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Pre-transplant factors associated with mortality after lung transplantation in cystic fibrosis: A systematic review and meta-analysis

  • Angela Koutsokera
    Correspondence
    Corresponding author at: Division of Respiratory Medicine, Lausanne University Hospital, Rue du Bugnon 46, BH-06, 1011 Lausanne, Switzerland.
    Affiliations
    Division of Respirology, Department of Medicine, Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Division of Respirology, Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, ON, Canada

    Division of Respiratory Medicine, University Hospital of Lausanne, Lausanne, Switzerland
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  • Rhea A. Varughese
    Affiliations
    Division of Respirology, Department of Medicine, Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Division of Respiratory Medicine, Department of Medicine, University of Calgary, Calgary, AB, Canada
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  • Jenna Sykes
    Affiliations
    Division of Respirology, Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, ON, Canada
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  • Ani Orchanian-Cheff
    Affiliations
    Library and Information Services, University Health Network, Toronto, ON, Canada
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  • Prakesh S. Shah
    Affiliations
    Departments of Paediatrics and HPME, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada
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  • Cecilia Chaparro
    Affiliations
    Division of Respirology, Department of Medicine, Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Division of Respirology, Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, ON, Canada
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  • Elizabeth Tullis
    Affiliations
    Division of Respirology, Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, ON, Canada
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Lianne G. Singer
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Respirology, Department of Medicine, Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Anne L. Stephenson
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Respirology, Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, ON, Canada
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open ArchivePublished:October 25, 2018DOI:https://doi.org/10.1016/j.jcf.2018.10.013

      Abstract

      Background

      Mortality risk stratification is essential in lung transplantation (LTx) to allow listing, prioritization and mitigating strategies. In cystic fibrosis (CF) patients, predictors of post-LTx mortality are not established.

      Methods

      For this systematic review and meta-analysis, seven databases were searched until January 3, 2018 to identify predictors of post-LTx mortality in CF. We excluded studies of multi-organ transplantation, re-transplantation and graft survival. For multiple studies assessing the same population during overlapping time-periods, the largest one was analyzed. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). Pooled hazard ratios were calculated using random-effects models.

      Results

      Fifty-four studies were included in the systematic review and 11 studies in the meta-analyses (low-to-moderate bias risk, NOS score ≥ 5). Among 10 factors assessed in the meta-analysis, B. cepacia complex (BCC) (N = 1451, unadjusted HR = 2.35, 95%CI:1.80–3.06; I2 = 20.4% and adjusted HR = 2.49, 95%CI:1.74–3.57; I2 = 46.2%) and ascending chronological year of LTx (N = 4207, unadjusted HR = 0.98, 95%CI:0.97–0.98, I2 = 4.8%) were predictors of post-LTx mortality. Male gender (N = 2903, adjusted HR = 1.12, 95%CI:1.0–1.26, I2 = 0%) and age in adults (N = 3677, unadjusted HR = 0.99, 95%CI:0.97–1.00; I2 = 64.1% and N = 2605, adjusted HR = 0.98, 95%CI:0.97–0.99; I2 = 34.3%) had borderline significant associations with post-LTx mortality. P. aeruginosa colonization, forced expiratory volume in one second (FEV1), pulmonary hypertension, body mass index (BMI), pancreatic insufficiency and CF-related diabetes (CFRD) were not predictors of mortality.

      Conclusions

      BCC was associated with a higher post-LTx mortality whereas FEV1, pulmonary hypertension, BMI, CFRD and female gender were not associated with post-LTx mortality. These findings indicate that CF-specific risk estimates of post-LTx mortality should be considered.

      Keywords

      Abbreviations:

      BCC (Burkholderia cepacia complex), BMI (Body mass index), CF (Cystic fibrosis), CFRD (CF-related diabetes), FEV1 (Forced expiratory volume in one second), ISHLT (International Society for Heart and Lung Transplantation), LAS (Lung allocation score), LTx (Lung transplantation), MV (Mechanical ventilation), NOS (Newcastle-Ottawa scale), PH (Pulmonary hypertension)

      1. Introduction

      Lung transplantation (LTx) has become the standard of care for cystic fibrosis (CF) patients with end-stage lung disease, and CF is a common indication for LTx in children and adults [
      • Chambers D.C.
      • Yusen R.D.
      • Cherikh W.S.
      • et al.
      The registry of the international society for heart and lung transplantation: thirty-fourth adult lung and heart-lung transplantation report-2017; focus theme: allograft ischemic time.
      ,
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The registry of the international society for heart and lung transplantation: thirty-first adult lung and heart-lung transplant report—2014; focus theme: retransplantation.
      ]. CF patients have a superior post-LTx survival compared to other diagnoses [
      • Chambers D.C.
      • Yusen R.D.
      • Cherikh W.S.
      • et al.
      The registry of the international society for heart and lung transplantation: thirty-fourth adult lung and heart-lung transplantation report-2017; focus theme: allograft ischemic time.
      ,
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The registry of the international society for heart and lung transplantation: thirty-first adult lung and heart-lung transplant report—2014; focus theme: retransplantation.
      ] and, in appropriately selected patients, LTx offers a survival benefit [
      • Thabut G.
      • Christie J.D.
      • Mal H.
      • et al.
      Survival benefit of lung transplant for cystic fibrosis since lung allocation score implementation.
      ,
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ].
      Prospective LTx candidates undergo a detailed evaluation to identify patients who would benefit from the procedure. This patient risk stratification is essential to allow listing, prioritization and targeted interventions for modifiable risk factors [
      Organ procurement and transplantation network (OPTN) policy 10: allocation of lungs.
      ,
      • Weill D.
      • Benden C.
      • Corris P.A.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014—an update from the pulmonary transplantation council of the international society for heart and lung transplantation.
      ]. Due to the medical complexity of LTx candidates and the often contradictory published evidence, risk estimation can be challenging. A recent consensus document provides guidance for LTx referral and listing [
      • Weill D.
      • Benden C.
      • Corris P.A.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014—an update from the pulmonary transplantation council of the international society for heart and lung transplantation.
      ] but, in contrast to the LTx indications which are CF-specific, contraindications highlight areas of concern for all diagnoses reflecting the lack of clearly established, CF-specific risk factors for post-LTx mortality. Among the relative contraindications, progressive or severe malnutrition and colonization with highly resistant microorganisms are the most relevant in CF [
      • Weill D.
      • Benden C.
      • Corris P.A.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014—an update from the pulmonary transplantation council of the international society for heart and lung transplantation.
      ]. Moreover, as shown by a recent survey, it is often unclear whether parameters associated with higher mortality before LTx also increase post-transplant mortality and this becomes a barrier to LTx referral [
      • Ramos K.J.
      • Somayaji R.
      • Lease E.D.
      • Goss C.H.
      • Aitken M.L.
      Cystic fibrosis physicians' perspectives on the timing of referral for lung transplant evaluation: a survey of physicians in the United States.
      ].
      The aim of this systematic review and meta-analysis was to assess associations of pre-LTx factors with post-LTx mortality in CF and to consider a) whether factors associated with pre-LTx/waitlist mortality also confer a higher risk for post-LTx mortality and b) whether current contraindications for LTx apply to the CF population.

      2. Methods

      2.1 Search strategy and selection criteria

      A systematic literature search was performed to identify studies on CF, LTx, mortality and survival. Ovid Medline, Ovid Medline In-Process and Other Non-Indexed Citations, Ovid EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Clinical Trials, CINAHL and PubMed were searched from inception until January 3, 2018 for articles in English, French, or German. Citations specific to heart-lung transplantation, animal-only studies and book or conference materials were excluded. These searches were complemented by a manual search of reference lists of included articles. The search strategy is detailed in the Appendix A.
      Two independent reviewers (AK, RV) screened the titles and abstracts of all retrieved references. The full-text of relevant articles and also the annual slides of the International Society for Heart and Lung Transplantation (ISHLT) were evaluated. Studies eligible for inclusion were: a) original research articles, b) articles assessing CF patients subjected to LTx and c) articles analyzing pre-operative factors in association with post-LTx mortality. Studies of multi-organ transplantation or re-transplantation were excluded unless they analyzed primary LTx. Studies using graft survival (instead of patient survival) were also excluded. Disagreements over inclusion were resolved by consensus, by contacting the study authors and/or by consulting a 3rd reviewer (LGS, ALS). Literature assessment was done in accordance with the PRISMA guideline [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].
      Pre-LTx factors were extracted and categorized as microbiological and non-microbiological. Donor, intra-operative and post-operative factors were excluded. For each pre-LTx factor, we identified all articles reporting descriptive and/or numeric results. When two or more studies assessed the same patient population during an overlapping time-period, the study with the largest sample size was used for data synthesis. If available, ISHLT registry results were reported but were not included in the meta-analysis due to probable duplicate data with other cohorts. Study authors were contacted when there was uncertainty about patient characteristics, definitions of pre-LTx factors or outcomes, and when the hazard ratio (HR) and 95% confidence interval (CI) were not published. Factors evaluated in ≥2 distinct populations were included in the meta-analysis.

      2.2 Risk of bias assessment

      The risk for bias in included studies was assessed by two independent reviewers (AK, RV) using the Newcastle-Ottawa scale (NOS) for cohort studies [
      • Wells G.
      • Shea B.
      • O'Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      ]. The scale assesses 3 domains: selection, comparability and outcome (details provided in the appendix A - Table S2 footnote). The score ranges from 0 (very high risk of bias) to 9 (very low risk of bias) [
      • Wells G.
      • Shea B.
      • O'Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      ].

      2.3 Data analysis

      Data for the meta-analysis were extracted independently, in duplicate and analyzed in accordance with the PRISMA guideline and the Cochrane Handbook [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ,
      ]. Disagreements were resolved by discussion between the two reviewers and/or by consulting a 3rd author (ALS, LGS, JS). Extracted variables included a) patient characteristics (e.g. age), b) pre-LTx factors, c) outcome of interest (e.g. global mortality and mortality at specific time-points if results differed from those of global mortality, duration of follow-up) and d) summary measures [such as HR (95%CI), odds ratios, risk ratios or data from which they could be extracted]. When the HR (95%CI) was not available but a Kaplan-Meier curve was published, we extracted the HR (95% CI) from the Kaplan-Meier curve [
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • Burdett S.
      • Sydes M.R.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      ]. For BMI, results were synthesized for adults only as BMI is not applicable to children [
      The WHO child growth standards.
      ].
      Clinical heterogeneity between studies was assessed by evaluating a) the study design [e.g. cohort or other, registry or LTx center(s)], b) the population characteristics (adult or pediatric), c) the definitions of factors (discrepant or identical) [
      • Fletcher J.
      What is heterogeneity and is it important?.
      ]. Statistical heterogeneity was assessed by calculating I2 values (I2 > 75% indicating high heterogeneity) [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. Random-effects models were used to calculate the pooled HR (95% CI) using R version 3.3.0 (metafor version 2.0 package). Univariate and multivariable HR reported in the published studies were pooled separately and forest plots were generated. Results of the meta-analyses were reported next to results from the ISHLT registry, if available.

      3. Results

      We screened 3260 references and assessed the full-text of 290 relevant articles, 54 of which were included in the systematic review and 11 in the meta-analysis. Fig. 1 presents the PRISMA flow-diagram [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ] of study selection and Table S1 shows the study characteristics. Twenty-eight (52%) were registry studies and 5 (9%) analyzed data from two or more countries. They included 12 to 7245 transplanted CF patients between 1987 and 2016. Eighteen (33%) studies assessed only adults and 3 (6%) only pediatric patients. All studies had a NOS score ≥ 5 indicating a low-to-moderate risk for bias and 38 (70%) had a score ≥ 7. The most common potential source of bias was the adequacy of follow-up which could not be ascertained for 39 (72%) studies (Table S2).
      Fig. 1
      Fig. 1Flow chart diagram of the search strategy and study selection.
      *Studies assessing multi-organ transplantation or retransplantation at study entry (Table S10), donor or intra-operative factors (Table S11) or graft survival as the outcome (instead of patient survival) (Table S12) were excluded from the systematic review.
      Of the 54 articles, 4 (7%) assessed microbiological factors, 37 (69%) non-microbiological factors and 13 (24%) assessed both. Tables S3-S5 summarize these factors, the process of study identification for the meta-analysis and the final CF sample size. For 5 [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Bartakova L.V.
      • Fila L.
      • Adamek S.
      • et al.
      Lung transplantation in cystic fibrosis patients in the Czech Republic: initial single-center experience.
      ,
      • Ruttens D.
      • Verleden S.E.
      • Vandermeulen E.
      • et al.
      Body mass index in lung transplant candidates: a contra-indication to transplant or not?.
      ,
      • Srour N.
      • Chaparro C.
      • Vandemheen K.
      • Singer L.G.
      • Keshavjee S.
      • Aaron S.D.
      Effect of infection with transmissible strains of Pseudomonas aeruginosa on lung transplantation outcomes in patients with cystic fibrosis.
      ,
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ] of the 11 articles included in the meta-analysis, unpublished results were provided by the authors (Tables S6 and S7). For 10 parameters, for which data from ≥2 studies were available, meta-analysis was performed: 2 microbiological [B. cepacia complex (BCC), P. aeruginosa] and 8 non-microbiological [age, gender, year of LTx, forced expiratory volume in one second (FEV1), pulmonary hypertension (PH), body mass index (BMI), pancreatic insufficiency and CF-related diabetes (CFRD)]. Table 1 provides information about the qualitative assessment of these factors.
      Table 1Qualitative assessment for the 10 predictors which were used for the meta-analysis (qualitative results for predictors not included in the meta-analysis of the Appendix A).
      PredictorStudies
      Studies which assessed these predictors.
      Qualitative assessment
      BCC7
      • -
        Two studies [
        • Liou T.G.
        • Adler F.R.
        • Huang D.
        Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
        ,
        • De Soyza A.
        • Meachery G.
        • Hester K.L.
        • et al.
        Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.
        ] reported no association with post-LTx mortality but in one of these [
        • Liou T.G.
        • Adler F.R.
        • Huang D.
        Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
        ] the association became significant when BCC-age interaction was excluded from the analysis (unpublished results provided by the authors).
      • -
        The other studies reported increased risk of post-LTx mortality.
      P. aeruginosa3None of the studies reported significant associations.
      Age29
      • -
        Eleven studies reported that older age was a protective factor: 8 [
        • Liou T.G.
        • Adler F.R.
        • Huang D.
        Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
        ,
        • Stephenson A.L.
        • Sykes J.
        • Berthiaume Y.
        • et al.
        Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
        ,
        • Hofer M.
        • Schmid C.
        • Benden C.
        • et al.
        Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
        ,
        • Hayes D.
        • Glanville A.R.
        • McGiffin D.
        • Tobias J.D.
        • Tumin D.
        Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
        ,
        • Hayes D.
        • Patel A.V.
        • Black S.M.
        • et al.
        Influence of diabetes on survival in patients with cystic fibrosis before and after lung transplantation.
        ,
        • Braun A.T.
        • Dasenbrook E.C.
        • Shah A.S.
        • Orens J.B.
        • Merlo C.A.
        Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients.
        ,
        • Hayes D.
        • Kopp B.T.
        • Kirkby S.E.
        • et al.
        Impact of donor arterial partial pressure of oxygen on outcomes after lung transplantation in adult cystic fibrosis recipients.
        ,
        • Weiss E.S.
        • Allen J.G.
        • Modi M.N.
        • Merlo C.A.
        • Conte J.V.
        • Shah A.S.
        Lung transplantation in older patients with cystic fibrosis: analysis of UNOS data.
        ,
        • Hayes D.
        • Tumin D.
        • Tobias J.D.
        Pre-transplant panel reactive antibody and survival in adult cystic fibrosis patients after lung transplantation.
        ,
        • Tumin D.
        • Foraker R.E.
        • Tobias J.D.
        • Hayes D.
        No survival benefit to gaining private health insurance coverage for post-lung transplant care in adults with cystic fibrosis.
        ,
        • Hayes D.
        • Sweet S.C.
        • Benden C.
        • et al.
        Transplant center volume and outcomes in lung transplantation for cystic fibrosis.
        ] assessed both adults and pediatric patients and 2 [
        • Braun A.T.
        • Dasenbrook E.C.
        • Shah A.S.
        • Orens J.B.
        • Merlo C.A.
        Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients.
        ,
        • Tumin D.
        • Foraker R.E.
        • Tobias J.D.
        • Hayes D.
        No survival benefit to gaining private health insurance coverage for post-lung transplant care in adults with cystic fibrosis.
        ] assessed adults only.
      • -
        One study [
        • Hayes D.
        • Auletta J.J.
        • Whitson B.A.
        • et al.
        Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
        ] reported that older age was a risk factor for pediatric patients and a protective factor for adults.
      • -
        One study [
        • Gries C.J.
        • Rue T.C.
        • Heagerty P.J.
        • Edelman J.D.
        • Mulligan M.S.
        • Goss C.H.
        Development of a predictive model for long-term survival after lung transplantation and implications for the lung allocation score.
        ] assessed adults and reported a lower mortality risk for the age group 18–25 years old.
      • -
        Two studies [
        • Hayes D.
        • Glanville A.R.
        • McGiffin D.
        • Tobias J.D.
        • Tumin D.
        Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
        ,
        • Villac Adde F.
        • Vidal Campos S.
        • de Oliveira Braga Teixeira R.H.
        • Rodrigues J.C.
        Indications for lung resection surgery and lung transplant in South American children with cystic fibrosis.
        ] assessed age as a categorical variable (pediatric patients vs adults) and reported that pediatric patients had a worse survival
      • -
        The other studies did not report significant associations.
      Gender25
      • -
        One study [
        • Martin C.
        • Hamard C.
        • Kanaan R.
        • et al.
        Causes of death in French cystic fibrosis patients: the need for improvement in transplantation referral strategies!.
        ] reported a lower risk for males.
      • -
        One study [
        • Gries C.J.
        • Rue T.C.
        • Heagerty P.J.
        • Edelman J.D.
        • Mulligan M.S.
        • Goss C.H.
        Development of a predictive model for long-term survival after lung transplantation and implications for the lung allocation score.
        ] reported a higher risk for males.
      • -
        The other studies did not report significant associations.
      Year of LTx16
      • -
        Five studies [
        • Liou T.G.
        • Adler F.R.
        • Huang D.
        Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
        ,
        • Stephenson A.L.
        • Sykes J.
        • Berthiaume Y.
        • et al.
        Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
        ,
        • Hofer M.
        • Schmid C.
        • Benden C.
        • et al.
        Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
        ,
        • Christie J.D.
        • Edwards L.B.
        • Kucheryavaya A.Y.
        • et al.
        The registry of the international society for heart and lung transplantation: Twenty-eighth adult lung and heart-lung transplant report-2011.
        ,
        • Hayes D.
        • Tumin D.
        • Tobias J.D.
        Pre-transplant panel reactive antibody and survival in adult cystic fibrosis patients after lung transplantation.
        ] reported a protective role for more recent years of LTx.
      • -
        The other studies did not report significant associations.
      FEV116
      • -
        Two studies [
        • Hayes D.
        • Auletta J.J.
        • Whitson B.A.
        • et al.
        Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
        ,
        • Hayes D.
        • Tumin D.
        • Tobias J.D.
        Pre-transplant panel reactive antibody and survival in adult cystic fibrosis patients after lung transplantation.
        ] reported that higher FEV1 was protective for post-LTx mortality.
      • -
        The other studies did not report significant associations.
      PH5None of the studies reported significant associations.
      Nutrition/BMI
      Nutritional parameters included BMI, weight % predicted, weight for age z score and fat free mass index. Only for BMI data were sufficient for a meta-analysis.
      25
      • -
        Factors other than BMI were not significantly associated with post-LTx mortality.
      • -
        One study reported an increased risk for higher BMI [
        • Kopp B.T.
        • Groner J.
        • Tobias J.D.
        • Whitson B.A.
        • Kirkby S.
        • Hayes D.
        Cigarette smoking effect on survival after lung transplant in cystic fibrosis.
        ] and two studies [
        • Allen J.G.
        • Arnaoutakis G.J.
        • Weiss E.S.
        • Merlo C.A.
        • Conte J.V.
        • Shah A.S.
        The impact of recipient body mass index on survival after lung transplantation.
        ,
        • Lederer D.J.
        • Wilt J.S.
        • D'Ovidio F.
        • et al.
        Obesity and underweight are associated with an increased risk of death after lung transplantation.
        ] reported a bimodal risk (for underweight and overweight patients): all three studies were performed using the UNOS cohort.
      • -
        The other studies did not report significant associations.
      PI3
      • -
        One study [
        • Stephenson A.L.
        • Sykes J.
        • Berthiaume Y.
        • et al.
        Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
        ] reported an increased risk for pancreatic sufficient patients.
      • -
        The other studies did not report significant associations.
      CFRD17
      • -
        Four [
        • Belle-Van Meerkerk G.
        • van de Graaf E.A.
        • Kwakkel-Van Erp J.M.
        • et al.
        Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.
        ,
        • Gries C.J.
        • Rue T.C.
        • Heagerty P.J.
        • Edelman J.D.
        • Mulligan M.S.
        • Goss C.H.
        Development of a predictive model for long-term survival after lung transplantation and implications for the lung allocation score.
        ,
        • Weiss E.S.
        • Allen J.G.
        • Modi M.N.
        • Merlo C.A.
        • Conte J.V.
        • Shah A.S.
        Lung transplantation in older patients with cystic fibrosis: analysis of UNOS data.
        ,
        • Bradbury R.A.
        • Shirkhedkar D.
        • Glanville A.R.
        • Campbell L.V.
        Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.
        ] studies reported an increased risk of post-LTx mortality: two of these studies [
        • Belle-Van Meerkerk G.
        • van de Graaf E.A.
        • Kwakkel-Van Erp J.M.
        • et al.
        Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.
        ,
        • Bradbury R.A.
        • Shirkhedkar D.
        • Glanville A.R.
        • Campbell L.V.
        Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.
        ] had a small sample size and a small number of events. The other two studies were performed on the UNOS and ISHLT cohorts [
        • Gries C.J.
        • Rue T.C.
        • Heagerty P.J.
        • Edelman J.D.
        • Mulligan M.S.
        • Goss C.H.
        Development of a predictive model for long-term survival after lung transplantation and implications for the lung allocation score.
        ,
        • Weiss E.S.
        • Allen J.G.
        • Modi M.N.
        • Merlo C.A.
        • Conte J.V.
        • Shah A.S.
        Lung transplantation in older patients with cystic fibrosis: analysis of UNOS data.
        ].
      • -
        The other studies did not report significant associations.
      Abbreviations: BCC=Burkholderia cepacia complex, CFRD = CF-related diabetes, FEV1 = forced expiratory volume in one second, LAS = lung allocation system, LTx = lung transplantation, PH = pulmonary hypertension, PI = pancreatic insufficiency.
      a Studies which assessed these predictors.
      b Nutritional parameters included BMI, weight % predicted, weight for age z score and fat free mass index. Only for BMI data were sufficient for a meta-analysis.
      Presence of BCC was associated with post-LTx mortality (3 studies [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Bartakova L.V.
      • Fila L.
      • Adamek S.
      • et al.
      Lung transplantation in cystic fibrosis patients in the Czech Republic: initial single-center experience.
      ,
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ], N = 1451, unadjusted HR = 2.35, 95%CI:1.80–3.06; I2 = 20.4% and 3 studies [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Bartakova L.V.
      • Fila L.
      • Adamek S.
      • et al.
      Lung transplantation in cystic fibrosis patients in the Czech Republic: initial single-center experience.
      ,
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ], N = 1451, adjusted HR = 2.49, 95%CI:1.74–3.57; I2 = 46.2%; Fig. 2). P. aeruginosa colonization was not associated with post-LTx mortality (2 studies [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ], N = 1428, unadjusted HR = 0.81, 95%CI:0.61–1.07; I2 = 0%; Fig. 2). Only one study reported a multivariable HR which was not statistically significant [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ].
      Fig. 2
      Fig. 2Forest plots of pre-LTx microbiological factors in association to post-LTx mortality in CF: a) B. cepacia complex and b) P. aeruginosa.
      Footnote: n signifies the number of events and N the number of patients.
      Microbiological factors not included in the meta-analysis are presented in Table S8. Three studies suggested that species other than B. cenocepacia were not associated with post-LTx mortality [
      • Aris R.M.
      • Routh J.C.
      • Lipuma J.J.
      • Heath D.G.
      • Gilligan P.H.
      Lung transplantation for cystic fibrosis patients with Burkholderia cepacia complex: Survival linked to genomovar type.
      ,
      • De Soyza A.
      • Meachery G.
      • Hester K.L.
      • et al.
      Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.
      ,
      • Murray S.
      • Charbeneau J.
      • Marshall B.C.
      • Lipuma J.J.
      Impact of burkholderia infection on lung transplantation in cystic fibrosis.
      ]. The study of Murray et al. showed a higher mortality risk for B. cenocepacia strains other than PHDC or Midwest and also for B. gladioli [
      • Murray S.
      • Charbeneau J.
      • Marshall B.C.
      • Lipuma J.J.
      Impact of burkholderia infection on lung transplantation in cystic fibrosis.
      ]. Regarding P. aeruginosa strains [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Srour N.
      • Chaparro C.
      • Vandemheen K.
      • Singer L.G.
      • Keshavjee S.
      • Aaron S.D.
      Effect of infection with transmissible strains of Pseudomonas aeruginosa on lung transplantation outcomes in patients with cystic fibrosis.
      ,
      • Pritchard J.
      • Thakrar M.V.
      • Somayaji R.
      • et al.
      Epidemic Pseudomonas aeruginosa infection in patients with cystic fibrosis is not a risk factor for poor clinical Outcomes following lung transplantation.
      ], no significant associations were reported but one study assessing panresistant bacteria other than BCC (all but 2 isolates were P. aeruginosa) described an increased mortality risk [
      • Hadjiliadis D.
      • Steele M.P.
      • Chaparro C.
      • et al.
      Survival of lung transplant patients with cystic fibrosis harboring panresistant bacteria other than Burkholderia cepacia, compared with patients harboring sensitive bacteria.
      ].
      For all patients, age at LTx was not associated with post-LTx mortality but studies were heterogeneous (3 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ,
      • Hofer M.
      • Schmid C.
      • Benden C.
      • et al.
      Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
      ], N = 4307, unadjusted HR = 0.99, 95%CI:0.97–1.01; I2 = 74.2% and 2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 2903, adjusted HR = 1, 95%CI:0.94–1.06; I2 = 97.2%; Fig. 3). For pediatric patients, age was not associated with post-LTx mortality but the studies were heterogeneous (2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 530, unadjusted HR = 0.91, 95%CI:0.74–1.12; I2 = 82.6%; Fig. 3). For adults, older age had a borderline association with lower post-LTx mortality (2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 3677, unadjusted HR = 0.99, 95%CI:0.97–1; I2 = 64.1% and 2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 2605, HR = 0.98, 95%CI:0.97–0.99; I2 = 34.3%; Fig. 3). The latter finding is in accordance with the largest ISHLT study evaluating adult and pediatric CF patients [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ].
      Fig. 3
      Fig. 3Forest plots of non-microbiological factors in association to post-LTx mortality in CF: a) age at LTx, b) gender*, c) year of LTx, d) FEV1, e) pulmonary hypertension, f) BMI†, g) pancreatic insufficiency and h) CF-related diabetes (CFRD).
      *For one study [
      • Hofer M.
      • Schmid C.
      • Benden C.
      • et al.
      Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
      ], the reference category was not given and we considered it was female as in the other papers (sensitivity analysis using male as the reference category provided similar results: HR = 0.97, 95%CI:0.89–1.06; I2 = 7.3%).
      †BMI: Hayes et al. [
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ] range 11.1–42.6 kg/m2, Stephenson et al. [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ] range 13.4–29.6 kg/m2 (31.3% had BMI < 18.5 kg/ m2; 6.4% had BMI < 16 kg/ m2).
      The study of Hayes et al. [
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ] assessed adult and pediatric patients separately. Whenever applicable (i.e. for age-overall, gender, FEV1) both populations were included in the meta-analysis. n signifies the number of events and N the number of patients.
      Regarding gender, for one study [
      • Hofer M.
      • Schmid C.
      • Benden C.
      • et al.
      Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
      ], the reference category was not given and we considered it was female as in the other papers (sensitivity analysis using male as the reference category provided similar results). Male gender had a borderline significant association with post-LTx mortality only in the adjusted analysis (3 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ,
      • Hofer M.
      • Schmid C.
      • Benden C.
      • et al.
      Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
      ], N = 4307, unadjusted HR = 0.98, 95%CI:0.9–1.06; I2 = 4.4% and 2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 2903, adjusted HR = 1.12, 95%CI:1–1.26; I2 = 0%; Fig. 3). The largest ISHLT study did not show significant associations [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ].
      Four unique studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ,
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ,
      • Christie J.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The registry of the international society for heart and lung transplantation: Twenty-eighth adult lung and heart-lung transplant report-2011.
      ] assessed the year of LTx as a continuous covariate. Post-LTx mortality was lower in more recent years in the unadjusted analysis (2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 4207, unadjusted HR = 0.98, 95%CI:0.97–0.98; I2 = 4.8% and 2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 2903, adjusted HR = 0.98, 95%CI:0.97–1; I2 = 52.5%; Fig. 3). The largest ISHLT study assessed year of LTx before and after 2006 as a categorical covariate. LTx before 2006 was associated with an increased post-LTx mortality in the univariate but not in the multivariable analysis [
      • Christie J.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The registry of the international society for heart and lung transplantation: Twenty-eighth adult lung and heart-lung transplant report-2011.
      ].
      FEV1 was not associated with post-LTx mortality (3 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ,
      • Hofer M.
      • Schmid C.
      • Benden C.
      • et al.
      Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
      ], N = 3985, unadjusted HR = 1, 95%CI:0.99–1; I2 = 64.4% and 2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 2903, adjusted HR = 0.99, 95%CI:0.99–1; I2 = 26.6%; Fig. 3).
      Regarding PH, one study [
      • Belle-Van Meerkerk G.
      • Cramer M.J.
      • Kwakkel-Van Erp J.M.
      • et al.
      Pulmonary hypertension is a mild comorbidity in end-stage cystic fibrosis patients.
      ] published a Kaplan-Meier curve from which we extracted the HR. PH was not associated with post-LTx mortality (2 studies [
      • Belle-Van Meerkerk G.
      • Cramer M.J.
      • Kwakkel-Van Erp J.M.
      • et al.
      Pulmonary hypertension is a mild comorbidity in end-stage cystic fibrosis patients.
      ,
      • Kopp B.T.
      • Groner J.
      • Tobias J.D.
      • Whitson B.A.
      • Kirkby S.
      • Hayes D.
      Cigarette smoking effect on survival after lung transplant in cystic fibrosis.
      ], N = 1889, unadjusted HR = 0.98, 95%CI:0.85–1.14; I2 = 0%; Fig. 3). The only study reporting multivariable results also did not find statistically significant association [
      • Singh V.K.
      • Patricia George M.
      • Gries C.J.
      Pulmonary hypertension is associated with increased post-lung transplant mortality risk in patients with chronic obstructive pulmonary disease.
      ].
      BMI was not associated with post-LTx mortality (2 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], N = 3674, unadjusted HR = 0.99, 95%CI:0.97–1.01; I2 = 6.5%; Fig. 3). The largest unique study providing multivariable results showed no associations [
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ], similar to an ISHLT study [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ] (unpublished results, Table S7).
      Pancreatic insufficiency was not associated with post-LTx mortality but the studies were significantly heterogeneous (2 studies [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ], N = 1430, unadjusted HR = 1.24, 95%CI:0.39–3.96; I2 = 86.8%; Fig. 3). One study provided a multivariable HR and reported a higher post-LTx mortality risk for pancreatic sufficient patients [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ].
      CFRD was not associated with post-LTx mortality (3 studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Belle-Van Meerkerk G.
      • van de Graaf E.A.
      • Kwakkel-Van Erp J.M.
      • et al.
      Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.
      ,
      • Hayes D.
      • Patel A.V.
      • Black S.M.
      • et al.
      Influence of diabetes on survival in patients with cystic fibrosis before and after lung transplantation.
      ], N = 2080, unadjusted HR = 1.02, 95%CI:0.87–1.19; I2 = 0% and 2 studies [
      • Srour N.
      • Chaparro C.
      • Vandemheen K.
      • Singer L.G.
      • Keshavjee S.
      • Aaron S.D.
      Effect of infection with transmissible strains of Pseudomonas aeruginosa on lung transplantation outcomes in patients with cystic fibrosis.
      ,
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ], N = 2817, adjusted HR = 1.09, 95%CI:0.96–1.23; I2 = 0%; Fig. 3). The largest available ISHLT study did not report significant associations [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ].
      Table S9 summarizes non-microbiological factors with insufficient data for a meta-analysis. Those associated with a higher risk of post-LTx mortality in a multivariate analysis were infectious/inflammatory lesions on chest imaging [
      • Belle-Van Meerkerk G.
      • de Jong P.A.
      • de Valk H.W.
      • et al.
      Pretransplant HRCT characteristics are associated with worse outcome of lung transplantation for cystic fibrosis patients.
      ], hypoalbuminemia [
      • Baldwin M.R.
      • Arcasoy S.M.
      • Shah A.
      • et al.
      Hypoalbuminemia and early mortality after lung transplantation: a cohort study.
      ] and non-private insurance in the US [
      • Braun A.T.
      • Dasenbrook E.C.
      • Shah A.S.
      • Orens J.B.
      • Merlo C.A.
      Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients.
      ]. Results for pre-LTx mechanical ventilation were inconsistent across studies but the largest unique study reported a statistically significant association with increased post-LTx mortality [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ]. Pediatric transplantation performed in a pediatric LTx center was protective [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ].

      4. Discussion

      This is the first systematic review and meta-analysis assessing transplanted CF patients. We synthesized results from 54 cohort studies reporting pre-LTx factors in association with post-LTx mortality. Pooled estimates of risk were calculated for 10 parameters (BCC, P. aeruginosa, age, gender, chronological year of LTx, FEV1, PH, BMI, pancreatic insufficiency and CFRD) derived from 11 studies. Of these parameters, only BCC was consistently associated with an increased mortality after LTx. Earlier years of LTx were associated with post-LTx mortality only in the univariate synthesis, whereas younger age in adults and male gender had borderline associations with post-LTx mortality. Considering these results collectively, factors such as low FEV1, PH, low BMI, female gender and CFRD known to be associated with pre-LTx/waitlist mortality were not associated with post-LTx mortality, suggesting that risk estimates of post-LTx mortality based on these factors may underestimate the LTx survival benefit in CF. Among other factors, specific strains of B. cenocepacia, B. gladioli, panresistant bacteria other than BCC, mechanical ventilation, infectious/inflammatory lesions in chest imaging, hypoalbuminemia and a poor socio-economic status may be associated with higher post-LTx mortality based on limited evidence.
      BCC infection is associated with an increased risk for pre-LTx mortality [
      • Fauroux B.
      • Hart N.
      • Belfar S.
      • et al.
      Burkholderia cepacia is associated with pulmonary hypertension and increased mortality among cystic fibrosis patients.
      ,
      • Chamnan P.
      • Shine B.S.
      • Haworth C.S.
      • Bilton D.
      • Adler A.I.
      Diabetes as a determinant of mortality in cystic fibrosis.
      ,
      • Folescu T.W.
      • da Costa C.H.
      • Cohen R.W.
      • da Conceicao Neto O.C.
      • Albano R.M.
      • Marques E.A.
      Burkholderia cepacia complex: clinical course in cystic fibrosis patients.
      ,
      • Ramos K.J.
      • Quon B.S.
      • Heltshe S.L.
      • et al.
      Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States.
      ], and, as shown by the meta-analysis, post-LTx mortality. Although species and strain level data were not available, the geographic distribution of the 3 studies included in the meta-analysis suggests B. cenocepacia as the prominent species, with PHDC and Midwest strains being common in US [
      • Murray S.
      • Charbeneau J.
      • Marshall B.C.
      • Lipuma J.J.
      Impact of burkholderia infection on lung transplantation in cystic fibrosis.
      ,
      • Chen J.S.
      • Witzmann K.A.
      • Spilker T.
      • Fink R.J.
      • Lipuma J.J.
      Endemicity and inter-city spread of Burkholderia cepacia genomovar III in cystic fibrosis.
      ], ET12 in Canada [
      • Chaparro C.
      • Maurer J.
      • Gutierrez C.
      • et al.
      Infection with Burkholderia cepacia in cystic fibrosis: outcome following lung transplantation.
      ] and ST32 in the Czech Republic [
      • Fila L.
      • Drevinek P.
      Burkholderia cepacia complex in cystic fibrosis in the post-epidemic period: multilocus sequence typing-based approach.
      ]. Several studies reported that species other than B. cenocepacia are not associated with patient mortality [
      • Aris R.M.
      • Routh J.C.
      • Lipuma J.J.
      • Heath D.G.
      • Gilligan P.H.
      Lung transplantation for cystic fibrosis patients with Burkholderia cepacia complex: Survival linked to genomovar type.
      ,
      • De Soyza A.
      • Meachery G.
      • Hester K.L.
      • et al.
      Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.
      ,
      • Murray S.
      • Charbeneau J.
      • Marshall B.C.
      • Lipuma J.J.
      Impact of burkholderia infection on lung transplantation in cystic fibrosis.
      ] or graft failure [
      • Alexander B.D.
      • Petzold E.W.
      • Reller L.B.
      • et al.
      Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia cepacia complex.
      ,
      • Aris R.M.
      • Gilligan P.H.
      • Neuringer I.P.
      • Gott K.K.
      • Rea J.
      • Yankaskas J.R.
      The effects of panresistant bacteria in cystic fibrosis patients on lung transplant outcome.
      ], however heterogeneity and lack of data precluded meta-analysis. Limited evidence suggests that B. gladioli [
      • Murray S.
      • Charbeneau J.
      • Marshall B.C.
      • Lipuma J.J.
      Impact of burkholderia infection on lung transplantation in cystic fibrosis.
      ] and B. dolosa [
      • Wang R.
      • Welsh S.K.
      • Budev M.
      • et al.
      Survival after Lung Transplantation of Cystic Fibrosis patients Infected with Burkholderia dolosa (Genomovar VI).
      ] may also be associated with worse post-LTx survival. The study of Murray et al. demonstrated that identification of BCC should not in itself be viewed as a sufficient contraindication to LTx and that identification at a strain level is necessary for risk estimation [
      • Ramos K.J.
      • Somayaji R.
      • Lease E.D.
      • Goss C.H.
      • Aitken M.L.
      Cystic fibrosis physicians' perspectives on the timing of referral for lung transplant evaluation: a survey of physicians in the United States.
      ]. In addition to infection control measures and development of anti-BCC treatments, multicenter studies to further refine risk stratification of patients with BCC are needed.
      Lower FEV1 [
      • Chamnan P.
      • Shine B.S.
      • Haworth C.S.
      • Bilton D.
      • Adler A.I.
      Diabetes as a determinant of mortality in cystic fibrosis.
      ,
      • Ramos K.J.
      • Quon B.S.
      • Heltshe S.L.
      • et al.
      Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States.
      ,
      • Kerem E.
      • Reisman J.
      • Corey M.
      • Canny G.J.
      • Levison H.
      Prediction of mortality in patients with cystic fibrosis.
      ,
      • Sharma R.
      • Florea V.G.
      • Bolger A.P.
      • et al.
      Wasting as an independent predictor of mortality in patients with cystic fibrosis.
      ,
      • Rosenfeld M.
      • Davis R.
      • Fitzsimmons S.
      • Pepe M.
      • Ramsey B.
      Gender gap in cystic fibrosis mortality.
      ,
      • Belkin R.A.
      • Henig N.R.
      • Singer L.G.
      • et al.
      Risk factors for death of patients with cystic fibrosis awaiting lung transplantation.
      ] or PH [
      • Venuta F.
      • Tonelli A.R.
      • Anile M.
      • et al.
      Pulmonary hypertension is associated with higher mortality in cystic fibrosis patients awaiting lung transplantation.
      ,
      • Selimovic N.
      • Andersson B.
      • Bergh C.H.
      • et al.
      Pulmonary hemodynamics as predictors of mortality in patients awaiting lung transplantation.
      ,
      • Tonelli A.R.
      Pulmonary hypertension survival effects and treatment options in cystic fibrosis.
      ], especially in female patients [
      • Chamnan P.
      • Shine B.S.
      • Haworth C.S.
      • Bilton D.
      • Adler A.I.
      Diabetes as a determinant of mortality in cystic fibrosis.
      ,
      • Ramos K.J.
      • Quon B.S.
      • Heltshe S.L.
      • et al.
      Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States.
      ,
      • Rosenfeld M.
      • Davis R.
      • Fitzsimmons S.
      • Pepe M.
      • Ramsey B.
      Gender gap in cystic fibrosis mortality.
      ,
      • Harness-Brumley C.L.
      • Elliott A.C.
      • Rosenbluth D.B.
      • Raghavan D.
      • Jain R.
      Gender differences in outcomes of patients with cystic fibrosis.
      ,
      • McColley S.A.
      • Schechter M.S.
      • Morgan W.J.
      • Pasta D.J.
      • Craib M.L.
      • Konstan M.W.
      Risk factors for mortality before age 18 years in cystic fibrosis.
      ] and CFRD [
      • Chamnan P.
      • Shine B.S.
      • Haworth C.S.
      • Bilton D.
      • Adler A.I.
      Diabetes as a determinant of mortality in cystic fibrosis.
      ,
      • Ramos K.J.
      • Quon B.S.
      • Heltshe S.L.
      • et al.
      Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States.
      ,
      • Lewis C.
      • Blackman S.M.
      • Nelson A.
      • et al.
      Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex.
      ] have been consistently associated with mortality risk in the general CF population and are considered indications for LTx referral [
      • Weill D.
      • Benden C.
      • Corris P.A.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014—an update from the pulmonary transplantation council of the international society for heart and lung transplantation.
      ]. Pooled risk estimates did not show significant associations between post-LTx mortality and any of these factors. For FEV1 and PH, this is not surprising since LTx leads to their improvement. For gender, results are of particular interest and indicate that the gender gap conferring a worse survival for women before LTx [
      • Chamnan P.
      • Shine B.S.
      • Haworth C.S.
      • Bilton D.
      • Adler A.I.
      Diabetes as a determinant of mortality in cystic fibrosis.
      ,
      • Rosenfeld M.
      • Davis R.
      • Fitzsimmons S.
      • Pepe M.
      • Ramsey B.
      Gender gap in cystic fibrosis mortality.
      ,
      • Harness-Brumley C.L.
      • Elliott A.C.
      • Rosenbluth D.B.
      • Raghavan D.
      • Jain R.
      Gender differences in outcomes of patients with cystic fibrosis.
      ,
      • McColley S.A.
      • Schechter M.S.
      • Morgan W.J.
      • Pasta D.J.
      • Craib M.L.
      • Konstan M.W.
      Risk factors for mortality before age 18 years in cystic fibrosis.
      ] is not observed after LTx. Interestingly, the multivariable synthesis showed a borderline significant mortality risk for male gender, a trend previously reported by Gries et al. [
      • Gries C.J.
      • Rue T.C.
      • Heagerty P.J.
      • Edelman J.D.
      • Mulligan M.S.
      • Goss C.H.
      Development of a predictive model for long-term survival after lung transplantation and implications for the lung allocation score.
      ] However, the univariate synthesis was not statistically significant, and this result may reflect the adjustment for different factors between studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ]. Finally, CFRD diagnosed before LTx was not associated with post-LTx mortality in the meta-analysis. Although no study has assessed the effect of pre-LTx glycemic control on post-LTx outcomes, a recent study evaluating diabetes after LTx showed that CF patients have worse glycemic control than patients with other diagnoses and that poor glycemic control is associated with increased mortality [
      • Hackman K.L.
      • Snell G.I.
      • Bach L.A.
      Poor Glycemic Control is Associated with Decreased Survival in Lung Transplant Recipients.
      ]. Future research on diabetic control may improve risk stratification of patients with CFRD.
      Malnutrition is a relative contraindication for LTx [
      • Weill D.
      • Benden C.
      • Corris P.A.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014—an update from the pulmonary transplantation council of the international society for heart and lung transplantation.
      ] and BMI is the most commonly used parameter to assess nutritional status in adult LTx candidates [
      • Allen J.G.
      • Arnaoutakis G.J.
      • Weiss E.S.
      • Merlo C.A.
      • Conte J.V.
      • Shah A.S.
      The impact of recipient body mass index on survival after lung transplantation.
      ,
      • Lederer D.J.
      • Wilt J.S.
      • D'Ovidio F.
      • et al.
      Obesity and underweight are associated with an increased risk of death after lung transplantation.
      ]. In the general CF population, poor nutritional status has been consistently associated with increased pre-LTx/waitlist mortality [
      • Ramos K.J.
      • Quon B.S.
      • Heltshe S.L.
      • et al.
      Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States.
      ,
      • Sharma R.
      • Florea V.G.
      • Bolger A.P.
      • et al.
      Wasting as an independent predictor of mortality in patients with cystic fibrosis.
      ,
      • Rosenfeld M.
      • Davis R.
      • Fitzsimmons S.
      • Pepe M.
      • Ramsey B.
      Gender gap in cystic fibrosis mortality.
      ,
      • Belkin R.A.
      • Henig N.R.
      • Singer L.G.
      • et al.
      Risk factors for death of patients with cystic fibrosis awaiting lung transplantation.
      ,
      • McColley S.A.
      • Schechter M.S.
      • Morgan W.J.
      • Pasta D.J.
      • Craib M.L.
      • Konstan M.W.
      Risk factors for mortality before age 18 years in cystic fibrosis.
      ,
      • Snell G.I.
      • Bennetts K.
      • Bartolo J.
      • et al.
      Body mass index as a predictor of survival in adults with cystic fibrosis referred for lung transplantation.
      ]. Regarding post-LTx survival, no studies evaluated progressive malnutrition but several assessed BMI values at listing and 3 studies from the US reported significant associations [
      • Kopp B.T.
      • Groner J.
      • Tobias J.D.
      • Whitson B.A.
      • Kirkby S.
      • Hayes D.
      Cigarette smoking effect on survival after lung transplant in cystic fibrosis.
      ,
      • Allen J.G.
      • Arnaoutakis G.J.
      • Weiss E.S.
      • Merlo C.A.
      • Conte J.V.
      • Shah A.S.
      The impact of recipient body mass index on survival after lung transplantation.
      ,
      • Lederer D.J.
      • Wilt J.S.
      • D'Ovidio F.
      • et al.
      Obesity and underweight are associated with an increased risk of death after lung transplantation.
      ]. Lederer et al. studied adult CF and non-CF LTx recipients and reported a higher post-transplant mortality risk for underweight and overweight patients. However, for CF, only 2% patients were overweight and being underweight was associated with 5-year but not 1-year mortality [
      • Lederer D.J.
      • Wilt J.S.
      • D'Ovidio F.
      • et al.
      Obesity and underweight are associated with an increased risk of death after lung transplantation.
      ]. In the meta-analysis, the pooled risk estimates from the two largest unique studies [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ] did not reach statistical significance, findings corroborated by an ISHLT report [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ] and six additional studies excluded from the meta-analysis because they evaluated graft survival [
      • Ruttens D.
      • Verleden S.E.
      • Vandermeulen E.
      • et al.
      Body mass index in lung transplant candidates: a contra-indication to transplant or not?.
      ,
      • Levine H.
      • Prais D.
      • Raviv Y.
      • et al.
      Lung transplantation in cystic fibrosis patients in Israel: the importance of ethnicity and nutritional status.
      ] or included cases of multi-organ transplantation and/or retransplantation [
      • Snell G.I.
      • Bennetts K.
      • Bartolo J.
      • et al.
      Body mass index as a predictor of survival in adults with cystic fibrosis referred for lung transplantation.
      ,
      • Levine H.
      • Prais D.
      • Raviv Y.
      • et al.
      Lung transplantation in cystic fibrosis patients in Israel: the importance of ethnicity and nutritional status.
      ,
      • Merlo C.A.
      • Clark S.C.
      • Arnaoutakis G.J.
      • et al.
      National healthcare delivery systems influence lung transplant outcomes for cystic fibrosis.
      ,
      • Dobbin C.
      • Maley M.
      • Harkness J.
      • Benn R.
      • Malouf M.
      • Glanville A.
      • Bye P.
      The impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral Centre.
      ]. Two potential explanations for this lack of observed association could be a biphasic effect of BMI on post-LTx mortality which cannot be captured by the pooled risk estimates and a patient selection bias resulting from the exclusion of severely malnourished patients from LTx. However, the low incidence of overweight CF LTx candidates mitigates the effect of the former. Concerning the latter, although we cannot exclude that the low proportion of severely malnourished patients could contribute to the absence of statistical significance, the BMI range of the studies synthesized in the meta-analysis [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ,
      • Hayes D.
      • Auletta J.J.
      • Whitson B.A.
      • et al.
      Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.
      ] (Table S7) shows that patients with severe malnutrition were included in the studied population. For the pediatric population, limited nutritional status data did not allow a meta-analysis but an ISHLT registry study did not find significant associations between the BMI percentile or the grade of thinness (International Obesity Task Force cut-offs) and post-LTx survival in children with CF. [
      • Benden C.
      • Ridout D.A.
      • Edwards L.B.
      • Boehler A.
      • Christie J.D.
      • Sweet S.C.
      Body mass index and its effect on outcome in children after lung transplantation.
      ] These results indicate that BMI may not be a sufficiently sensitive marker of nutritional status to allow risk stratification in this setting. More importantly, since patients with low BMI are at high risk for waitlist mortality but not necessarily post-LTx mortality, they may have an increased survival benefit from LTx. Thus, delaying listing on the basis of low BMI alone may be associated with an increased risk of death on the waitlist for these patients.
      The two factors with significant heterogeneity in the meta-analysis were age at LTx and pancreatic insufficiency. Results for age in pediatric patients were not significant but hampered by study heterogeneity. For adults, the meta-analysis indicated a protective effect of older age, similar to the results reported from the ISHLT registry [
      • Hayes D.
      • Glanville A.R.
      • McGiffin D.
      • Tobias J.D.
      • Tumin D.
      Age-related survival disparity associated with lung transplantation in cystic fibrosis: an analysis of the registry of the International Society for Heart and Lung Transplantation.
      ]. However, the borderline significant association and the adjustment for different factors between studies in the multivariable analysis does not allow for definite conclusions. Regarding pancreatic insufficiency, the pooled estimates of risk did not reach significance and only one study provided adjusted HR for this factor showing a higher mortality risk for pancreatic sufficient patients [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ]. Considering the very high prevalence of pancreatic insufficiency in CF LTx candidates (exceeding 90%) and potential interactions of this factor with age, malnutrition and CFRD, interpretation of this finding is challenging [
      • Liou T.G.
      • Adler F.R.
      • Huang D.
      Use of lung transplantation survival models to refine patient selection in cystic fibrosis.
      ,
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ].
      The limitations of observational and registry studies also apply to meta-analyses [
      • Norgaard M.
      • Ehrenstein V.
      • Vandenbroucke J.P.
      Confounding in observational studies based on large health care databases: problems and potential solutions - a primer for the clinician.
      ,
      • Urschel S.
      Apples, oranges, and statistical magic: Limitations of registry studies and need for collaborative studies.
      ]. Patient selection bias, publication bias and residual confounding may be present. The selection bias is particularly relevant for LTx studies which include only patients accepted for LTx. Moreover, acceptance criteria vary across centers and across allocation systems. We could not assess publication bias in our review due to small number of studies in each analysis. However, based on the exhaustive search and discussion with prominent investigators in the field, we are confident that we have not missed significant studies in our review. In order to assess adjusted estimates, we pooled data from studies which reported adjusted HR. This should be interpreted with caution as there were differences in the covariates used in various studies. Additionally, all studies being observational in nature, residual confounding due to unmeasured confounders always remains. The largest populations in the meta-analysis were from North America, possibly reducing the generalizability of the results. Finally, despite the many factors retrieved from the literature, data on several key variables that may affect post-LTx outcomes (e.g. psychosocial issues or rare microbial pathogens such as Scedosporium spp) were lacking or described in case reports only. Moreover, none of the previously studied factors could recapitulate the multidimensional assessment performed at listing. Concerning donor and/or intraoperative factors, although these were excluded from the systematic review, they could also affect patient outcomes. However, their interpretation can be more difficult considering that recipients' characteristics may also influence decisions about donor and/or intra-operative factors. These limitations were considered during the interpretation of our findings.
      The main strengths of this systematic review and meta-analysis are the rigorous methodology for study selection, analysis and heterogeneity assessment, the low risk for bias of the included studies and their large sample size. The main difficulties encountered were the lack of harmonized definitions for many factors, studies including multi-organ transplantation or re-transplantation, different outcomes (patient survival, graft survival), studies assessing the same patient population and partially published results. Our methodology addressed each of these issues and, in many cases, study authors were contacted for clarification and unpublished results, facilitating data synthesis and interpretation. This emphasizes the need for standardized reporting in studies of predictive models as proposed by the published TRIPOD statement [
      • Collins G.S.
      • Reitsma J.B.
      • Altman D.G.
      • Moons K.G.
      Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement.
      ]. We believe that these recommendations should be a requirement for future publications on this subject.
      In conclusion, risk stratification of LTx candidates is a complex integration of patient-specific data, evidence from the literature and clinical expertise from the multidisciplinary LTx team. This systematic literature review and meta-analysis is a comprehensive summary of current evidence on pre-LTx factors and post-LTx mortality in CF. Although a large number of parameters have been studied in this setting, data sufficient for a meta-analysis were available only for 10 factors. These factors are currently used in clinical practice during the evaluation of LTx candidates but they cannot recapitulate the comprehensive assessment performed by the LTx and CF teams. Concerning microbiological parameters, pre-LTx BCC colonization was associated with increased post-LTx mortality, whereas, for P. aeruginosa, colonization did not confer an increased mortality risk but limited evidence suggested that panresistant isolates may be associated with worse post-LTx outcomes. The main finding was that parameters, such FEV1, PH, BMI, CFRD and female gender, associated with increased mortality before LTx do not confer a higher risk for post-LTx mortality. Risk estimates of post-LTx mortality based on these factors may underestimate the LTx survival benefit in CF, and the current use of BMI as a relative contraindication may need to be adjusted for the CF-population. These findings support the use of CF-specific estimates of risk for LTx listing and prioritization. Future research focusing on more granular information (e.g. BCC strains, glycemic control, malnutrition measures other than BMI), potentially modifiable factors, multidimensional factors such as frailty, as well as separate analyses for adult and pediatric populations may help refine patient risk stratification, optimize access to LTx and improve post-LTx outcomes. Moreover, to understand independent impact of these factors on outcomes, an individual patient data meta-analysis using either retrospective or prospective data would help us to refine the quantitative role of individual predictors. Finally, standardized reporting should be a requirement for publications on this subject to facilitate future integration and interpretation of the results.

      Contributors

      AK contributed to the study concept and design, study selection, data extraction, quality assessment, manuscript drafting and revision. AK had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. RV contributed to study selection, data extraction, quality assessment and revision of the manuscript. JS contributed to data analysis and revision of the manuscript. AOC designed the literature search strategy, performed the literature search and contributed to the revision of the manuscript. PSS provided methodological and statistical advice and revised the manuscript for important intellectual content. CC and ET revised the manuscript for important intellectual content. LGS and ALS contributed to the study design and supervision, and revised the manuscript for important intellectual content. All authors reviewed the study findings, read and approved the final version before submission.

      Funding sources

      During this study, AK received grants from the Swiss National Science Foundation (grant P300PB_164733) and the University Hospital of Lausanne (Fond de perfectionnement). The funding sources had no role in study design, data collection, data analysis or writing of the report.

      Conflict of interest

      We declare no competing interests.

      Acknowledgments

      We would like to thank all the authors who replied to our enquiries, and especially Dr. Fred Adler, Dr. Hubert Chen, Dr. Libor Fila, Dr. Denis Hadjiliadis, Dr. Jan Havlin, Dr. Don Hayes, Dr. Markus Hofer, Dr. Naritaka Kimura, Dr. Theodore G. Liou, Dr. Robert Lischke, Dr. Michael Parkins, Dr. Julia Pritchard, Dr. Antoine Roux, Dr. Nadim Srour, Dr. Dmitry Tumin, Dr. Lucie Valentova-Bartakova and Dr. Stijn Verleden for so kindly providing additional results and information for their studies that helped us perform this systematic review and meta-analysis.

      Appendix A. Supplementary data

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