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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Cystic fibrosis foundation consensus statements for the care of cystic fibrosis lung transplant recipients

Open AccessPublished:April 22, 2021DOI:https://doi.org/10.1016/j.healun.2021.04.011
      Cystic fibrosis (CF) is the indication for transplantation in approximately 15% of recipients worldwide, and Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have excellent long-term outcomes. Yet, CFLTRs have unique comorbidities that require specialized care. The objective of this document is to provide recommendations to CF and lung transplant clinicians for the management of perioperative and underlying comorbidities of CFLTRs and the impact of transplantation on these comorbidities. The Cystic Fibrosis Foundation (CFF) organized a multidisciplinary committee to develop CF Lung Transplant Clinical Care Recommendations. Three workgroups were formed to develop focused questions. Following a literature search, consensus recommendations were developed by the committee members based on literature review, committee experience and iterative revisions, and in response to public comment. The committee formulated 32 recommendation statements in the topics related to infectious disease, endocrine, gastroenterology, pharmacology, mental health and family planning. Broadly, the committee recommends close coordination of care between the lung transplant team, the cystic fibrosis care center, and specialists in other disciplines with experience in the care of CF and lung transplant recipients. These consensus statements will help lung transplant providers care for CFLTRs in order to improve post-transplant outcomes in this population.

      KEYWORDS

      Abbreviations:

      A1C (glycosylated hemoglobin), BAL (bronchoalveolar lavage), BOS (bronchiolitis obliterans syndrome), BMI (body mass index), CFF (Cystic Fibrosis Foundation), CFLD (cystic fibrosis liver disease), CFLTRs (cystic fibrosis lung transplant recipients), CFRD (cystic fibrosis-related diabetes), CFTR (cystic fibrosis transmembrane conductance regulator), CLAD (chronic lung allograft dysfunction), CRS (chronic rhinosinusitis), DGE (delayed gastric emptying), DIOS (dital intestinal obstruction syndrome), ECFS (European Cystic Fibrosis Society), ICMH (International Committee on Mental Health), IPC (infection prevention and control), OGTT (oral glucose tolerance test), PEG (polyethylene glycol), PERT (pancreatic enzyme replacement therapy), PI (pancreatic insufficiency), SBGM (self-blood glucose monitoring), SNOT-22 (sino-nasal outcome test-22)
      Cystic fibrosis (CF) is the indication for lung transplantation in approximately 15% of adults and 50% of children worldwide.
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      International society for H, lung T. The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-sixth adult lung and heart-lung transplantation report-2019; focus theme: donor and recipient size match.
      ,
      • Hayes Jr., D
      • Cherikh WS
      • Chambers DC
      • et al.
      International society for H, lung T. The international thoracic organ transplant registry of the international society for heart and lung transplantation: twenty-second pediatric lung and heart-lung transplantation report-2019; focus theme: donor and recipient size match.
      Furthermore, adult Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have the best survival among all pre-transplant diagnostic groups after transplantation, with a 10-year survival of 49%.
      • Chambers DC
      • Cherikh WS
      • Harhay MO
      • et al.
      International society for H, lung T. The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-sixth adult lung and heart-lung transplantation report-2019; focus theme: donor and recipient size match.
      However, the considerable variability in the proportion of patients transplanted for CF at different centers, appears to be independent of overall lung transplant center volume.

      Services USDoHH. Organ Procurement and Transplantation Network: Build Advanced. Accessed November 6, 2019. https://optn.transplant.hrsa.gov/data/view-data-reports/build-advanced.

      Thus, even at large-volume transplant centers, clinicians may have limited experience in the management of CF-associated comorbidities such as malnutrition, malabsorption, sinus disease, osteoporosis, diabetes, and infectious risks. Notably, higher center transplant volume for individuals with CF, but not overall center transplant volume, was independently associated with a significant survival advantage among CFLTRs.
      • Hayes Jr., D
      • Sweet SC
      • Benden C
      • et al.
      Transplant center volume and outcomes in lung transplantation for cystic fibrosis.
      This suggests CF-specific expertise may improve long-term survival among CFLTRs. The goal of these consensus statements is to provide practical recommendations to lung transplant clinicians on topics important for the care of CFLTRs immediately prior to and after transplantation. These recommendations (summarized in Table 1) do not cover general advanced lung disease management, transplant referral and post-transplant topics that are not CF-specific. Existing, relevant, Cystic Fibrosis Foundation (CFF) clinical care guidelines are referenced (Table 2).
      Table 1Summary of Consensus Recommendations for the care of Cystic Fibrosis Lung Transplant Recipients
      GENERAL CARE% vote
      1The CF Foundation recommends that CF Lung Transplant Recipients follow up with a multidisciplinary CF care team within 6-12 months of transplant to resume extra-pulmonary CF care. Communication between the transplant and CF care teams is essential for coordination of care100%
      2The CF Foundation recommends that CF and Transplant programs operationalize infection prevention and control policies across all services as indicated by the CF Foundation's Infection Prevention and Control Guidelines
      • Saiman L
      • Siegel JD
      • LiPuma JJ
      • et al.
      Cystic fibrous F, society for healthcare epidemiology of A. Infection prevention and control guideline for cystic fibrosis: 2013 update.
      95%
      INFECTIOUS DISEASE
      3The CF Foundation recommends that non–invasive CF-specific bacterial, fungal, and AFB respiratory cultures be obtained by the transplant or CF center every 3 months in actively waitlisted transplant candidates and that clinicians review prior pathogen history to guide the peri-operative antibiotic regimen100%
      4The CF Foundation recommends an intraoperative CF bacterial, fungal and AFB culture of the native lung be obtained at the time of lung transplantation100%
      5In CF Lung Transplant Recipients with multidrug resistant pathogens, susceptibility-driven antimicrobials should be administered when the recipient has a susceptible antibiotic choice with acceptable toxicity. In the absence of a susceptibility-driven perioperative choice, consider previously effective regimens100%
      6For CF Lung Transplant Recipients, the CF Foundation found insufficient evidence to recommend for or against routine intraoperative pleural and tracheal irrigation with antimicrobial agents to decrease infections after transplant100%
      7The CF Foundation recommends consideration of perioperative and/or early posttransplant inhaled antibiotics for bacterial pathogens isolated prior to transplant as a complement to systemic antimicrobials in CF Lung Transplant Recipients100%
      8The CF Foundation found insufficient evidence to recommend for or against the use of inhaled antibiotics for prevention of recolonization or chronic lung allograft dysfunction (CLAD)100%
      9The CF Foundation found insufficient evidence to recommend for or against the routine collection of sputum for bacterial, fungal or AFB cultures in asymptomatic CF Lung Transplant Recipients100%
      10The CF Foundation found insufficient evidence to recommend for or against the use of antimicrobials for bacteria isolated from the airways in asymptomatic CF Lung Transplant Recipients95%
      SINUS DISEASE
      11In individuals with CF and asymptomatic chronic rhinosinusitis (CRS), the CF Foundation recommends against pre-transplant prophylactic sinus surgery for the prevention of lung graft colonization.100%
      12The CF Foundation recommends screening CF Lung Transplant Recipients for symptoms of CRS at least annually100%
      13The CF Foundation recommends that CF Lung Transplant Recipients with moderate or severe symptomatic CRS be seen in consultation with an otolaryngologist experienced in CF for consideration of optimal topical therapies and endoscopic sinus surgery100%
      14The CF Foundation recommends that CF Lung Transplant Recipients who have had multiple bacterial allograft infections be seen in consultation with an otolaryngologist with CF expertise regardless of their CRS symptoms100%
      NUTRITION and GASTROINTESTINAL COMPLICATIONS
      15For CF Lung Transplant Recipients, the CF Foundation recommends ongoing consultation with a dietitian with CF expertise, in order to receive individualized nutritional therapy to achieve an established BMI or weight-for-length goal100%
      16In CF Lung Transplant Recipients, the CF Foundation recommends continuation of Vitamin D supplementation, discontinuation of combination vitamin A,D,E,K supplements after lung transplantation, measuring fat soluble vitamin levels by 3 months after transplant, and individually repleting and following levels as needed.100%
      17The CF Foundation recommends daily symptom assessment for early signs of obstipation and obstruction in hospitalized patients that might herald emergence of distal intestinal obstruction syndrome (DIOS), particularly within the immediate post-operative period and with any opiate medication administration100%
      18In CF Lung Transplant Recipients who develop DIOS, the CF Foundation recommends consideration of early enteral lavage. Refractory DIOS should be managed in coordination with experts in CF gastrointestinal complications to reduce risk for prolonged obstruction and potential need for operative management100%
      19For CF Lung Transplant Recipients who experience new or worsening symptoms of gastrointestinal dysmotility, the CF Foundation recommends consultation with a gastroenterologist and a dietitian with CF expertise to guide the approach to symptom control and potential interventions100%
      20The CF Foundation recommends that CF Lung Transplant Recipients have liver enzyme monitoring for CF Liver Disease (CFLD) at least annually, and when elevated, non-invasive imaging techniques for initial evaluation
      DIABETES and BONE HEALTH
      21In CF Lung Transplant Recipients who do not have Cystic Fibrosis-Related Diabetes (CFRD), the CF Foundation recommends screening with an oral glucose tolerance test (OGTT) at 3-6 months after transplant, then annually following the recommended screening guidelines for CFRD
      • Karlas T
      • Neuschulz M
      • Oltmanns A
      • Wirtz H
      • Keim V
      • Wiegand J.
      ARFI and transient elastography for characterization of cystic fibrosis related liver disease: first longitudinal follow-up data in adult patients.
      95%
      22For CF Lung Transplant Recipients who have CFRD, the CF Foundation recommends treatment with insulin, continued intensive self-blood glucose monitoring (SBGM), and individualized close clinical follow-up, in addition to lifestyle modifications. Furthermore, the CF Foundation recommends consultation with an endocrinologist with CF and transplant associated DM expertise, when possible
      23For CF Lung Transplant Recipients, the CF Foundation recommends that bone density be assessed with dual energy X-ray absorptiometry (DEXA) at 6-12 months after transplant100%
      MENTAL HEALTH and FAMILY PLANNING
      24The CF Foundation recommends that CF Lung Transplant Recipients have mental health screening and consultation for depression, anxiety, and post-traumatic stress disorder (PTSD) within 6 months of transplant, then resume annual screening per the International Committee on Mental Health (ICMH) Depression and Anxiety Guidelines(157)100%
      25The CF Foundation recommends screening caregivers of CF Lung Transplant Recipients for depression, anxiety, and PTSD within 6 months of transplant and referral for further assessment if necessary90%
      26The CF Foundation recommends that females with CF who are post-lung transplant and are considering pregnancy carefully assess their individual risks through shared decision making with maternal fetal medicine and transplant providers100%
      27The CF Foundation recommends that females with CF who are post-lung transplant avoid pregnancy for at least the first 2 years after transplantation because of the increased risk of acute rejection, accelerated chronic rejection, and death100%
      PHARMACOLOGY and THERAPEUTICS
      28The CF Foundation found insufficient evidence to recommend for or against the use of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators for CF Lung Transplant Recipients100%
      29The CF Foundation found insufficient evidence to recommend for or against the use of induction immunosuppression for CF Lung Transplant Recipients100%
      30The CF Foundation recommends that CF Lung Transplant Recipients have close monitoring of calcineurin inhibitor drug levels because of altered pharmacokinetics100%
      31Reduced renal function is common in CF Lung Transplant Recipients, and serum creatinine is often a poor surrogate for renal function. Therefore, the CF Foundation recommends medication dosing appropriate for glomerular filtration rate (GFR), and when available, the use of therapeutic drug monitoring100%
      32The CF Foundation found insufficient evidence to recommend for or against the routine use of airway clearance, dornase alfa, or hypertonic saline among CF Lung Transplant Recipients100%
      Topics reviewed where no consensus was reached:
      PICOStatementvoting
      Should azithromycin be resumed shortly after lung transplant in patients with CF?The Committee could not reach a consensus regarding the routine use of azithromycin in individuals with CF in the immediate period after lung transplantation to decrease the risk of CLAD.10 – for

      9 -against
      Table 2Relevant Existing CF Foundation Clinical Care Guidelines
      Care topic in CFExisting CF foundation guidelines
      Colorectal Cancer ScreeningHadjiliadis D, Khoruts A, Zauber AG et al. Cystic Fibrosis Colorectal Cancer Screening Consensus Recommendations. Gastroenterology. 2018
      Enteral Tube FeedingSchwarzenberg SJ, Hempstead SE, McDonald CM et al. Enteral Tube Feeding for Individuals with Cystic Fibrosis: CFF Evidence-Informed Guidelines. J Cyst Fibros. 2016.
      Nutrition in Children and AdultsStallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systemic review. J Am Diet Assoc. 2008.
      Vitamin D DeficiencyTangpricha V, Kelly A, Stephenson A, et al. An Update on the Screening, Diagnosis, Management and Treatment of Vitamin D Deficiency in Individuals with Cystic Fibrosis: Evidence-Based Recommendations from the Cystic Fibrosis Foundation. J Clin Endocrinol Metab. 2012
      Bone HealthAris RM, Merkel PA, Bachrach LK, et al. Guide to Bone Health and Disease in Cystic Fibrosis. J Clin Endocrinol Metab. 2005.
      DiabetesMoran A, Brunzell C, Cohen R, et al. Clinical Care Guidelines for Cystic Fibrosis-Related Diabetes. Diabetes Care. 2010
      Liver DiseaseSokol RJ, Durie PR, et al. Recommendations for Management of Liver and Biliary Tract Disease in Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 1999.
      Depression and AnxietyQuittner AL, Abbott J, Georgiopoulos AM, et al. International Committee on Mental Health in Cystic Fibrosis: CFF and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety. Thorax. 2016.
      Infection Prevention and ControlSaiman L, Siegel JD, LiPuma JJ, et al. Infection Prevention and Control Guideline for Cystic Fibrosis: 2013 Update Infect Control Hosp Epidemiol. 2014 Aug;35 Suppl 1:S1-S67. Epub 2014 Jul 1.
      Advanced CF Lung DiseaseKapnadak SG, Dimango E, Hajiliadis D et al. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease. J. Cystic Fibros. 2020
      Lung Transplant ReferralRamos KJ, Smith PJ, McKone EF, Pilewski JM, et al. Lung transplant referral for individuals with cystic fibrosis: Cystic Fibrosis Foundation consensus guidelines. J Cyst Fibros. 2019 May;18(3):321-333.
      Models of Palliative CareKavalieratos D, Georgiopoulos AM, Dhingra L, Basile MJ, Rabinowitz E, Hempstead SE, Faro A, Dellon EP. Models of Palliative Care Delivery for Individuals with Cystic Fibrosis: Cystic Fibrosis Foundation Evidence-Informed Consensus Guidelines. J Palliat Med. 2021 Jan;24(1):18-30.
      Additional and new CF Foundation Clinical Care Guidelines can be found on this website: https://www.cff.org/Care/Clinical-Care-Guidelines/
      As of publication upcoming guidelines include ENT, and an update to CFLD.

      Methods

      The CFF invited a multidisciplinary team of adult and pediatric transplant pulmonologists, infectious diseases, gastroenterology, endocrinology physicians, transplant coordinator, dietitian, pharmacist, psychologist, 2 adult CFLTRs, and a caregiver to participate in the development of these consensus statements. The committee met in June 2018 to determine the scope of the work and divided into 3 workgroups focused on Infectious Disease, extra-pulmonary CF considerations, and psychologic and pharmacologic considerations.  Information about the literature search and results can be found in the prisma diagram (Figure 1) and in the supplemental material. The workgroups developed draft recommendations based on these results and established an a priori voting threshold of 80% agreement for approval of a recommendation. For topics in which there was insufficient evidence-based literature to guide best practice (e.g., recommendations 3, 4, 9, 11, and 13), the recommendations were based on consensus opinion from the committee. The committee reconvened in September 2019 to iteratively revise and vote on the draft recommendation statements. Voting on any statements that were not finalized at that meeting was completed via video conference. Committee members who were unable to attend the conference were provided with a recording of the meeting and voted by email.
      The manuscript was reviewed by the committee before distribution for public comment in February 2020. The committee reviewed and acknowledged and/or addressed each of the comments received during public comment. The literature searches for each workgroup were run again in March 2020 to ensure new publications had not been missed.
      • 1)
        The CFF recommends that CFLTRs follow up with a multidisciplinary CF care team within 6-12 months of transplant to resume extra-pulmonary CF care. Communication between the transplant and CF care teams is essential for coordination of care.
      Although no studies have examined the impact of multidisciplinary CF care after lung transplantation, extra-pulmonary manifestations of CF persist after transplant and require expertise in CF care.
      • Kurland G
      • Orenstein DM.
      Lung transplantation and cystic fibrosis: the psychosocial toll.
      • Yankaskas JR
      • Aris R.
      Outpatient care of the cystic fibrosis patient after lung transplantation.
      • Corris PA.
      Post heart/lung transplantation management.
      • Hirche TO
      • Knoop C
      • Hebestreit H
      • et al.
      Practical guidelines: lung transplantation in patients with cystic fibrosis.
      Individuals with CF should resume CF care at either their referring or transplant institution's CF care center and continue follow-up at minimum every 12 months, or more frequently depending on the individual's clinical course. CF care may be also provided at the transplant center provided sufficient local expertise and resources for individuals with CF. Close communication between the individual with CF, lung transplant and the CF care team is essential to ensure coordination of care.
      • Yankaskas JR
      • Aris R.
      Outpatient care of the cystic fibrosis patient after lung transplantation.
      ,
      • Hirche TO
      • Knoop C
      • Hebestreit H
      • et al.
      Practical guidelines: lung transplantation in patients with cystic fibrosis.

      Infectious disease

      • 2)
        The CFF recommends that CF and Transplant programs operationalize infection prevention and control policies across all services as indicated by the CFF's Infection Prevention and Control Guidelines.
        • Saiman L
        • Siegel JD
        • LiPuma JJ
        • et al.
        Cystic fibrous F, society for healthcare epidemiology of A. Infection prevention and control guideline for cystic fibrosis: 2013 update.
      After transplant, individuals with CF may still be at risk of acquiring or transmitting pathogens that are present in their upper respiratory tract. Pre-transplant person-to-person and equipment-based transmission with fatal outbreaks are well documented in individuals with CF, which led to the CFF's Infection Prevention and Control (IPC) guidelines.
      • Saiman L
      • Siegel JD
      • LiPuma JJ
      • et al.
      Cystic fibrous F, society for healthcare epidemiology of A. Infection prevention and control guideline for cystic fibrosis: 2013 update.
      ,
      • Aitken ML
      • Limaye A
      • Pottinger P
      • et al.
      Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center.
      Early epidemiologic studies confirmed the isolation of strains of pathogens after transplant that were isolated from the same individual before transplant, but person-to-person transmission after transplant has yet to be documented.
      • Aitken ML
      • Limaye A
      • Pottinger P
      • et al.
      Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center.
      • Choi KJ
      • Cheng TZ
      • Honeybrook AL
      • et al.
      Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis.
      • Steinbach S
      • Sun L
      • Jiang RZ
      • et al.
      Transmissibility of Pseudomonas cepacia infection in clinic patients and lung-transplant recipients with cystic fibrosis.
      • Walter S
      • Gudowius P
      • Bosshammer J
      • et al.
      Epidemiology of chronic Pseudomonas aeruginosa infections in the airways of lung transplant recipients with cystic fibrosis.
      • Rademacher J
      • Fuge J
      • Welte T
      • Gottlieb J
      • Suhling H.
      Infection transmission among lung transplant couples.
      Nonetheless, the potential for person-to-person transmission after transplant, or between individuals with CF before and after transplant exists, especially if those individuals are cared for in a shared clinical setting.
      • Egan JJ
      • Chadwick P
      • Lowe L
      • Woodcock AA.
      The potential of nosocomial transmission of Pseudomonas cepacia exists at cardiopulmonary transplant centers.
      Therefore, CFF recommends that all healthcare personnel caring for individuals with CF regardless of transplant status implement policies per CFF IPC guidelines.
      • Saiman L
      • Siegel JD
      • LiPuma JJ
      • et al.
      Cystic fibrous F, society for healthcare epidemiology of A. Infection prevention and control guideline for cystic fibrosis: 2013 update.
      This should be done anywhere these individuals receive care, including in-patient and out-patient units such as clinics, wards, rehabilitation units, pulmonary function laboratories, bronchoscopy and radiology suites. The recommendations include universal and contact precautions (gown, gloves and hand hygiene) for all staff caring for individuals with CF, and the use of a mask for all individuals with CF in clinical facilities. Individuals with CF, regardless of transplant status, should follow 6-foot (2 meters) separation between themselves from others with CF.
      • 3)
        The CFF recommends that non–invasive CF-specific bacterial, fungal, and AFB respiratory cultures be obtained by the transplant or CF center every 3 months in actively waitlisted transplant candidates and that clinicians review prior pathogen history to guide the peri-operative antibiotic regimen.
      • 4)
        The CFF recommends an intraoperative CF bacterial, fungal and AFB culture of the native lung be obtained at the time of lung transplantation.
      • 5)
        In CFLTRs with multidrug resistant pathogens, susceptibility-driven antimicrobials should be administered when the recipient has a susceptible antibiotic choice with acceptable toxicity. In the absence of a susceptibility-driven perioperative choice, consider previously effective regimens.
      Individuals with CF awaiting lung transplant may have chronic respiratory infection with bacteria, fungi, and mycobacteria, which are often multidrug resistant. While no randomized controlled trials exist to determine the optimal peri-operative antimicrobial management, retrospective studies suggest treatment with susceptibility-targeted antimicrobials is ideal.
      • Flume PA
      • Egan TM
      • Paradowski LJ
      • Detterbeck FC
      • Thompson JT
      • Yankaskas JR.
      Infectious complications of lung transplantation. Impact of cystic fibrosis.
      • Madden BP
      • Kamalvand K
      • Chan CM
      • Khaghani A
      • Hodson ME
      • Yacoub M.
      The medical management of patients with cystic fibrosis following heart-lung transplantation.
      • Aris RM
      • Gilligan PH
      • Neuringer IP
      • Gott KK
      • Rea J
      • Yankaskas JR.
      The effects of panresistant bacteria in cystic fibrosis patients on lung transplant outcome.
      • Nunley DR
      • Grgurich W
      • Iacono AT
      • et al.
      Allograft colonization and infections with pseudomonas in cystic fibrosis lung transplant recipients.
      • Haja Mydin H
      • Corris PA
      • Nicholson A
      • et al.
      Targeted antibiotic prophylaxis for lung transplantation in cystic fibrosis patients colonised with pseudomonas aeruginosa using multiple combination bactericidal testing.
      • Howell CK
      • Paciullo CA
      • Lyon GM
      • et al.
      Effect of positive perioperative donor and recipient respiratory bacterial cultures on early post-transplant outcomes in lung transplant recipients.
      • Raats D
      • Lorent N
      • Saegeman V
      • et al.
      Successful lung transplantation for chronic Mycobacterium abscessus infection in advanced cystic fibrosis, a case series.
      Individuals with CF are often infected with organisms with changing sensitivity profiles, due to variation in the dominant strain(s) and susceptibilities. The number and range of organisms may vary due to overgrowth of a predominant organism limiting the ability of the laboratory to identify all organisms present.
      Therefore, routine collection of sputum cultures every 3 months for individuals on the transplant waitlist is recommended. In addition, sampling of the native lung for cultures at the time of transplantation is recommended, although the optimal sampling strategy is unclear. Published strategies include expectorated sputum prior to surgery, intra-operative bronchoalveolar lavage (BAL) prior to explantation, or large airway swab and/or tissue culture of the native lung.
      There are no data to guide the timeframe of growth to inform peri-operative antimicrobial therapy. However, if an organism is repeatedly recovered from prior respiratory samples, targeted susceptibility-driven peri-operative antimicrobial therapy is appropriate, even if the isolate is not present on the most recent culture.
      • 6)
        For CFLTRs, the CFF found insufficient evidence to recommend for or against routine intraoperative pleural and tracheal irrigation with antimicrobial agents to decrease infections after transplant.
      There are several reports of the use of topical disinfecting agents, such as taurolidine and povidone-iodine, at the time of surgery to irrigate the chest cavity and reduce bacterial load in conjunction with systemic antimicrobials to reduce the severity of respiratory infections after lung transplantation. These studies included patients colonized with Burkholderia cenocepacia along with other pathogens.
      • Aris RM
      • Gilligan PH
      • Neuringer IP
      • Gott KK
      • Rea J
      • Yankaskas JR.
      The effects of panresistant bacteria in cystic fibrosis patients on lung transplant outcome.
      ,
      • Egan TM
      • Detterbeck FC
      • Mill MR
      • et al.
      Improved results of lung transplantation for patients with cystic fibrosis.
      • Khan SU
      • Gordon SM
      • Stillwell PC
      • Kirby TJ
      • Arroliga AC.
      Empyema and bloodstream infection caused by Burkholderia gladioli in a patient with cystic fibrosis after lung transplantation.
      • Nash EF
      • Coonar A
      • Kremer R
      • et al.
      Survival of Burkholderia cepacia sepsis following lung transplantation in recipients with cystic fibrosis.
      • De Soyza A
      • Meachery G
      • Hester KL
      • et al.
      Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.
      • Zeriouh M
      • Sabashnikov A
      • Patil NP
      • et al.
      Use of taurolidine in lung transplantation for cystic fibrosis and impact on bacterial colonization.
      However, most studies employed pleural irrigation in conjunction with other antimicrobial management and did not specifically examine the effect of irrigation on outcomes after transplant. Two studies noted that taurolidine irrigation was associated with a reduction in short-term infections; however, this agent is not available in many countries.
      • Zeriouh M
      • Sabashnikov A
      • Patil NP
      • et al.
      Use of taurolidine in lung transplantation for cystic fibrosis and impact on bacterial colonization.
      ,
      • Perry JD
      • Riley G
      • Johnston S
      • Dark JH
      • Gould FK.
      Activity of disinfectants against Gram-negative bacilli isolated from patients undergoing lung transplantation for cystic fibrosis.
      Although these agents have minimal adverse effects and little evidence of systemic absorption, higher quality studies comparing different agents and administration techniques are needed to determine optimal use.
      • 7)
        The CFF recommends consideration of perioperative and/or early posttransplant inhaled antibiotics for bacterial pathogens isolated prior to transplant as a complement to systemic antimicrobials in CFLTRs.
      • 8)
        The CFF found insufficient evidence to recommend for or against the use of inhaled antibiotics for prevention of re-infection or chronic lung allograft dysfunction (CLAD).
      CFLTRs are at risk for re-infection with pathogens which they were infected with before transplant. Susceptibility-driven antimicrobial therapy in the perioperative period is recommended, although antimicrobial regimens may be limited by toxicity. Randomized-controlled studies are lacking, but inhaled antimicrobials in conjunction with systemic therapy may help reduce infections during the period of the most intensive immunosuppression early after transplant while reducing toxicity from systemic therapy.
      • Alexander BD
      • Petzold EW
      • Reller LB
      • et al.
      Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia cepacia complex.
      ,
      • Suhling H
      • Rademacher J
      • Greer M
      • et al.
      Inhaled colistin following lung transplantation in colonised cystic fibrosis patients.
      Prevention of re-infection using inhaled antibiotics remains controversial, and the impact of re-infection may be related to specific organisms. Up to 87% of CFLTRs infected with Burkholderia cepacia complex before transplant had positive cultures after transplant despite inhaled antibiotics.
      • Alexander BD
      • Petzold EW
      • Reller LB
      • et al.
      Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia cepacia complex.
      Recovery of gram-negative bacteria in CFLTRs who were infected pre-transplant was not affected by inhaled antipseudomonal antibiotics in at least 2 cohorts,
      • Suhling H
      • Rademacher J
      • Greer M
      • et al.
      Inhaled colistin following lung transplantation in colonised cystic fibrosis patients.
      ,
      • Moore CA
      • Pilewski JM
      • Venkataramanan R
      • et al.
      Effect of aerosolized antipseudomonals on Pseudomonas positivity and bronchiolitis obliterans syndrome after lung transplantation.
      however, a subset of patients without pre-transplant infection receiving inhaled colistin did not develop any positive cultures after transplant.
      • Suhling H
      • Rademacher J
      • Greer M
      • et al.
      Inhaled colistin following lung transplantation in colonised cystic fibrosis patients.
      No studies have examined on inhaled antibiotics for the prevention of CLAD; however 2 retrospective studies showed no benefit of inhaled antibiotics in reducing CLAD progression.
      • Suhling H
      • Rademacher J
      • Greer M
      • et al.
      Inhaled colistin following lung transplantation in colonised cystic fibrosis patients.
      ,
      • Moore CA
      • Pilewski JM
      • Venkataramanan R
      • et al.
      Effect of aerosolized antipseudomonals on Pseudomonas positivity and bronchiolitis obliterans syndrome after lung transplantation.
      Caution should be used with inhaled tobramycin when renal function is impaired, as tobramycin may accumulate systemically and worsen renal function.
      • Ahya VN
      • Doyle AM
      • Mendez JD
      • et al.
      Renal and vestibular toxicity due to inhaled tobramycin in a lung transplant recipient.
      • Kahler DA
      • Schowengerdt KO
      • Fricker FJ
      • Mansfield M
      • Visner GA
      • Faro A.
      Toxic serum trough concentrations after administration of nebulized tobramycin.
      • Hoffmann IM
      • Rubin BK
      • Iskandar SS
      • Schechter MS
      • Nagaraj SK
      • Bitzan MM.
      Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy.
      • Edson RS
      • Brey RH
      • McDonald TJ
      • Terrell CL
      • McCarthy JT
      • Thibert JM.
      Vestibular toxicity due to inhaled tobramycin in a patient with renal insufficiency.
      • 9)
        The CFF found insufficient evidence to recommend for or against the routine collection of sputum for bacterial, fungal or AFB cultures in asymptomatic CFLTRs.
      • 10)
        The CFF found insufficient evidence to recommend for or against the use of antimicrobials for bacteria isolated from the airways in asymptomatic CFLTRs.
      While there is consensus on the importance of prompt diagnosis and treatment of symptomatic infections, the utility of routine sputum cultures in asymptomatic individuals after transplant is uncertain. Most literature regarding the impact of infection after transplant were based on BAL samples from clinically indicated or surveillance bronchoscopy (SB).
      • Valentine VG
      • Gupta MR
      • Weill D
      • et al.
      Single-institution study evaluating the utility of surveillance bronchoscopy after lung transplantation.
      • Guilinger RA
      • Paradis IL
      • Dauber JH
      • et al.
      The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients.
      • Starobin D
      • Fink G
      • Shitrit D
      • et al.
      The role of fiberoptic bronchoscopy evaluating transplant recipients with suspected pulmonary infections: analysis of 168 cases in a multi-organ transplantation center.
      Small studies implicated the persistent isolation of Pseudomonas aeruginosa in airway samples after transplant with the development of CLAD, but these findings were not validated in larger, multivariate analyses.
      • Vos R
      • Vanaudenaerde BM
      • Geudens N
      • Dupont LJ
      • Van Raemdonck DE
      • Verleden GM.
      Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation?.
      ,
      • Gottlieb J
      • Mattner F
      • Weissbrodt H
      • et al.
      Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis.
      Retrospective studies that examined the incidence of P aeruginosa re-isolation and CLAD progression stratified by treatment with aerosolized antibiotics did not find an association between treatment and CLAD progression among CFLTRs.
      • Suhling H
      • Rademacher J
      • Greer M
      • et al.
      Inhaled colistin following lung transplantation in colonised cystic fibrosis patients.
      ,
      • Moore CA
      • Pilewski JM
      • Venkataramanan R
      • et al.
      Effect of aerosolized antipseudomonals on Pseudomonas positivity and bronchiolitis obliterans syndrome after lung transplantation.
      Similarly, a single-center study of antibiotic treatment of Stenotrophomonas in asymptomatic CFLTRs showed no impact on microbial clearance or lung function.
      • Hofmann P
      • Hombach M
      • Seifert B
      • et al.
      Isolation of Stenotrophomonas maltophilia in asymptomatic lung transplant recipients: effects of treatment on eradication and outcome.
      The pathogenicity of bacteria in asymptomatic individuals post-transplant is unclear, but emerging data suggest that isolation of strain-specific pathogens present prior to transplant may not confer the same risk of CLAD in CFLTRs as the isolation of new strains, even within the same species.
      • Hofmann P
      • Hombach M
      • Seifert B
      • et al.
      Isolation of Stenotrophomonas maltophilia in asymptomatic lung transplant recipients: effects of treatment on eradication and outcome.
      ,
      • Willner DL
      • Hugenholtz P
      • Yerkovich ST
      • et al.
      Reestablishment of recipient-associated microbiota in the lung allograft is linked to reduced risk of bronchiolitis obliterans syndrome.
      However, no studies specifically examined whether antimicrobial therapy in asymptomatic CFLTRs directed against de novo vs pre-transplant isolates confers protection from acute pneumonia and/or CLAD. Thus, no specific management recommendation regarding the use of antimicrobials for asymptomatic bacterial airway isolates can be made.

      Sinus disease

      • 11)
        In individuals with CF and asymptomatic chronic rhinosinusitis (CRS), the CFF recommends against pre-transplant prophylactic sinus surgery for the prevention of lung graft colonization.
      • 12)
        The CFF recommends screening CFLTRs for symptoms of CRS at least annually.
      • 13)
        The CFF recommends that CFLTRs with moderate or severe symptomatic CRS be seen in consultation with an otolaryngologist experienced in CF for consideration of optimal topical therapies and endoscopic sinus surgery.
      • 14)
        The CFF recommends that CFLTRs who have had multiple bacterial allograft infections be seen in consultation with an otolaryngologist with CF expertise regardless of their CRS symptoms.
      CRS is seen in the majority of CFLTRs.
      • Morlacchi LC
      • Greer M
      • Tudorache I
      • et al.
      The burden of sinus disease in cystic fibrosis lung transplant recipients.
      Although evidence is sparse, screening tools, such as the Sino-Nasal Outcome Test-22 (SNOT-22), discriminated symptomatic CRS from asymptomatic CRS, while radiologic imaging was less sensitive.
      • Kang SH
      • Meotti CD
      • Bombardelli K
      • Piltcher OB
      • de Tarso Roth Dalcin P.
      Sinonasal characteristics and quality of life by SNOT-22 in adult patients with cystic fibrosis.
      • Habib AR
      • Quon BS
      • Buxton JA
      • et al.
      The sino-nasal outcome test-22 as a tool to identify chronic rhinosinusitis in adults with cystic fibrosis.
      • Ayoub N
      • Thamboo A
      • Habib AR
      • Nayak JV
      • Hwang PH.
      Determinants and outcomes of upfront surgery versus medical therapy for chronic rhinosinusitis in cystic fibrosis.
      Observational studies assessing the utility of pre- or post- transplant sinus surgery on CFTLRs regardless of symptoms found no substantive impact on post-transplant outcomes including CLAD, graft re-infection, or survival.
      • Morlacchi LC
      • Greer M
      • Tudorache I
      • et al.
      The burden of sinus disease in cystic fibrosis lung transplant recipients.
      ,
      • Holzmann D
      • Speich R
      • Kaufmann T
      • et al.
      Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience.
      • Leung MK
      • Rachakonda L
      • Weill D
      • Hwang PH.
      Effects of sinus surgery on lung transplantation outcomes in cystic fibrosis.
      • Vital D
      • Hofer M
      • Boehler A
      • Holzmann D.
      Posttransplant sinus surgery in lung transplant recipients with cystic fibrosis: a single institutional experience.
      • Vital D
      • Hofer M
      • Benden C
      • Holzmann D
      • Boehler A.
      Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients.
      • Aanaes K
      • von Buchwald C
      • Hjuler T
      • Skov M
      • Alanin M
      • Johansen HK.
      The effect of sinus surgery with intensive follow-up on pathogenic sinus bacteria in patients with cystic fibrosis.
      • Cheng TZ
      • Choi KJ
      • Honeybrook AL
      • et al.
      Decreased antibiotic utilization after sinus surgery in cystic fibrosis patients with lung transplantation.
      Evidence for the impact of sinus surgery on the reduction in microbial isolates from BAL in asymptomatic CFLTRs is mixed; some studies report decreases and others report no change.
      • Morlacchi LC
      • Greer M
      • Tudorache I
      • et al.
      The burden of sinus disease in cystic fibrosis lung transplant recipients.
      ,
      • Leung MK
      • Rachakonda L
      • Weill D
      • Hwang PH.
      Effects of sinus surgery on lung transplantation outcomes in cystic fibrosis.
      ,
      • Vital D
      • Hofer M
      • Benden C
      • Holzmann D
      • Boehler A.
      Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients.
      CFLTRs with symptomatic CRS had sinus cultures that strongly correlated with BAL cultures, particularly for P aeruginosa, MRSA, and B cepacia complex.
      • Choi KJ
      • Cheng TZ
      • Honeybrook AL
      • et al.
      Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis.
      ,
      • Morlacchi LC
      • Greer M
      • Tudorache I
      • et al.
      The burden of sinus disease in cystic fibrosis lung transplant recipients.
      ,
      • Vital D
      • Hofer M
      • Benden C
      • Holzmann D
      • Boehler A.
      Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients.
      ,
      • Ciofu O
      • Johansen HK
      • Aanaes K
      • et al.
      P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs.
      One investigation observed similar gene expression profiles in P aeruginosa strains between both compartments, suggesting bidirectional movement.
      • Ciofu O
      • Johansen HK
      • Aanaes K
      • et al.
      P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs.
      For symptomatic CRS, endoscopic sinus surgery after lung transplantation resulted in fewer positive bacterial isolates from the allograft, fewer infections, and less antibiotic utilization in single center observational studies.
      • Holzmann D
      • Speich R
      • Kaufmann T
      • et al.
      Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience.
      ,
      • Vital D
      • Hofer M
      • Boehler A
      • Holzmann D.
      Posttransplant sinus surgery in lung transplant recipients with cystic fibrosis: a single institutional experience.
      ,
      • Aanaes K
      • von Buchwald C
      • Hjuler T
      • Skov M
      • Alanin M
      • Johansen HK.
      The effect of sinus surgery with intensive follow-up on pathogenic sinus bacteria in patients with cystic fibrosis.
      ,
      • Cheng TZ
      • Choi KJ
      • Honeybrook AL
      • et al.
      Decreased antibiotic utilization after sinus surgery in cystic fibrosis patients with lung transplantation.
      ,
      • Virgin FW
      • Rowe SM
      • Wade MB
      • et al.
      Extensive surgical and comprehensive postoperative medical management for cystic fibrosis chronic rhinosinusitis.
      • Vital D
      • Holzmann D
      • Boehler A
      • Hofer M.
      Nasal polyposis in lung transplant recipients with cystic fibrosis.
      • Liang J
      • Higgins TS
      • Ishman SL
      • Boss EF
      • Benke JR
      • SY Lin
      Surgical management of chronic rhinosinusitis in cystic fibrosis: a systematic review.
      • Aanaes K
      • Johansen HK
      • Skov M
      • et al.
      Clinical effects of sinus surgery and adjuvant therapy in cystic fibrosis patients - can chronic lung infections be postponed?.
      • Liang J
      • Higgins T
      • Ishman SL
      • Boss EF
      • Benke JR
      • SY Lin
      Medical management of chronic rhinosinusitis in cystic fibrosis: a systematic review.
      • Alanin MC
      • Aanaes K
      • Hoiby N
      • et al.
      Sinus surgery postpones chronic Gram-negative lung infection: cohort study of 106 patients with cystic fibrosis.
      The use of perioperative intravenous antibiotics in CFLTRs who undergo sinus surgery may be beneficial despite lack of evidence and therefore close coordination between otolaryngology, the CF team and the lung transplant team is necessary to determine the optimal timing and duration of treatment in relation to sinus surgery.
      Although small randomized-controlled trials and systematic reviews have reported improved quality of life (QOL) and decreases in SNOT-22 scores in patients with CF and CRS with the use of topical nasal dornase alfa, steroids, antimicrobials, isotonic and hypertonic saline, there is no available data on these therapies in CFLTRs.
      • Liang J
      • Higgins T
      • Ishman SL
      • Boss EF
      • Benke JR
      • SY Lin
      Medical management of chronic rhinosinusitis in cystic fibrosis: a systematic review.
      ,
      • Lim M
      • Citardi MJ
      • Leong JL.
      Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review.
      • Mainz JG
      • Schadlich K
      • Schien C
      • et al.
      Sinonasal inhalation of tobramycin vibrating aerosol in cystic fibrosis patients with upper airway Pseudomonas aeruginosa colonization: results of a randomized, double-blind, placebo-controlled pilot study.
      • Mainz JG
      • Schumacher U
      • Schadlich K
      • et al.
      Sino nasal inhalation of isotonic versus hypertonic saline (6.0%) in CF patients with chronic rhinosinusitis - Results of a multicenter, prospective, randomized, double-blind, controlled trial.
      • Mainz JG
      • Schiller I
      • Ritschel C
      • et al.
      Sinonasal inhalation of dornase alfa in CF: a double-blind placebo-controlled cross-over pilot trial.
      • Shah GB
      • De Keyzer L
      • Russell JA
      • Halderman A.
      Treatment of chronic rhinosinusitis with dornase alfa in patients with cystic fibrosis: a systematic review.
      One small study examined the impact of a CFTR modulator, ivacaftor, on CRS and reported a clinically insignificant decrease in SNOT-22 scores and improved QOL.
      • McCormick J
      • Cho DY
      • Lampkin B
      • et al.
      Ivacaftor improves rhinologic, psychologic, and sleep-related quality of life in G551D cystic fibrosis patients.
      Since appropriate sinus treatment could potentially decrease allograft infection in CFLTRs, consultation with an otolaryngologist with CF expertise is recommended to individualize therapy for CFLTRs with symptomatic CRS.

      Extra-pulmonary CF considerations

      • 15)
        For CFLTRs, the CFF recommends ongoing consultation with a dietitian with CF expertise, in order to receive individualized nutritional therapy to achieve an established BMI or weight-for-length goal.
      • 16)
        In CFLTRs, the CFF recommends continuation of Vitamin D supplementation, discontinuation of combination vitamin A, D, E, K supplements after lung transplantation, measuring fat soluble vitamin levels by 3 months after transplant, and individually repleting and following levels as needed.
      Approximately 90% of individuals with CF have pancreatic insufficiency (PI) and experience malabsorption despite pancreatic enzyme replacement therapy (PERT).
      • Schindler T
      • Michel S
      • Wilson AW.
      Nutrition management of cystic fibrosis in the 21st century.
      Immediately after lung transplantation, CF-related metabolic and gastrointestinal comorbidities impact nutrition.
      • Holcombe BJ
      • Resler R.
      Nutrition support for lung transplant patients.
      ,
      • Toussaint E
      • Van Gossum A
      • Ballarin A
      • et al.
      Percutaneous endoscopic jejunostomy in patients with gastroparesis following lung transplantation: feasibility and clinical outcome.
      Predictive equations often underestimate energy needs in both the peri-operative transplant periods with needs ranging from 110% to 200% compared to individuals without CF.
      • Hollander FM
      • Kok A
      • de Roos NM
      • et al.
      Prediction equations underestimate resting energy expenditure in patients with end-stage cystic fibrosis.
      ,
      • Carney KC
      • Bronzell-Wynder T
      • Gronek K.
      Lung transplant for the critical care nurse.
      Energy needs gradually decline after lung transplant due to decreased energy expenditure from reduced pulmonary demands and improved appetite.
      • Holcombe BJ
      • Resler R.
      Nutrition support for lung transplant patients.
      ,
      • Madill J
      • Maurer JR
      • de Hoyos A.
      A comparison of preoperative and postoperative nutritional states of lung transplant recipients.
      Nutritional status typically improves after transplant, with the most significant weight gains seen in those previously malnourished.
      • Chamogeorgakis T
      • Mason DP
      • Murthy SC
      • et al.
      Impact of nutritional state on lung transplant outcomes.
      ,
      • Hollander FM
      • van Pierre DD
      • de Roos NM
      • et al.
      Effects of nutritional status and dietetic interventions on survival in cystic fibrosis patients before and after lung transplantation.
      In CFLTRs, achieving goal body mass index (BMI) at 1 year after transplant was associated with improved survival and freedom from CLAD.
      • Levine H
      • Prais D
      • Raviv Y
      • et al.
      Lung transplantation in cystic fibrosis patients in Israel: the importance of ethnicity and nutritional status.
      ,
      • Benden C
      • Ridout DA
      • Edwards LB
      • Boehler A
      • Christie JD
      • Sweet SC.
      Body mass index and its effect on outcome in children after lung transplantation.
      Given fluctuating energy needs, ongoing consultation by a CF dietitian is recommended to avoid malnutrition and obesity.
      • Hollander FM
      • Kok A
      • de Roos NM
      • et al.
      Prediction equations underestimate resting energy expenditure in patients with end-stage cystic fibrosis.
      ,
      • Rafii M
      • Chapman K
      • Stewart C
      • et al.
      Changes in response to insulin and the effects of varying glucose tolerance on whole-body protein metabolism in patients with cystic fibrosis.
      • Kalnins D
      • Pencharz PB
      • Grasemann H
      • Solomon M.
      Energy expenditure and nutritional status in pediatric patients before and after lung transplantation.
      • Staufer K
      • Halilbasic E
      • Hillebrand P
      • et al.
      Impact of nutritional status on pulmonary function after lung transplantation for cystic fibrosis.
      The development of hypervitaminosis A and E has been observed in CF and non-CFLTRs; thus, the routine continuation of CF-specific combination vitamins after transplant is not recommended.
      • Stephenson A
      • Brotherwood M
      • Robert R
      • et al.
      Increased vitamin A and E levels in adult cystic fibrosis patients after lung transplantation.
      • Ho T
      • Gupta S
      • Brotherwood M
      • et al.
      Increased serum vitamin A and E levels after lung transplantation.
      • Colombo C
      • Costantini D
      • Rocchi A
      • et al.
      Effects of liver transplantation on the nutritional status of patients with cystic fibrosis.
      Instead, monitoring fat soluble vitamin levels starting at 3 months after transplant and repleting individual deficiencies as needed is recommended.
      • Schindler T
      • Michel S
      • Wilson AW.
      Nutrition management of cystic fibrosis in the 21st century.
      ,
      • Hubert G
      • Chung TT
      • Prosser C
      • et al.
      Bone mineral density and fat-soluble vitamin status in adults with cystic fibrosis undergoing lung transplantation: a pilot study.
      In addition to well-known effects on bone health, single-center investigations have demonstrated an association between vitamin D deficiency and acute cellular rejection, but the impact of vitamin D replacement on this risk is unclear.
      • Lowery EM
      • Bemiss B
      • Cascino T
      • et al.
      Low vitamin D levels are associated with increased rejection and infections after lung transplantation.
      • Lee P
      • Samaras K
      • Glanville AR
      • Center JR.
      Transplant recipients on the edge of the hypocalcemia abyss.
      • Verleden SE
      • Vos R
      • Geenens R
      • et al.
      Vitamin D deficiency in lung transplant patients: is it important?.
      Continuation of Vitamin D supplementation after transplant with dose adjustment based on serum levels is recommended.
      • 17)
        The CFF recommends daily symptom assessment for early signs of obstipation and obstruction in hospitalized patients that might herald emergence of distal intestinal obstruction syndrome (DIOS), particularly within the immediate post-operative period and with any opiate medication administration.
      • 18)
        In CFLTRs who develop DIOS, the CFF recommends consideration of early enteral lavage. Refractory DIOS should be managed in coordination with experts in CF gastrointestinal complications to reduce risk for prolonged obstruction and potential need for operative management.
      DIOS is a common complication in CFLTRs, with up to 20% higher prevalence in those with a history of meconium ileus or abdominal surgery.
      • Gilljam M
      • Chaparro C
      • Tullis E
      • Chan C
      • Keshavjee S
      • Hutcheon M.
      GI complications after lung transplantation in patients with cystic fibrosis.
      • Minkes RK
      • Langer JC
      • Skinner MA
      • et al.
      Intestinal obstruction after lung transplantation in children with cystic fibrosis.
      • Morton JR
      • Ansari N
      • Glanville AR
      • Meagher AP
      • Lord RV.
      Distal intestinal obstruction syndrome (DIOS) in patients with cystic fibrosis after lung transplantation.
      As DIOS occurring in the immediate post-operative period carries significant morbidity,
      • Minkes RK
      • Langer JC
      • Skinner MA
      • et al.
      Intestinal obstruction after lung transplantation in children with cystic fibrosis.
      ,
      • Paul S
      • Escareno CE
      • Clancy K
      • Jaklitsch MT
      • Bueno R
      • Lautz DB.
      Gastrointestinal complications after lung transplantation.
      ,
      • Grass F
      • Schafer M
      • Cristaudi A
      • et al.
      Incidence and risk factors of abdominal complications after lung transplantation.
      medical measures to reduce its incidence should be optimized and aggressively pursued. Single-center experiences suggest that pre-operative bowel lavage with osmotic laxative may reduce the development of DIOS in the immediate post-operative period.
      • Gilljam M
      • Chaparro C
      • Tullis E
      • Chan C
      • Keshavjee S
      • Hutcheon M.
      GI complications after lung transplantation in patients with cystic fibrosis.
      ,
      • Boyle MP
      • Orens JB.
      Distal intestinal obstruction syndrome after surgery in cystic fibrosis.
      Immediately after transplant, interventions including early enteral feeding, resumption of Pancreatic Enzyme Replacement Therapy, prophylactic bowel regimens, minimization of medications that impair bowel motility, ambulation,and adequate fluid and electrolyte repletion may help reduce the development of DIOS.
      • Gilljam M
      • Chaparro C
      • Tullis E
      • Chan C
      • Keshavjee S
      • Hutcheon M.
      GI complications after lung transplantation in patients with cystic fibrosis.
      ,
      • Boyle MP
      • Orens JB.
      Distal intestinal obstruction syndrome after surgery in cystic fibrosis.
      • Houwen RH
      • van der Doef HP
      • Sermet I
      • et al.
      Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.
      • Colombo C
      • Ellemunter H
      • Houwen R
      • Munck A
      • Taylor C
      • Wilschanski M
      Ecfs
      Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients.
      Some centers employ post-operative enteral infusion of intestinal lavage solution such as polyethylene glycol (PEG, macrogol) as data suggest a potential decrease in the prevalence of DIOS.
      • Gilljam M
      • Chaparro C
      • Tullis E
      • Chan C
      • Keshavjee S
      • Hutcheon M.
      GI complications after lung transplantation in patients with cystic fibrosis.
      ,
      • Boyle MP
      • Orens JB.
      Distal intestinal obstruction syndrome after surgery in cystic fibrosis.
      If DIOS develops, early diagnosis and treatment is critical. History, exam, and imaging are important to diagnose DIOS and exclude other pathologies, such as malignancies or infections.
      • Minkes RK
      • Langer JC
      • Skinner MA
      • et al.
      Intestinal obstruction after lung transplantation in children with cystic fibrosis.
      ,
      • Houwen RH
      • van der Doef HP
      • Sermet I
      • et al.
      Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.
      • Colombo C
      • Ellemunter H
      • Houwen R
      • Munck A
      • Taylor C
      • Wilschanski M
      Ecfs
      Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients.
      • Hadjiliadis D
      • Khoruts A
      • Zauber AG
      • Hempstead SE
      • Maisonneuve P
      • Lowenfels AB
      Cystic fibrosis colorectal cancer screening task F. cystic fibrosis colorectal cancer screening consensus recommendations.
      There is no evidence-based optimal regimen to treat DIOS, particularly after transplantation. Outcomes are largely similar using intestinal lavage formulations such as PEG-based therapy or water-soluble iodinated radiopaque contrast (diatrizoate meglumine and diatrizoate sodium solution) given orally, enterally, or via enema), often in combination with therapies such as laxatives, prokinetics, enteral feeding, PERT, intestinal secretagogues, and/or oral mucolytics.
      • Houwen RH
      • van der Doef HP
      • Sermet I
      • et al.
      Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.
      ,
      • Colombo C
      • Ellemunter H
      • Houwen R
      • Munck A
      • Taylor C
      • Wilschanski M
      Ecfs
      Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients.
      ,
      • Koletzko S
      • Stringer DA
      • Cleghorn GJ
      • Durie PR.
      Lavage treatment of distal intestinal obstruction syndrome in children with cystic fibrosis.
      • Green J
      • Carroll W
      • Gilchrist FJ.
      Interventions for treating distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.
      • Green J
      • Gilchrist FJ
      • Carroll W.
      Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.
      Patients with risk factors for or known episodes of post-transplant DIOS, may require initiation or increase of a maintenance bowel regimen to reduce the risk of recurrence. For refractory DIOS, surgical intervention may consist of adhesiolysis, milking of inspissated stool contents into the colon or via enterotomy, gastrograffin instillation via colonoscopy or intestinal resection.
      • Minkes RK
      • Langer JC
      • Skinner MA
      • et al.
      Intestinal obstruction after lung transplantation in children with cystic fibrosis.
      ,
      • Morton JR
      • Ansari N
      • Glanville AR
      • Meagher AP
      • Lord RV.
      Distal intestinal obstruction syndrome (DIOS) in patients with cystic fibrosis after lung transplantation.
      ,
      • Shidrawi RG
      • Murugan N
      • Westaby D
      • Gyi K
      • Hodson ME.
      Emergency colonoscopy for distal intestinal obstruction syndrome in cystic fibrosis patients.
      • 19)
        For CFLTRs who experience new or worsening symptoms of gastrointestinal dysmotility, the CFF recommends consultation with a gastroenterologist and a dietitian with CF expertise to guide the approach to symptom control and potential interventions.
      Delayed solid and liquid phase gastric emptying is often seen after lung transplantation among individuals with CF, though not all patients with delayed gastric emptying (DGE) are symptomatic.
      • Bodet-Milin C
      • Querellou S
      • Oudoux A
      • et al.
      Delayed gastric emptying scintigraphy in cystic fibrosis patients before and after lung transplantation.
      • Raviv Y
      • D'Ovidio F
      • Pierre A
      • et al.
      Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes.
      • Hirji SA
      • Gulack BC
      • Englum BR
      • et al.
      Lung transplantation delays gastric motility in patients without prior gastrointestinal surgery-A single-center experience of 412 consecutive patients.
      • Fisichella PM
      • Jalilvand A.
      The role of impaired esophageal and gastric motility in end-stage lung diseases and after lung transplantation.
      Gastric emptying scintigraphy should primarily be performed to evaluate symptoms of DGE, or if there is concern for complications such as GERD or micro-aspiration.
      • Bodet-Milin C
      • Querellou S
      • Oudoux A
      • et al.
      Delayed gastric emptying scintigraphy in cystic fibrosis patients before and after lung transplantation.
      ,
      • Raviv Y
      • D'Ovidio F
      • Pierre A
      • et al.
      Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes.
      No validated strategies guide optimal medical management, such as prokinetic medications or enteral feeding supplementation in CFLTRs; however, many of the recommendations for enteral feeding in individuals with cystic fibrosis may apply after transplant.
      • Schwarzenberg SJ
      • Hempstead SE
      • McDonald CM
      • et al.
      Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
      Use of enteral feeding tube placement should be individualized utilizing a multidisciplinary approach.
      • Toussaint E
      • Van Gossum A
      • Ballarin A
      • et al.
      Percutaneous endoscopic jejunostomy in patients with gastroparesis following lung transplantation: feasibility and clinical outcome.
      ,
      • Hirji SA
      • Gulack BC
      • Englum BR
      • et al.
      Lung transplantation delays gastric motility in patients without prior gastrointestinal surgery-A single-center experience of 412 consecutive patients.
      ,
      • Schwarzenberg SJ
      • Hempstead SE
      • McDonald CM
      • et al.
      Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
      Surgical management for severe symptomatic DGE should be reserved for highly-selected patients.
      • Raviv Y
      • D'Ovidio F
      • Pierre A
      • et al.
      Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes.
      • Hirji SA
      • Gulack BC
      • Englum BR
      • et al.
      Lung transplantation delays gastric motility in patients without prior gastrointestinal surgery-A single-center experience of 412 consecutive patients.
      • Fisichella PM
      • Jalilvand A.
      The role of impaired esophageal and gastric motility in end-stage lung diseases and after lung transplantation.
      It remains unclear if treatment of DGE improves clinically-meaningful outcomes of GERD or CLAD, and further studies are needed.
      • 20)
        The CFF recommends that CFLTRs have liver enzyme monitoring for CF Liver Disease (CFLD) at least annually, and when elevated, non-invasive imaging techniques for initial evaluation.
      The natural history of CFLD progression after transplant is not well-defined.
      • Klima LD
      • Kowdley KV
      • Lewis SL
      • Wood DE
      • Aitken ML.
      Successful lung transplantation in spite of cystic fibrosis-associated liver disease: a case series.
      ,
      • Mallea J
      • Bolan C
      • Cortese C
      • Harnois D.
      Cystic fibrosis-associated liver disease in lung transplant recipients.
      Ursodiol remains a mainstay of treatment for CFLD, though its efficacy and impact on disease progression are unclear. Data suggest that use of ursodiol after transplant is associated with improvement in aminotransferases, bile composition and flow, and liver stiffness in CFLD.
      • Colombo C
      • Crosignani A
      • Assaisso M
      • et al.
      Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study.
      • Colombo C
      • Battezzati PM
      • Podda M
      • Bettinardi N
      • Giunta A.
      Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian group for the study of ursodeoxycholic acid in cystic fibrosis.
      • van der Feen C
      • van der Doef HP
      • van der Ent CK
      • Houwen RH.
      Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients.
      Abdominal ultrasound is a widely-available and non-invasive modality for monitoring CFLD, and should be performed annually in patients with known or suspected CFLD.
      • Lenaerts C
      • Lapierre C
      • Patriquin H
      • et al.
      Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors.
      • Williams R.
      Liver disease in the UK: startling findings & urgent need for action.
      • Sellers ZM
      • Lee LW
      • Barth RA
      • Milla C.
      New algorithm for the integration of ultrasound into cystic fibrosis liver disease screening.
      Liver metrics and liver stiffness measurement via transient elastography may help avoid liver biopsy in CFLD, but additional investigation is needed.
      • Leung DH
      • Khan M
      • Minard CG
      • et al.
      Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease.
      • Stonebraker JR
      • Ooi CY
      • Pace RG
      • et al.
      Features of severe liver disease with portal hypertension in patients with cystic fibrosis.
      • Lemaitre C
      • Dominique S
      • Billoud E
      • et al.
      Relevance of 3D cholangiography and transient elastography to assess cystic fibrosis-associated liver disease?.
      • Aqul A
      • Jonas MM
      • Harney S
      • et al.
      Correlation of transient elastography with severity of cystic fibrosis-related liver disease.
      • Karlas T
      • Neuschulz M
      • Oltmanns A
      • et al.
      Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.
      • Karlas T
      • Neuschulz M
      • Oltmanns A
      • Wirtz H
      • Keim V
      • Wiegand J.
      ARFI and transient elastography for characterization of cystic fibrosis related liver disease: first longitudinal follow-up data in adult patients.
      CFLTRs with abnormal imaging or persistent lab abnormalities should be referred to a hepatologist for further evaluation.
      • 21)
        In CFLTRs who do not have Cystic Fibrosis-Related Diabetes (CFRD), the CFF recommends screening with an oral glucose tolerance test (OGTT) at 3-6 months after transplant, then annually following the recommended screening guidelines for CFRD.
        • Moran A
        • Brunzell C
        • Cohen RC
        • et al.
        Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      After transplant, diabetes mellitus is common; up to 80% of cases diagnosed within 6 months post-transplant.
      • Nieuwenhuis MG
      • Kirkels JH.
      Predictability and other aspects of post-transplant diabetes mellitus in heart transplant recipients.
      • Hadjiliadis D
      • Madill J
      • Chaparro C
      • et al.
      Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.
      • Belle-van Meerkerk G
      • van de Graaf EA
      • Kwakkel-van Erp JM
      • et al.
      Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.
      • Paolillo JA
      • Boyle GJ
      • Law YM
      • et al.
      Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression.
      • Winhofer Y
      • Wolf P
      • Fellinger P
      • et al.
      Markedly delayed insulin secretion and a high rate of undetected overt diabetes characterize glucose metabolism in adult patients with cystic fibrosis after lung transplantation.
      • Andersen HU
      • Lanng S
      • Pressler T
      • Laugesen CS
      • Mathiesen ER.
      Cystic fibrosis-related diabetes: the presence of microvascular diabetes complications.
      • Riou M
      • Renaud-Picard B
      • Munch M
      • et al.
      Organized management of diabetes mellitus in lung transplantation: study of glycemic control and patient survival in a single center.
      Current guidelines for CFRD recommend that glucose should be monitored closely after surgery, and that individuals without a diagnosis of diabetes be screened annually with an OGTT.
      • Moran A
      • Brunzell C
      • Cohen RC
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      Glycosylated hemoglobin (A1C) is not recommended for screening as this may not differ significantly between those with and those without CFRD.
      • Lam GY
      • Sissons S
      • Smith MP
      • et al.
      How reliable is your HbA1c test? Revisiting the use of HbA1c in cystic fibrosis-related diabetes (CFRD) screening.
      • Choudhury M
      • Taylor P
      • Morgan PH
      • et al.
      Association between HbA1c and the development of cystic fibrosis-related diabetes.
      • Gilmour JA
      • Sykes J
      • Etchells E
      • Tullis E.
      Cystic fibrosis-related diabetes screening in adults: a gap analysis and evaluation of accuracy of glycated hemoglobin levels.
      • Burgess JC
      • Bridges N
      • Banya W
      • et al.
      HbA1c as a screening tool for cystic fibrosis related diabetes.
      • Moran A
      • Pillay K
      • Becker DJ
      • Acerini CL
      International Society for P, adolescent D. ISPAD clinical practice consensus guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
      Since most CFLTRs without pre-existing CFRD develop CFRD early after transplant, screening at 3-6 months is recommended, once the glucocorticoid dose is stable.
      • Hadjiliadis D
      • Madill J
      • Chaparro C
      • et al.
      Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.
      ,
      • Paolillo JA
      • Boyle GJ
      • Law YM
      • et al.
      Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression.
      ,
      • Ye X
      • Kuo HT
      • Sampaio MS
      • Jiang Y
      • Bunnapradist S.
      Risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients.
      CFLTRs who screen positive for CFRD by OGTT should undergo confirmatory testing, per current guidelines.
      • Moran A
      • Brunzell C
      • Cohen RC
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      • 22)
        For CFLTRs who have CFRD, the CFF recommends treatment with insulin, continued intensive self-blood glucose monitoring (SBGM), and individualized close clinical follow-up, in addition to lifestyle modifications. Furthermore, the CFF recommends consultation with an endocrinologist with CF and transplant associated DM expertise, when possible.
      The prevalence of CFRD increases with age.
      • Hadjiliadis D
      • Madill J
      • Chaparro C
      • et al.
      Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.
      ,
      • Andersen HU
      • Lanng S
      • Pressler T
      • Laugesen CS
      • Mathiesen ER.
      Cystic fibrosis-related diabetes: the presence of microvascular diabetes complications.
      ,
      • Ye X
      • Kuo HT
      • Sampaio MS
      • Jiang Y
      • Bunnapradist S.
      Risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients.
      Risk factors for CFRD such as genotype, pancreatic insufficiency, and family history of Type 2 Diabetes persist after transplant and the highest incidence occurs within 2 years after transplant.
      • Hadjiliadis D
      • Madill J
      • Chaparro C
      • et al.
      Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.
      ,
      • Andersen HU
      • Lanng S
      • Pressler T
      • Laugesen CS
      • Mathiesen ER.
      Cystic fibrosis-related diabetes: the presence of microvascular diabetes complications.
      ,
      • Ye X
      • Kuo HT
      • Sampaio MS
      • Jiang Y
      • Bunnapradist S.
      Risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients.
      Studies are equivocal regarding the association of pre-transplant CFRD with morbidity and mortality post-transplant.
      • Belle-van Meerkerk G
      • van de Graaf EA
      • Kwakkel-van Erp JM
      • et al.
      Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.
      ,
      • Bradbury RA
      • Shirkhedkar D
      • Glanville AR
      • Campbell LV.
      Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.
      • Mainbourg S
      • Philit F
      • Touzet S
      • et al.
      Cystic fibrosis-related diabetes before lung transplantation is associated with lower survival but does not affect long-term renal function.
      • Hofer M
      • Schmid C
      • Benden C
      • et al.
      Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation.
      However, perioperative glycemic control correlates with survival, and should be implemented promptly.
      • Riou M
      • Renaud-Picard B
      • Munch M
      • et al.
      Organized management of diabetes mellitus in lung transplantation: study of glycemic control and patient survival in a single center.
      ,
      • Hackman KL
      • Snell GI
      • Bach LA.
      Prevalence and predictors of diabetes after lung transplantation: a prospective, longitudinal study.
      ,
      • Hackman KL
      • Snell GI
      • Bach LA.
      Poor glycemic control is associated with decreased survival in lung transplant recipients.
      Post-transplant, glycemic management in CFLTRs is complicated by changes in appetite, glucocorticoids, and renal function.
      • Andersen HU
      • Lanng S
      • Pressler T
      • Laugesen CS
      • Mathiesen ER.
      Cystic fibrosis-related diabetes: the presence of microvascular diabetes complications.
      ,
      • Riou M
      • Renaud-Picard B
      • Munch M
      • et al.
      Organized management of diabetes mellitus in lung transplantation: study of glycemic control and patient survival in a single center.
      CFTLR's with CFRD are insulin-deficient, thus insulin is the only recommended therapy. Insulin use pre-transplant is associated with improved BMI and lung function, decreased hospitalizations and mortality.
      • Moran A
      • Brunzell C
      • Cohen RC
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      ,
      • Moran A
      • Pillay K
      • Becker DJ
      • Acerini CL
      International Society for P, adolescent D. ISPAD clinical practice consensus guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
      ,
      • Moran A
      • Hardin D
      • Rodman D
      • et al.
      Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report.
      • Middleton PG
      • Wagenaar M
      • Matson AG
      Australian standards of care for cystic fibrosis-related diabetes.
      • Moran A
      • Pekow P
      • Grover P
      • et al.
      Cystic fibrosis related diabetes therapy study G. insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial.
      In this population, insulin pump use is associated with improved glycemic control, lean body mass, and reduced protein catabolism but data post-transplant are limited.
      • Hardin DS
      • Rice J
      • Rice M
      • Rosenblatt R.
      Use of the insulin pump in treat cystic fibrosis related diabetes.
      Data on safety of noninsulin agents in CFRD are limited and toxicity has been reported; therefore, these should not be used routinely.
      • Moran A
      • Brunzell C
      • Cohen RC
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      ,
      • Moran A
      • Pillay K
      • Becker DJ
      • Acerini CL
      International Society for P, adolescent D. ISPAD clinical practice consensus guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
      ,
      • Moran A
      • Hardin D
      • Rodman D
      • et al.
      Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report.
      ,
      • Onady GM
      • Stolfi A.
      Insulin and oral agents for managing cystic fibrosis-related diabetes.
      • Moran A
      • Phillips J
      • Milla C.
      Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes.
      • Rosenecker J
      • Eichler I
      • Barmeier H
      • von der Hardt H
      Diabetes mellitus and cystic fibrosis: comparison of clinical parameters in patients treated with insulin versus oral glucose-lowering agents.
      • Ballmann M
      • Hubert D
      • Assael BM
      • et al.
      Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial.
      • Onady GM
      • Langdon LJ.
      Insulin versus oral agents in the management of Cystic Fibrosis Related Diabetes: a case based study.
      • Geyer MC
      • Sullivan T
      • Tai A
      • et al.
      Exenatide corrects postprandial hyperglycaemia in young people with cystic fibrosis and impaired glucose tolerance: a randomized crossover trial.
      Close SBGM is necessary post-transplant as insulin requirements may change.
      • Valour F
      • Brault C
      • Abbas-Chorfa F
      • et al.
      Outcome of cystic fibrosis-related diabetes two years after lung transplantation.
      In pre-transplant individuals with CFRD, use of continuous glucose monitoring to guide insulin titration is associated with improved lung function and weight, but further studies are needed to determine transplant specific benefits beyond improved glucose monitoring.
      • Frost F
      • Dyce P
      • Nazareth D
      • Malone V
      • Walshaw MJ.
      Continuous glucose monitoring guided insulin therapy is associated with improved clinical outcomes in cystic fibrosis-related diabetes.
      • 23)
        For CFLTRs, the CFF recommends that bone density be assessed with dual energy X-ray absorptiometry (DEXA) at 6 to 12 months after transplant.
      Lung transplant recipients typically have more severe osteoporosis than other solid organ recipients.
      • Aris RM
      • Neuringer IP
      • Weiner MA
      • Egan TM
      • Ontjes D.
      Severe osteoporosis before and after lung transplantation.
      • Aringer M
      • Kiener HP
      • Koeller MD
      • et al.
      High turnover bone disease following lung transplantation.
      • Ferrari SL
      • Nicod LP
      • Hamacher J
      • et al.
      Osteoporosis in patients undergoing lung transplantation.
      Osteoporosis is prevalent in individuals with CF, and bone loss can be most pronounced in the first 6 to 12 months after transplant, increasing the risk of fractures, a presenting manifestation in up to 20% of CFLTRs, compromising lung function and QOL.
      • Hubert G
      • Chung TT
      • Prosser C
      • et al.
      Bone mineral density and fat-soluble vitamin status in adults with cystic fibrosis undergoing lung transplantation: a pilot study.
      ,
      • Aris RM
      • Neuringer IP
      • Weiner MA
      • Egan TM
      • Ontjes D.
      Severe osteoporosis before and after lung transplantation.
      ,
      • Aringer M
      • Kiener HP
      • Koeller MD
      • et al.
      High turnover bone disease following lung transplantation.
      ,
      • Robinson CA
      • Hofer M
      • Benden C
      • Schmid C.
      Evaluation of bone disease in patients with cystic fibrosis and end-stage lung disease.
      • Glendenning P
      • Kent GN
      • Adler BD
      • et al.
      High prevalence of osteoporosis in cardiac transplant recipients and discordance between biochemical turnover markers and bone histomorphometry.
      • Henderson K
      • Eisman J
      • Keogh A
      • et al.
      Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation.
      • Papaioannou A
      • Kennedy CC
      • Freitag A
      • et al.
      Longitudinal analysis of vertebral fracture and BMD in a Canadian cohort of adult cystic fibrosis patients.
      • Putman MS
      • Simoneau T
      • Feldman HA
      • Haagensen A
      • Boyer D.
      Low bone density and fractures before and after pediatric lung transplantation.
      Factors that affect bone health in CFLTRs include: pancreatic exocrine insufficiency, fat-soluble vitamin malabsorption, CFRD, hypogonadism, low peak bone mass and BMI, mobility, inflammation, and use of cyclosporine and/or glucocorticoids.
      • Hubert G
      • Chung TT
      • Prosser C
      • et al.
      Bone mineral density and fat-soluble vitamin status in adults with cystic fibrosis undergoing lung transplantation: a pilot study.
      ,
      • Aris RM
      • Neuringer IP
      • Weiner MA
      • Egan TM
      • Ontjes D.
      Severe osteoporosis before and after lung transplantation.
      Screening for osteoporosis should be performed with a DEXA in the first 6-12 months after transplant, and then at intervals depending on the severity of bone disease.
      • Aris RM
      • Merkel PA
      • Bachrach LK
      • et al.
      Guide to bone health and disease in cystic fibrosis.
      Management of low bone density should be individualized, and include assessments and optimization of secondary causes in addition to treatment based on the evaluation.

      Psychological considerations

      • 24)
        The CFF recommends that CFLTRs have mental health screening and consultation for depression, anxiety, and post-traumatic stress disorder (PTSD) within 6 months of transplant, then resume annual screening per the International Committee on Mental Health (ICMH) Depression and Anxiety Guidelines.
        • Quittner AL
        • Abbott J
        • Georgiopoulos AM
        • et al.
        International committee on mental health in cystic fibrosis: cystic fibrosis foundation and European cystic fibrosis society consensus statements for screening and treating depression and anxiety.
      Lung transplant recipients are at increased risk of mental health symptoms, and those who develop depression or PTSD early after transplant are at increased risk of medical non-adherence, morbidity, rejection, and death.
      • Stilley CS
      • Dew MA
      • Stukas AA
      • et al.
      Psychological symptom levels and their correlates in lung and heart-lung transplant recipients.
      • Dew MA
      • DiMartini AF
      • DeVito Dabbs AJ
      • et al.
      Onset and risk factors for anxiety and depression during the first 2 years after lung transplantation.
      • Dew MA
      • Rosenberger EM
      • Myaskovsky L
      • et al.
      Depression and anxiety as risk factors for morbidity and mortality after organ transplantation: a systematic teview and meta-analysis.
      • Sredl D
      • Werner T
      • Springhart D
      • Watkins D
      • Shaner M
      • McBride G.
      An evidence-based pilot study exploring relationships between psychologic and physiologic factors in post-lung-transplant adolescents with cystic fibrosis.
      • Smith PJ
      • Blumenthal JA
      • Snyder LD
      • et al.
      Depressive symptoms and early mortality following lung transplantation: a pilot study.
      • Smith PJ
      • Blumenthal JA
      • Trulock EP
      • et al.
      Psychosocial predictors of mortality following lung ransplantation.
      Anxiety post-transplant can lead to emotional distress and decreased QOL.
      • Dew MA
      • Rosenberger EM
      • Myaskovsky L
      • et al.
      Depression and anxiety as risk factors for morbidity and mortality after organ transplantation: a systematic teview and meta-analysis.
      ,
      • Emre S.
      Posttraumatic stress disorder in posttransplant children: creating a clinical program to address their needs.
      ,
      • Perez San Gregorio MA
      • Martin Rodriguez A
      • Perez Bernal J
      Psychological differences of patients and relatives according to post-transplantation anxiety.
      Therefore, mental health screening and consultation is recommended at minimum by 6 months post-transplant, and at least annually thereafter following ICMH and CFF guidelines. Suggested screening tools are provided in Table 3. Appropriately trained healthcare providers should perform screening, and individuals with positive screens should be referred to a mental health provider for further management. Consistent involvement of mental health professional for psychological symptoms and transplant-relevant topics (e.g., body image, behavioral activation) is suggested throughout the post-transplant period.
      • 25)
        The CFF recommends screening caregivers of CFLTRs for depression, anxiety, and PTSD within 6 months of transplant and referral for further assessment if necessary.
      Table 3Suggested Screening Measures for Depression, Anxiety, and PTSD
      DomainMeasure# itemsAge range (years)Positive score
      DepressionPatient screening: Patient Health Questionnaire (PHQ)-9

      Caregiver screening: PHQ-8 or PHQ-2

      Recommended in the ICMH Depression and Anxiety Guidelines
      9

      8, 2
      12+≥5 (PHQ-9 and 8)

      ≥3 (PHQ-2)
      AnxietyPatient screening: Generalized Anxiety Disorder-7 (GAD-7)

      Caregiver screening: GAD-7 or GAD-2

      Recommended in the ICMH Depression and Anxiety Guidelines
      7

      7, 2
      12+≥5

      ≥3 (GAD-2)
      PTSDPediatric patient screening: Child and Adolescent Trauma Screen (CATS) - caregiver report203-6≥15
      Pediatric patient screening: Child and Adolescent Trauma Screen (CATS) – caregiver report, youth report
      • Perez San Gregorio MA
      • Martin Rodriguez A
      • Perez Bernal J
      Psychological differences of patients and relatives according to post-transplantation anxiety.
      available from: https://depts.washington.edu/hcsats/PDF/TF-%20CBT/pages/assessment.html
      207-17≥15
      Adult patient screening, caregiver screening: Primary Care PTSD Screen for DSM-5 (PC-PTSD-5)
      Based on staffing and resources, for adult lung recipients either measure (PC-PTSD-5 or PCL-5) may be used.
      (167) available from: https://www.ptsd.va.gov/professional/assessment/screens/pc-ptsd.asp
      518+≥3
      Adult patient screening, caregiver screening: PTSD Checklist for DSM-5 Version (PCL-5)
      Based on staffing and resources, for adult lung recipients either measure (PC-PTSD-5 or PCL-5) may be used.
      (168) available from: https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp
      2018+≥31
      Notes: All measures are freely available in both English and Spanish. See reference section for information on obtaining these measures. For pediatric PTSD screening, many other screeners may be available and are acceptable for use; this screener was chosen as an example as it is freely available, provides caregiver report for ages 3-6, in addition to caregiver and child self-report for age 7-17, and is available in Spanish.
      a Based on staffing and resources, for adult lung recipients either measure (PC-PTSD-5 or PCL-5) may be used.
      Primary caregivers of pediatric and adult CFLTRs are at increased risk for mental health symptoms. Caregivers may experience increased stress, anxiety, depression, and PTSD after transplant,
      • Stukas Jr., AA
      • Dew MA
      • Switzer GE
      • DiMartini A
      • Kormos RL
      • Griffith BP
      PTSD in heart transplant recipients and their primary family caregivers.
      ,
      • Cousino MK
      • Rea KE
      • Schumacher KR
      • Magee JC
      • Fredericks EM.
      A systematic review of parent and family functioning in pediatric solid organ transplant populations.
      which may be associated with adherence concerns and a negative impact on the health of CFLTRs.
      • Cousino MK
      • Rea KE
      • Schumacher KR
      • Magee JC
      • Fredericks EM.
      A systematic review of parent and family functioning in pediatric solid organ transplant populations.
      ,
      • Stuber ML
      • Shemesh E
      • Saxe GN.
      Posttraumatic stress responses in children with life-threatening illnesses.
      Screening primary caregivers of CFLTRs for depression, anxiety, and PTSD within 6 months of transplant is recommended, though the process may differ for caregivers of pediatric and adult recipients (Table 3). CFF/ECFS guidelines for screening for depression and anxiety should continue to be followed for the screening of caregivers of pediatric recipients and expanded to caregivers of adult recipients. Caregivers with elevated scores should be referred for evaluation and treatment to a primary care or mental health provider. Transplant or CF providers should provide education and recommendation for screening as part of the psychosocial assessment.
      • 26)
        The CFF recommends that females with CF who are post-lung transplant and are considering pregnancy carefully assess their individual risks through shared decision making with maternal fetal medicine and transplant providers.
      • 27)
        The CFF recommends that females with CF who are post-lung transplant avoid pregnancy for at least the first 2 years after transplantation because of the increased risk of acute rejection, accelerated chronic rejection, and death.
      Individuals with CF are capable of conception, carrying pregnancies to term, and giving birth, but there are increased risks associated with pregnancy, particularly after transplant (Table 4). Pregnancy is contraindicated in lung transplant recipients with an unstable clinical course.
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      The decision to pursue pregnancy should be made cautiously in collaboration with maternal fetal medicine specialists, genetic counselors, and transplant providers. Providers should discuss the unique risks of pregnancy (Table 4) with women and their partners before conception
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      and provide counseling and appropriate contraception to avoid unplanned pregnancies.
      • Thakrar MV
      • Morley K
      • Lordan JL
      • et al.
      Pregnancy after lung and heart-lung transplantation.
      Successful pregnancies have typically occurred late after lung transplantation.
      • Bry C
      • Hubert D
      • Reynaud-Gaubert M
      • et al.
      Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies.
      ,
      • Shaner J
      • Coscia LA
      • Constantinescu S
      • et al.
      Pregnancy after lung transplant.
      It is recommended that CFLTRs wait at least 2 years after transplantation before attempting to become pregnant. This approach allows: (1) a careful assessment of allograft function and risk of CLAD, (2) lower risk of acute rejection, (3) lower intensity of immunosuppression, and (4) optimization of comorbidities.
      • Armenti VT
      • Gertner GS
      • Eisenberg JA
      • McGrory CH
      • Moritz MJ.
      National transplantation pregnancy registry: outcomes of pregnancies in lung recipients.
      • McArdle JR.
      Pregnancy in cystic fibrosis.
      • Gertner G
      • Coscia L
      • McGrory C
      • Moritz M
      • Armenti V.
      Pregnancy in lung transplant recipients.
      Reporting of pregnancy outcomes to the Transplant Pregnancy Registry International

      Transplant Pregnancy Registry International: A Division of Gift of Life Institute. Accessed August 28, 2020. https://www.transplantpregnancyregistry.org/about-us.

      is encouraged to improve research on pregnancy in CFTLRs.
      Table 4Risks Associated With Pregnancy After Lung Transplantation
      DomainSpecific considerations to discuss with patients
      Need for contraceptionHigh rates of unplanned pregnancies in lung/heart-lung transplant recipients (up to 41%)
      • Shaner J
      • Coscia LA
      • Constantinescu S
      • et al.
      Pregnancy after lung transplant.


      Some medications (e.g., Mycophenolate Mofetil) are teratogenic, necessitating discontinuation prior to conception to avoid fetal exposure
      • Armenti VT
      • Gertner GS
      • Eisenberg JA
      • McGrory CH
      • Moritz MJ.
      National transplantation pregnancy registry: outcomes of pregnancies in lung recipients.
      Genetic risk of CFGenetic counseling to discuss risk of transmission of CF to a child
      Fertility challengesIncreased likelihood of need for medically assisted treatment for conception (21% in one study)
      • Armenti VT
      • Gertner GS
      • Eisenberg JA
      • McGrory CH
      • Moritz MJ.
      National transplantation pregnancy registry: outcomes of pregnancies in lung recipients.
      Termination of pregnancyIncreased risk for spontaneous and therapeutic abortions (25%, and 17% respectively
      • McArdle JR.
      Pregnancy in cystic fibrosis.
      ,
      • Gertner G
      • Coscia L
      • McGrory C
      • Moritz M
      • Armenti V.
      Pregnancy in lung transplant recipients.
      ,
      • Mitchell RM
      • Jones AM
      • Barry PJ.
      CFTR modulator therapy in patients with cystic fibrosis and an organ transplant.
      Maternal morbidityIncreased risk of comorbidities: hypertension (76%), infections (33%), diabetes (33%), preeclampsia (5%), rejection (24%), and graft loss (14%)
      • McArdle JR.
      Pregnancy in cystic fibrosis.
      Maternal mortalityMaternal mortality after pregnancy is up to 33%
      • McArdle JR.
      Pregnancy in cystic fibrosis.
      ,
      • Jaksch P
      • Wiedemann D
      • Augustin V
      • et al.
      Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis.


      Female lung recipients may not live to see their children reach maturity given current survival rates.
      • McArdle JR.
      Pregnancy in cystic fibrosis.
      Fetal risksLive births among female lung recipients have increased risk of intrauterine growth restriction, prematurity, and low birthweight compared to other solid-organ transplant recipients
      • Mitchell RM
      • Jones AM
      • Barry PJ.
      CFTR modulator therapy in patients with cystic fibrosis and an organ transplant.
      ,
      • Jaksch P
      • Wiedemann D
      • Augustin V
      • et al.
      Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis.


      Mean birthweight is lower for babies born to mothers with CF than other lung transplant groups (1,980 g and 2,349 g, respectively)
      • McArdle JR.
      Pregnancy in cystic fibrosis.


      Higher incidence of preterm birth among babies born to mothers with CF compared to mothers with other indications for transplant (71% and 54%, respectively)
      • McArdle JR.
      Pregnancy in cystic fibrosis.


      Other complications may be present, and there is a risk of death for neonates
      • McArdle JR.
      Pregnancy in cystic fibrosis.

      Pharmacology and therapeutics

      • 28)
        The CFF found insufficient evidence to recommend for or against the use of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators for CFLTRs.
      While use of CFTR modulators for pulmonary indications after other solid organ transplants has been reported,
      • Mitchell RM
      • Jones AM
      • Barry PJ.
      CFTR modulator therapy in patients with cystic fibrosis and an organ transplant.
      ,
      • Chouchane I
      • Stremler-Lebel N
      • Reix P.
      Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles.
      and there may be unique scenarios where the use of CFTR modulators after lung transplantation is beneficial (e.g., malnutrition, chronic sinusitis); there have been no clinical trials examining the role of CFTR modulators in this setting. Additionally, there are potential drug-drug interactions between CFTR modulators and medications such as calcineurin inhibitors and azole antifungals. This emphasizes the need for experience in co-administration of these drugs, with careful monitoring and for toxicity and therapeutic drug levels. Further research is ongoing and will likely better inform clinical practice.
      • 29)
        The CFF found insufficient evidence to recommend for or against the use of induction immunosuppression for CFLTRs.
      There is no evidence that induction immunosuppression is associated with a higher risk of infection or other adverse events in CFLTRs.
      • Jaksch P
      • Wiedemann D
      • Augustin V
      • et al.
      Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis.
      • Fradet G
      • Smyth RL
      • Scott JP
      • et al.
      Cystic fibrosis: a new challenge for cardiothoracic surgery.
      • Bech B
      • Pressler T
      • Iversen M
      • et al.
      Long-term outcome of lung transplantation for cystic fibrosis–Danish results.
      Furthermore, retrospective analyses suggest that induction immunosuppression may be associated with a survival benefit among CFLTRs.
      • Jaksch P
      • Wiedemann D
      • Augustin V
      • et al.
      Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis.
      ,
      • Kirkby S
      • Whitson BA
      • Wehr AM
      • Lehman AM
      • Higgins RS
      • Hayes Jr., D
      Survival benefit of induction immunosuppression in cystic fibrosis lung transplant recipients.
      Randomized controlled trials have not consistently demonstrated better outcomes with induction immunosuppression although these studies have not stratified recipients by underlying diagnosis.
      • Snell GI
      • Westall GP
      • Levvey BJ
      • et al.
      Investigators ATGS. A randomized, double-blind, placebo-controlled, multicenter study of rabbit ATG in the prophylaxis of acute rejection in lung transplantation.
      • 30)
        The CFF recommends that CFLTRs have close monitoring of calcineurin inhibitor drug levels because of altered pharmacokinetics.
      CFLTRs have altered pharmacokinetics with several immunosuppressive medications. This is especially true with cyclosporine, where absorption may be erratic. The microemulsion cyclosporine formulation was designed to have better absorption, although relative bioavailability in CFTLRs is more than half of the relative bioavailability observed in those without CF.
      • Mikhail G
      • Eadon H
      • Leaver N
      • Khaghani A
      • Yacoub M
      • Banner N.
      Comparison of neoral and sandimmun cyclosporines for de novo lung transplantation in cystic fibrosis patients.
      • Kesten S
      • Scavuzzo M
      • Chaparro C
      • Szalai JP.
      Pharmacokinetic profile and variability of cyclosporine versus neoral in patients with cystic fibrosis after lung transplantation.
      • Trull A
      • Steel L
      • Sharples L
      • et al.
      Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients.
      • Knoop C
      • Vervier I
      • Thiry P
      • et al.
      Cyclosporine pharmacokinetics and dose monitoring after lung transplantation: comparison between cystic fibrosis and other conditions.
      Similarly, standard and extended release tacrolimus requires higher dosing to maintain similar levels in individuals with CF compared to those without CF.
      • Walker S
      • Habib S
      • Rose M
      • Yacoub M
      • Banner N.
      Clinical use and bioavailability of tacrolimus in heart-lung and double lung transplant recipients with cystic fibrosis.
      • Monchaud C
      • de Winter BC
      • Knoop C
      • et al.
      Population pharmacokinetic modelling and design of a Bayesian estimator for therapeutic drug monitoring of tacrolimus in lung transplantation.
      • Soto GAC
      • Ruiz-Antoran B
      • Laporta R
      • et al.
      Dose increase needed in most cystic fibrosis lung transplantation patients when changing from twice- to once-daily tacrolimus oral administration.
      Although optimal drug levels of mycophenolate have not been established, CFLTRs require higher doses of mycophenolate mofetil to achieve similar levels of absorption compared to LTR's without CF
      • Gerbase MW
      • Fathi M
      • Spiliopoulos A
      • Rochat T
      • Nicod LP.
      Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis.
      • de Winter BC
      • Monchaud C
      • Premaud A
      • et al.
      Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients.
      • Shaw LM
      • Figurski M
      • Milone MC
      • Trofe J
      • Bloom RD.
      Therapeutic drug monitoring of mycophenolic acid.
      • van Gelder T
      • Shaw LM.
      The rationale for and limitations of therapeutic drug monitoring for mycophenolate mofetil in transplantation.
      as they have reduced absorption and increased clearance of mycophenolate.
      • Stuckey L
      • Clark Ojo T
      • Park JM
      • Annesley T
      • Bartos C
      • Cibrik DM
      Mycophenolic acid pharmacokinetics in lung transplant recipients with cystic fibrosis.
      ,
      • Wang XX
      • Liu W
      • Zheng T
      • Park JM
      • Smith DE
      • Feng MR.
      Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis.
      Although data are limited, rapamycin pharmacokinetics appear to be unaltered in CFLTRs.
      • Doyle RL
      • Hertz MI
      • Dunitz JM
      • et al.
      RAD in stable lung and heart/lung transplant recipients: safety, tolerability, pharmacokinetics, and impact of cystic fibrosis.
      CFLTRs have variable azole plasma concentrations, and azoles reduce clearance of calcineurin inhibitors through modification of cytochrome P450s. Therefore, careful therapeutic drug monitoring is recommended for efficacy and reduced toxicity.
      • Stelzer D
      • Weber A
      • Ihle F
      • et al.
      Comparing azole plasma trough levels in lung transplant recipients: percentage of therapeutic levels and intrapatient variability.
      • Han K
      • Capitano B
      • Bies R
      • et al.
      Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients.
      • Berge M
      • Chevalier P
      • Benammar M
      • et al.
      Safe management of tacrolimus together with posaconazole in lung transplant patients with cystic fibrosis.
      • 31)
        Reduced renal function is common in CFLTRs, and serum creatinine is often a poor surrogate for renal function. Therefore, the CFF recommends medication dosing appropriate for glomerular filtration rate (GFR), and when available, the use of therapeutic drug monitoring.
      Because many individuals with CF have chronic inflammation, a hypermetabolic state and low BMI; serum creatinine may overestimates renal function. Therefore, therapeutic drug monitoring should be performed for medications in which clearance is based on renal function such as aminoglycosides. Renal function and pharmacokinetics (PK) of aminoglycosides may vary significantly with much inter and intra- patient variability before and after transplant, and PK parameters (peak and trough levels) should be assessed during each treatment course after transplant.
      • Dupuis RE
      • Sredzienski ES.
      Tobramycin pharmacokinetics in patients with cystic fibrosis preceding and following lung transplantation.
      ,
      • Walsh KA
      • Davis GA
      • Hayes Jr., D
      • Kuhn RJ
      • Weant KA
      • Flynn JD
      Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation.
      • 32)
        The CFF found insufficient evidence to recommend for or against the routine use of airway clearance, dornase alfa, or hypertonic saline among CFLTRs.
      Previous guidelines for the management of CFLTRs recommended the routine use of airway clearance
      • Hirche TO
      • Knoop C
      • Hebestreit H
      • et al.
      Practical guidelines: lung transplantation in patients with cystic fibrosis.
      ; however, there is no evidence to support this recommendation. Randomized controlled trials demonstrated no benefit with the use of dornase alpha during lower respiratory tract infection or the routine use of airway clearance after lung transplantation.
      • Tarrant BJ
      • Snell G
      • Ivulich S
      • Button B
      • Thompson B
      • Holland A.
      Dornase alfa during lower respiratory tract infection post-lung transplantation: a randomized controlled trial.
      ,
      • Munro PE
      • Button BM
      • Bailey M
      • Whitford H
      • Ellis SJ
      • Snell GI.
      Should lung transplant recipients routinely perform airway clearance techniques? A randomized trial.
      These studies included individuals who did not have CF, and it is possible that there may be a role for select airway clearance strategies in specific situations for CFLTR's.

      International considerations

      Many challenges remain in care delivery for CFLTRs in different countries which have adopted various healthcare funding models. Outside North America, healthcare expenditure and funding vary considerably, and these often dictate clinical care. Even within countries, different CF centers may be able to provide different levels of post-transplant care based on resources and funding. In general, there are 3 different models of care for CFLTRs in Europe. These are dependent on local resources and expertise, and distances between the individual's home and the CF and transplant centers. In the first model, the transplant center provides exclusive care. This is limited by fixed funding for transplant centers that does not account for complexity of care. Furthermore, additional specialty services (e.g., ENT, endocrinology, gastroenterology, psychiatry) and other integral components of traditional multi-disciplinary CF care are not remunerated per patient. Thus, financial and resource limitations may be real barriers to specialty care in this model. In the second model, both transplant and CF care centers provide longitudinal care. Here, communication between the 2 centers and the CFLTR is critical to harmonize care and avoid duplication of testing. In the third model, the CF center provides exclusive care. This is usually provided for CFLTRs who are beyond the first year after transplantation and with close guidance from the transplant center. This model is best-suited for CFLTRs who reside a distance from the transplant center but are close to a local CF center where they have developed strong relationships with their providers. In sum, care delivery models are variable internationally and are often constrained by financial and resource limitations resulting in significant challenges for transplant and CF centers as well as CFLTRs.

      No consensus

      The committee could not reach a consensus regarding the routine use of azithromycin in individuals with CF in the immediate period after lung transplantation to decrease the risk of CLAD.
      In a double-blind randomized controlled trial of lung transplant recipients with bronchiolitis obliterans syndrome (BOS), treatment with azithromycin resulted in better lung function than placebo.
      • Corris PA
      • Ryan VA
      • Small T
      • et al.
      A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation.
      In another randomized controlled trial, treatment with azithromycin early after transplantation reduced the risk of BOS.
      • Vos R
      • Vanaudenaerde BM
      • Verleden SE
      • et al.
      A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.
      However, the committee had concerns about applying results from these studies to individuals with CF because they were underrepresented in these relatively small studies, and it is not clear if they would derive the same benefit.

      Conclusions

      Despite improvement in the overall outcomes of individuals with CF, lung transplantation remains an important therapy in the spectrum of advanced CF lung disease. However, the success of transplantation is limited by CLAD and extra-pulmonary comorbidities. Providers caring for CFLTRs must not only recognize comorbidities related to transplant, but also recognize and manage CF-specific comorbidities and the impact of transplant on these conditions. These guidelines are intended to help providers identify and manage important conditions frequently encountered in CFLTRs. While the evidence for some of the recommendations is limited, the vast majority of recommendations were made with high degree of consensus and an acknowledgement of the limitations of published literature. At the core of these recommendations is a necessary long term partnership between multidisciplinary transplant teams, CF care teams, discipline specific specialty experts, and individuals with CF. Further, these recommendations highlight a critical need for ongoing research in lung transplantation of individuals with CF to better determine optimal care of this unique population.

      Committee and Authors’ contributions

      Pali Shah (Co-Chair): developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Ramsey Hachem (Co-Chair): developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Joshua Diamond: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Gary Visner: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Erika Lease: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Erin Lowery: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Cecilia Chaparro: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Fanny Vlahos: developed PICO questions, developed consensus statements, editing of the manuscript. Lara Danziger-Isakov: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Maggie Carroll: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. James Abraham: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Jessica Leonard: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Marina Litvin: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Zubin Bhakta: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Lillian Christon: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Chelsey Werchan: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript. Ray Poole: developed PICO questions, developed consensus statements, writing of the manuscript. Joseph Pilewski: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Erin Tallarico: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Albert Faro: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Sarah Hempstead: developed PICO questions, reviewed literature, developed consensus statements, writing of the manuscript, editing of the manuscript. Michelle Murray: writing of the manuscript.

      Disclosure statement

      Dr. Lease received grant funding from the Cystic Fibrosis Foundation. Dr. Danziger-Isakov has received grant funding from Merck, Astellas, Ansun Biopharma, and Takeda, and has received funding for service on an advisory board or consulting fees from GSK, Merck, and Takeda. Dr. Hachem has received grant funding from Bristol Myers Squibb and Mallinckrodt, and has received funding for service on an advisory board or speaker fees from Transmedics, CareDx, Theravance, and Vectura. The remaining authors have no conflicts of interest to disclose.
      Work to develop these consensus statements and write this manuscript was funded and supported by the Cystic Fibrosis Foundation.

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