below.

 

1. Polyclonal anti-lymphocyte antibodies

Included in this class are anti-lymphocyte globulin (ALG) and anti-thymocyte globulin (ATG), each of which could be either horse- or rabbit-derived.

 

2. Monoclonal anti-lymphocyte antibodies

Included in this class is the monoclonal anti-CD3 antibody (murmonab-CD3) which is mouse-derived and alemtuzumab which is a recombinant DNA-derived humanised monoclonal antibody. Alemtuzumab is currently approved for use in B-cell chronic lymphocytic leukaemia (B-CLL).

 

3. Interleukin-2 (IL-2) receptor antagonists

Included in this class are daclizumab and basiliximab which are chimeric (human or mouse) monoclonal antibodies.

 

4. Calcineurin inhibitors

These include cyclosporin A (CsA) which is a cyclic peptide produced by the fungus Tolypocladium inflatum and tacrolimus (Tac) which is a hydrophobic macrocyclic lactone derived from the actinomycete Streptomyces tsukubaensis.

 

5. Cell cycle inhibitors

These include azathioprine which is a nucleoside analogue and mycophenolate mofetil (MMF) which is a prodrug of mycophenolic acid (MPA).

 

6. Corticosteroids

These include prednisone (prednisolone) and methylprednisolone.

 

7. Mammalian target of rapamycin (mTOR) inhibitors

These include sirolimus (rapamycin) which is a macrolide antibiotic produced by the actinomycete Streptomyces hygroscopicus, and everolimus. Everolimus is a derivative of sirolimus but with higher oral bioavailability and shorter half-life.

Immunosuppressive therapy after lung transplantation usually consists of initial induction followed by maintenance regimens to prevent rejection.

Induction immunosuppressive therapy refers to the strategy of prophylactic use of immunosuppressive drugs during the early post-transplant period (Knoop 2003). The principle of induction therapy is to provide the strongest immunosuppression during the first few weeks following transplantation when the risk for rejection is at the maximum. The use of induction immunosuppressive therapy is associated with significantly higher survival after lung transplantation (Christie 2011). Biological agents best suited to induction therapy are those that cause profound and expedient depletion in the activation of T-lymphocytes. These include agents from the following classes: polyclonal anti-lymphocyte antibodies; monoclonal anti-lymphocyte antibodies; and interleukin-2 (IL-2) receptor antagonists (Knoop 2003).

Maintenance immunosuppressive therapy is geared towards the long-term prevention of episodes of acute and chronic graft rejection (Knoop 2003). The principle of maintenance therapy is to provide effective long-term prevention against rejection through combination therapy that minimises adverse effects of individual drugs. The aims of combination therapy are to maximise synergism, achieve multi-pathway inhibition of lymphocyte activation, and minimisation of cumulative toxicity (Hopkins 2008). The most commonly used combinations are triple-drug regimens including a calcineurin inhibitor, a cell cycle inhibitor, and a corticosteroid (Knoop 2003).

 

How the intervention might work

The mechanisms of action of each class of immunosuppressive drugs are described below:

 

1. Polyclonal anti-lymphocyte antibodies

The antibodies ALG and ATG (from either horse or rabbit sources) act by targeting numerous antigens on lymphocyte cell surfaces, thereby depleting the levels of circulating lymphocytes (Knoop 2003).

 

2. Monoclonal anti-lymphocyte antibodies

Murmonab-CD3 acts by specifically targeting the CD-3 complex, which is a series of proteins associated with the T-lymphocyte antigen receptor (TCR) (Knoop 2003). This binding causes opsonization and complement-mediated T-cell depletion (Cosimi 1981). Alemtuzumab binds to CD-52, an antigen present on the surface of T and B lymphocytes (Wierda 2005). This binding causes antibody-dependent lysis of lymphocytes.

 

3. Interleukin-2 (IL-2) receptor antagonists

The IL-2 plays a key role in T-cell activation and acute graft rejection (Hopkins 2008). It acts by binding to a high-affinity receptor located on the surface of T-cells, thus blocking IL-2 induced T-cell proliferation (Knoop 2003). Both daclizumab and basiliximab act by targeting the alpha chain (Tac subunit) of the IL-2 receptor (Hopkins 2008).

 

4. Calcineurin inhibitors

Calcineurin, through its enzymatic (phosphatase) activity in the cytoplasm of the cell, is critical for the transcription of cytokines like IL-2, IL-3, IL-4, IL-5, interferon-γ, tumour necrosis factor-α (TNF-α), and granulocyte/macrophage colony-stimulating factor (GM-CSF) (Knoop 2003). By binding with cyclophilin in the cytoplasm of the cell, CsA acquires its active form. This in turn inactivates calcineurin causing the downstream effect of reduced T-cell activation. Tac acts in a similar manner to CsA, but instead of binding with cyclophilin, it binds with FK-binding proteins (FKBPs) in the cytoplasm.

 

5. Cell cycle inhibitors

Azathioprine, a nucleoside analogue, acts by inhibiting deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and de novo purine synthesis (Hopkins 2008; Knoop 2003) This affects the proliferation of T- and B-lymphocytes without affecting the transcription of cytokines. MMF, which is not a nucleoside analogue, acts by converting to its active form MPA; MPA is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPD), which is the rate-limiting enzyme in the de novo purine synthetic pathway (Knoop 2003; Hopkins 2008).

 

6. Corticosteroids

Corticosteroids act by blunting the activation and proliferation of T-lymphocytes, diminishing the secretion of cytokines through reduced cytokine gene transcription, and directly lysing immature T-lymphocytes (King-Biggs 1997; Hopkins 2008).

 

7. Mammalian target of rapamycin (mTOR) inhibitors

The mechanism of action of sirolimus (rapamycin) is similar to Tac. However, although sirolimus binds with FKBP-12 (similar to Tac), it inhibits a kinase called mTOR (instead of calcineurin that Tac inhibits) (Knoop 2003; Hopkins 2008). The inhibition of mTOR in turn inhibits the T-cell proliferative response to cytokines and growth factors.

 

Why it is important to do this review

Immunosuppressive therapy is generally accepted as a necessary therapeutic modality to prevent graft rejection post transplantation, including lung transplantation. While much of the research in immunosuppressive drug therapy has focused on the general population of lung transplant recipients, little is known about the comparative effectiveness and safety of these agents in patients with CF. There is considerable variability in the use of immunosuppressive agents after lung transplantation in CF (Christie 2011; Lischke 2007). Variation exists for both induction and maintenance immunosuppressive therapy (Christie 2011).

The International Society for Heart and Lung Transplantation (ISHLT) maintains an international registry on heart and lung transplantation, in both CF and non-CF patients (ISHLT 2013). According to ISHLT registry data, about one in six (16.8%) of the 30,673 lung transplantations performed between January 1995 and June 2010 were in patients with CF (Christie 2011). The use of induction immunosuppressive therapy after lung transplantation has increased in recent times, with 60% of patients receiving it in 2010 compared to just 24% in 1997. In 2010, 41% of patients received IL-2 receptor antagonists, 15% received polyclonal anti-lymphocyte antibodies, and 8% received monoclonal anti-lymphocyte antibodies. The ISHLT registry data also indicate that, between 2002 and 2010, the use of IL-2 receptor antagonists in induction immunosuppressive therapy was associated with lower reported incidence of acute rejection compared to no induction or use of polyclonal anti-lymphocyte antibodies (Christie 2011). However, such data obtained from registries need to be interpreted with caution because of potential limitations. These include selection bias, missing data, reporting delays, and the fact that the data are not obtained from experimental clinical studies (Izquierdo 2000; Nathan 2007).

According to the ISHLT registry data from 2002 through 2007, the combination of a calcineurin inhibitor + a cell cycle inhibitor + a corticosteroid was the most commonly used regimen during maintenance immunosuppressive therapy (Christie 2011). However, there was no consensus on agents to be used within these classes. The combination of Tac + MMF + prednisone was the most commonly used (about 45% of patients at one year and about 34% of patients at five years post-transplant). The next most commonly used combination was Tac + azathioprine + prednisone (about 22% of patients at one year and about 19% of patients at five years post-transplant). Other combinations in use included CsA + MMF + prednisone; CsA + azathioprine + prednisone; sirolimus (rapamycin) + calcineurin inhibitors + prednisone; and sirolimus (rapamycin) + cell cycle inhibitors + prednisone. CsA-based regimens were associated with the highest rates of acute rejection, being highest for patients receiving the combination of CsA + azathioprine + prednisone. Tac-based regimens were associated with the lowest rates of acute rejection, being lowest for patients receiving the combination of Tac + MMF + prednisone (Christie 2011).

In addition, patients with CF suffer from high rates of chronic infections and usually receive multiple treatments for a variety of disease manifestations (Ratjen 2003). All these factors necessitate the study of immunosuppressive agents specifically in patients with CF.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms

The objective of this review is to assess the effects of immunosuppressive drug therapy to prevent rejection following lung transplantation in patients with CF. In particular, this review aims to assess the effects of individual drugs or combinations of individual drugs compared to placebo or other individual drugs or combinations of individual drugs.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised or quasi-randomised controlled studies.

 

Types of participants

Individuals with CF following lung transplantation (including lobe, single-lung, and bilateral transplants) or heart-lung transplantation. 

 

Types of interventions

We planned to include studies of comparisons of individual drugs (e.g. cyclosporine (CsA), tacrolimus (Tac), sirolimus (rapamycin), mycophenolate mofetil (MMF)) or combinations of individual drugs to placebo or other individual drugs or combinations of other individual drugs. We also planned to include comparisons of two drugs within the same class (e.g. daclizumab versus basiliximab).

 

Types of outcome measures

 

Primary outcomes

  1. Episodes of rejection
    1. hyperacute rejection
    2. acute rejection
    3. chronic rejection (bronchiolitis obliterans syndrome (BOS))
  2. Mortality
  3. Quality of life (QoL) - all instruments, of any validity, that measure the ability of participants to perform activities of daily living (including but not limited to the Cystic Fibrosis Questionnaire-Revised version (CFQ-R) (Quittner 2009) and the Cystic Fibrosis Quality of Life Questionnaire (CFQoL) (Gee 2000))

 

Secondary outcomes

  1. Opportunistic infections (including cytomegalovirus (CMV) and non-CMV infections)
  2. Adverse events (e.g. nephrotoxicity, cardiotoxicity, post-transplant development of diabetes mellitus)
  3. Lung function
    1. forced expiratory volume at one second (FEV1) (both in litres and per cent predicted)
    2. forced expiratory volume (FVC) (both in litres and per cent predicted)
    3. mid-expiratory flow (FEF25-75%)
  4. Patient preference
  5. Sputum weight (g)
    1. dry weight
    2. wet weight
  6. Oxygen saturation:
    1. arterial blood gas
    2. pulse oximetry
    3. transcutaneous oximetry
  7. Incidence of co-morbidities
    1. hypertension
    2. diabetes mellitus
    3. hyperlipidaemia
    4. renal dysfunction
  8. Hospitalisation (post hoc change)

 

Search methods for identification of studies

 

Electronic searches

We identified relevant studies from the Group's CF Trials Register using the terms: transplantation AND lung AND immunosuppressant.

The CF 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 CF 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 Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

Date of search: 22 August 2013.

 

Searching other resources

If we identify eligible studies for updates of the review, we will search the reference lists of included articles and other relevant studies and reviews to identify additional studies. We will also contact the authors of the included articles. We searched the www.clinicaltrials.gov trials registry to obtain information on unpublished and ongoing studies. We also handsearched the Journal of Heart and Lung Transplantation (for the years 2012 and 2013), which is the official publication of the International Society for Heart and Lung Transplantation (ISHLT).

 

Data collection and analysis

 

Selection of studies

We used a two-tier screening process to identify relevant articles. Initially, we screened the titles and abstracts of articles identified through searching and obtained the full text versions of those considered potentially relevant. We then screened the full text articles to identify those studies which should be included in the review and are eligible for data abstraction. Two review authors (IJS, OA) independently screened each article. We resolved any disagreements by consensus.

We planned to include studies which either included patients with CF exclusively or which included at least some patients with CF. However, this second kind of study would only be included provided we were able to abstract from the article, or obtain from its authors, specific data on outcomes related to patients with CF.

 

Data extraction and management

We imported search results into a reference management software (Procite, Thomson Reuters, New York, NY). We then screened citations and tracked results of the screening using the reference management software. We designed custom data abstraction forms to abstract information from eligible review articles. If we identify eligible studies for updates of the review, one author (IJS) will abstract data and a second author (OA) will review the abstracted data for completeness and accuracy. We will resolve any disagreements through consensus or consultation with a third reviewer (KAR). One author (IJS) will then enter the data into RevMan (RevMan 2012).

If we identify eligible studies for updates of the review, we will group studies together based on time of outcome assessment. We will consider outcomes as immediate if up to one week duration; short term if more than one week and up to one month duration; medium term if more than one month and up to six months duration; and long term if more than six months duration. If studies report data at multiple time points within an interval, we will analyse these separately if appropriate.

 

Assessment of risk of bias in included studies

If we identify eligible studies for updates of the review, we will assess the risk of bias in included studies through assessment of random sequence generation; allocation concealment; blinding of the study participants and personnel, blinding of outcome assessors; incomplete outcome data; selective reporting; and other sources of bias (compliance assessment; washout reporting; intention-to-treat analysis; and loss to follow up). We will assess studies using each of these criteria as having high, low, or unclear risk of bias. Two review authors (IJS, OA) will independently apply the methods for evaluating the risk of bias described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will resolve any disagreements through consensus or consultation with a third review author (KAR).

 

Measures of treatment effect

If we identify eligible studies for updates of the review, we will analyse continuous outcomes using the mean difference (MD) (or we will calculate standardised mean difference (SMD) if different scales of measurement have been used) and dichotomous outcomes using the risk ratio (RR). We will present all outcomes with associated 95% confidence intervals (CIs).

 

Unit of analysis issues

If we identify eligible studies for updates of the review, and when conducting analyses, we will take into consideration the level at which randomisation occurred (Higgins 2011c). Randomised controlled studies with parallel group designs are studies where individuals are independently randomised to intervention groups. In cross-over studies, individuals are randomised to more than one intervention. However, this design is not suitable for most immunosuppressive drug studies because the clinical outcomes of patients or graft survival may be highly dependent on the initial anti-rejection therapy (Leonard 2001). We will thus only include first arm data from cross-over studies.

 

Dealing with missing data

If we identify eligible studies for updates of the review, and in the event of missing, incomplete, or unclear data, we will contact the original investigators. This includes unreported outcomes, missing participants, and missing statistics (such as standard deviations). If we do not obtain the necessary data for analysis, we will provide a narrative summary of the studies.

 

Assessment of heterogeneity

If we identify eligible studies for updates of the review, we will assess clinical heterogeneity by considering variability in the participants, interventions, and comparisons in the included studies. We will also assess statistical heterogeneity within each outcome between the comparisons using the Chi2 test and I2 statistic (Higgins 2003). Under the null hypothesis of homogeneity, we will consider a P value of less than 0.10 to indicate the presence of heterogeneity in the Chi2 test (Higgins 2011c). We will interpret the results with care since the test could have low or high power. Low power is common when studies have a small sample size or there are a small number of studies, which may result in the lack of detection of heterogeneity when it is present. High power is common when there are many studies being analysed, resulting in the detection of heterogeneity that may be insignificant. The I2 statistic measures the proportion of inconsistency in individual studies that cannot be explained by sampling error. In this test the degree of heterogeneity is quantified. The values of I2 lie between 0 and 100%. We will consider I2 results which are less than 40% to indicate that heterogeneity might not be important; between 30% and 60% to indicate that heterogeneity may be moderate; between 50% and 90% to indicate that heterogeneity may be substantial; and between 75% and 100% to indicate considerable heterogeneity (Higgins 2011b).

 

Assessment of reporting biases

Should future updates of the review include more than 10 studies, we will assess reporting bias among the studies using the funnel plot method discussed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If asymmetry is present, we will explore possible causes including publication bias, risk of bias, outcome reporting bias, and true heterogeneity. Outcome reporting bias can occur when studies measure outcomes, but do not publish all of them. This can lead to misleading results (Kirkham 2010). The 'Methods' section of the paper will be compared to the 'Results' section to ensure all outcomes are reported. If we suspect outcome reporting bias, we will contact study authors for the data.

 

Data synthesis

If we identify eligible studies for updates of the review, we will enter data abstracted from included studies into RevMan 5.1 (RevMan 2012). If heterogeneity is low, as indicated by an I2 result less than 30%, we will use a fixed-effect model to synthesise the results. If heterogeneity is moderate, substantial, or considerable, as indicated by an I2 of 30% or higher, we will use a random-effects model to synthesise the results. We will synthesise results by combining studies of individual drugs as well as combining studies of drugs within the same class of immunosuppressants. If we do not find it appropriate to conduct meta-analysis, we will provide a narrative synthesis of the available data.

 

Subgroup analysis and investigation of heterogeneity

Should future updates of the review include at least 10 studies, we will investigate any heterogeneity we identify by the following subgroup analyses:

  1. age (children (up to 18 years old) versus adult patients);
  2. type of donor (among the deceased donors, DBD donors versus DCD donors);
  3. extent of tissue being transplanted (lobe, single lung, and bilateral lung transplants);
  4. pre-transplant lung function (FEV1% predicted over 60%, 41% to 59%, 21% to 40%, under 20%);
  5. pre-transplant ventilator status (on versus off ventilation).

 

Sensitivity analysis

If we identify more than one study in updates of the review, we will perform sensitivity analyses to identify the effects of unpublished studies, study size (stratified by sample size), study design (cross-over versus parallel studies), allocation concealment (high risk of bias versus low risk of bias), participant blinding (high risk of bias versus low risk of bias), assessor blinding (high risk of bias versus low risk of bias), and loss to follow up (high risk of bias versus low risk of bias) on the results.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms
 

Description of studies

 

Results of the search

We identified 10 records to seven studies. Of the 10 records, we identified six from the electronic search and four by handsearching. We excluded five records to five studies at the title and abstract screening stage. The five remaining records (four full-text articles and the single abstract) described two randomised controlled studies. We excluded these five records at the full-text screening stage because the investigators of the studies did not report any CF-specific information (Figure 1).

 FigureFigure 1. Study flow diagram.

 

Included studies

No studies were included.

 

Excluded studies

At the full-text screening stage, we excluded five records describing two randomised controlled studies because the investigators did not report results specific to participants with CF (Bhorade 2011; Iacono 2006). The earlier study compared 300 mg of inhaled cyclosporin A with aerosol placebo three days a week for the first two years after lung transplantation. In addition to nine patients with CF, the study included 45 other patients with diagnoses including chronic obstructive pulmonary disease (COPD) or emphysema, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension, and connective tissue disease (Iacono 2006). THe second study compared sirolimus with azathioprine in 181 lung transplant recipients, including patients with CF (Bhorade 2011). However, all results for both studies were only available for all participants combined.

We have contacted the investigators to obtain the information specific to patients with CF, but have not yet received the requested information.

 

Risk of bias in included studies

No studies were included in this version of the review.

 

Effects of interventions

No studies were included in this version of the review.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms
 

Summary of main results

This systematic review identified two randomised controlled studies; one comparing inhaled cyclosporin A versus placebo aerosol (Iacono 2006) and the other comparing sirolimus versus azathioprine (Bhorade 2011). However, these studies could not be included in the review because the investigators did not report CF-specific results. We have contacted the investigators for this information, but have yet to receive it. Thus, it is not possible to comment on the use of any of the immunosuppressive drugs among patients with CF.

 

Overall completeness and applicability of evidence

We did not identify any eligible studies with extractable information on the use of immunosuppressive drugs among patients with CF.

 

Quality of the evidence

As no studies were included in the review, we could not assess the quality of the evidence.

 

Potential biases in the review process

Given our comprehensive search strategy, it is unlikely that we have missed any relevant studies. However, we did identify studies that we could not include because the investigators did not report CF-specific results. Our attempts to obtain this information have not yet been successful. We will include any provided data in future updates of the review.

 

Agreements and disagreements with other studies or reviews

As no study was included in the review, we could not assess the agreement or disagreement with other studies. A recent Cochrane review comparing tacrolimus with cyclosporine in all patients with lung transplantation (not restricted to patients with CF) reported no significant difference in mortality and risk of acute rejection (Penninga 2013). However, participants receiving tacrolimus experienced a lower risk of BOS, RR 0.46 (95% CI 0.29 to 0.74) and arterial hypertension, RR 0.67 (95% CI 0.50 to 0.89). Participants receiving tacrolimus experienced higher risk of diabetes mellitus as an adverse event, RR 4.43 (95% CI 0.75 to 26.05). However, the investigators of the review noted the high risk of bias and small number of included studies (n = 3) in the review (Penninga 2013).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms

 

Implications for practice

The lack of currently available evidence specific to patients with CF makes it impossible to make conclusions about the comparative efficacy and safety of the various immunosuppressive drugs among patients with CF after lung transplantation.

It is generally accepted that, just like all patients after lung transplantation, immunosuppressive therapy is needed to prevent episodes of graft rejection among patients with CF. The use of immunosuppressive therapy prevents significant morbidity and mortality among patients with lung transplantation. However, the current evidence base does not inform the choice of use of one immunosuppressive drug versus another.

 
Implications for research

Well-designed, adequately-powered, multi-centre randomised controlled studies are required to provide evidence for the benefit and safety of the use of immunosuppressive therapy among patients with CF after lung transplantation.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms

This review has no analyses.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms
 

Appendix 1. Glossary


TermExplanation

chimeric antibodyA hybrid substance combining antibodies and parts of antibodies with the potential to track down and illuminate remote and microscopic tumours. It is less easily rejected by the body's immune system than the ordinary monoclonal antibody.

cyclic peptideAn unusual class of compounds that range from antibiotics, such as bacitracin and polymyxin B, to the immunosuppressant drug cyclosporin. They can also be toxins. They tend to survive the human digestive process and can bind proteins in the cell where traditional drugs cannot.

dyspnoeaLaboured or difficult breathing, shortness of breath, or breathlessness.

hydrophobicRepelled by water.

kinaseA type of enzyme that transfers phosphate groups from high-energy donor molecules, such as adenosine triphosphate (ATP), to specific substrates.

lysisThe breaking down of a cell.

macrocyclic lactoneChemical compounds that represent the main treatment for parasitic diseases of animals.

monoclonal antibodyA protein substance which is produced in the laboratory by a single population of cells.

non-cytomegalovirus infectionsInfections caused by organisms other than cytomegalovirus (CMV).

nucleoside analogueA range of antiviral products used to prevent viral replication in infected cells.

opsonizationThe process of making bacteria more liable to destruction by phagocytes (cells that ingest and destroy other cells, microorganisms, or other foreign matter in the blood and tissues).

polyclonal antibodiesAntibodies that are obtained from different B-cell resources.

radiographic infiltratesA collection of cells not usually present in that area visible through radiography.

synergismInteraction of discrete agents (such as drugs) such that the total effect is greater than the sum of the individual effects.

T-cellsCells which belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms


TASKWHO WILL UNDERTAKE THE TASK?

Protocol stage: draft the protocolAll authors

Review stage: select which studies to include (2 + 1 arbiter)All authors

Review stage: extract data from studies (2 people)Ian Saldanha and Oluwaseun Akinyede

Review stage: enter data into RevManIan Saldanha

Review stage: carry out the analysisIan Saldanha

Review stage: interpret the analysisAll authors

Review stage: draft the final reviewAll authors

Update stage: update the reviewAll authors



 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms

The authors have no relevant conflicts of interest to declare.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. Appendices
  10. Contributions of authors
  11. Declarations of interest
  12. Differences between protocol and review
  13. Index terms

Following the peer review process at review stage:

  1. we added 'Hospitalisation' as a secondary outcome;
  2. we deleted the planned subgroup analysis "deceased versus living donor";
  3. added two new proposed subgroup analyses:

  • pre-transplant LAS (higher versus lower)
  • pre-transplant ventilator status (on versus off ventilation)

* Indicates the major publication for the study

References

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Characteristics of studies
  15. References to studies excluded from this review
  16. Additional references
Bhorade 2011 {published and unpublished data}
  • Bhorade S, Ahya VN, Baz MA, Valentine VG, Arcasoy SM, Love RB, et al. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. American Journal of Respiratory and Critical Care Medicine 2011;183(3):379-87. [PUBMED: 20833822]
  • Ghassemieh B, Ahya VN, Baz MA, Valentine VG, Arcasoy SM, Love RB, et al. Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation. The Journal of Heart and Lung Transplantation: the official publication of the International Society for Heart Transplantation 2013;32(7):701-6. [PUBMED: 23664526]
Iacono 2006 {published data only (unpublished sought but not used)}
  • Groves S,  Galazka M, Johnson B, Corcoran T, Verceles A, Britt E, et al. Inhaled cyclosporine and pulmonary function in lung transplant recipients. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2010;23(1):31-9.
  • Iacono AT, Johnson BA, Grgurich WF, Corcoran TE, Youssef G, Smith-Seiler DA, et al. A randomized trial of inhalational cyclosporine in lung transplant recipients [abstract]. Pediatric Pulmonology 2004;38 Suppl 27:318. [CFGD Register: CO37; MEDLINE: 96204950]
  • Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. New England Journal of Medicine 2006;354(2):141-50.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Characteristics of studies
  15. References to studies excluded from this review
  16. Additional references
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Christie 2011
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