If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Reprint requests: Ramsey R. Hachem, MD, Division of Pulmonary and Critical Care, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8052, St. Louis, MO 63110. Telephone: (314) 454-7953. Fax: (314) 454-5571.
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.
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.
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%.
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.
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.
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
1
The 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 care
100%
2
The 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
The 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 regimen
100%
4
The CF Foundation recommends an intraoperative CF bacterial, fungal and AFB culture of the native lung be obtained at the time of lung transplantation
100%
5
In 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 regimens
100%
6
For 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 transplant
100%
7
The 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 Recipients
100%
8
The 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%
9
The 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 Recipients
100%
10
The 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 Recipients
95%
SINUS DISEASE
11
In 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%
12
The CF Foundation recommends screening CF Lung Transplant Recipients for symptoms of CRS at least annually
100%
13
The 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 surgery
100%
14
The 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 symptoms
100%
NUTRITION and GASTROINTESTINAL COMPLICATIONS
15
For 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 goal
100%
16
In 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%
17
The 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 administration
100%
18
In 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 management
100%
19
For 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 interventions
100%
20
The 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
21
In 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
For 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
23
For 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 transplant
100%
MENTAL HEALTH and FAMILY PLANNING
24
The 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%
25
The 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 necessary
90%
26
The 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 providers
100%
27
The 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 death
100%
PHARMACOLOGY and THERAPEUTICS
28
The CF Foundation found insufficient evidence to recommend for or against the use of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators for CF Lung Transplant Recipients
100%
29
The CF Foundation found insufficient evidence to recommend for or against the use of induction immunosuppression for CF Lung Transplant Recipients
100%
30
The CF Foundation recommends that CF Lung Transplant Recipients have close monitoring of calcineurin inhibitor drug levels because of altered pharmacokinetics
100%
31
Reduced 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 monitoring
100%
32
The 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 Recipients
100%
Topics reviewed where no consensus was reached:
PICO
Statement
voting
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.
Table 2Relevant Existing CF Foundation Clinical Care Guidelines
Care topic in CF
Existing CF foundation guidelines
Colorectal Cancer Screening
Hadjiliadis D, Khoruts A, Zauber AG et al. Cystic Fibrosis Colorectal Cancer Screening Consensus Recommendations. Gastroenterology. 2018
Enteral Tube Feeding
Schwarzenberg 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 Adults
Stallings 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 Deficiency
Tangpricha 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 Health
Aris RM, Merkel PA, Bachrach LK, et al. Guide to Bone Health and Disease in Cystic Fibrosis. J Clin Endocrinol Metab. 2005.
Diabetes
Moran A, Brunzell C, Cohen R, et al. Clinical Care Guidelines for Cystic Fibrosis-Related Diabetes. Diabetes Care. 2010
Liver Disease
Sokol RJ, Durie PR, et al. Recommendations for Management of Liver and Biliary Tract Disease in Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 1999.
Depression and Anxiety
Quittner 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 Control
Saiman 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 Disease
Kapnadak 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 Referral
Ramos 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 Care
Kavalieratos 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.
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.
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.
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.
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.
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.
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.
Therefore, CFF recommends that all healthcare personnel caring for individuals with CF regardless of transplant status implement policies per CFF IPC guidelines.
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.
Targeted antibiotic prophylaxis for lung transplantation in cystic fibrosis patients colonised with pseudomonas aeruginosa using multiple combination bactericidal testing.
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.
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.
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.
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.
Recovery of gram-negative bacteria in CFLTRs who were infected pre-transplant was not affected by inhaled antipseudomonal antibiotics in at least 2 cohorts,
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.
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).
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.
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.
Similarly, a single-center study of antibiotic treatment of Stenotrophomonas in asymptomatic CFLTRs showed no impact on microbial clearance or lung function.
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.
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.
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.
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.
Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients.
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.
Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients.
Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Markedly delayed insulin secretion and a high rate of undetected overt diabetes characterize glucose metabolism in adult patients with cystic fibrosis after lung transplantation.
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.
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.
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.
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.
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.
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.
Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.
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.
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.
International Society for P, adolescent D. ISPAD clinical practice consensus guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
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.
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.
International Society for P, adolescent D. ISPAD clinical practice consensus guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
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.
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.
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.
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.
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.
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.
An evidence-based pilot study exploring relationships between psychologic and physiologic factors in post-lung-transplant adolescents with cystic fibrosis.
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
Domain
Measure
# items
Age range (years)
Positive score
Depression
Patient 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)
Anxiety
Patient screening: Generalized Anxiety Disorder-7 (GAD-7) Caregiver screening: GAD-7 or GAD-2 Recommended in the ICMH Depression and Anxiety Guidelines
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,
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.
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
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.
Live births among female lung recipients have increased risk of intrauterine growth restriction, prematurity, and low birthweight compared to other solid-organ transplant recipients
Higher incidence of preterm birth among babies born to mothers with CF compared to mothers with other indications for transplant (71% and 54%, respectively)
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,
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.
Randomized controlled trials have not consistently demonstrated better outcomes with induction immunosuppression although these studies have not stratified recipients by underlying diagnosis.
Investigators ATGS. A randomized, double-blind, placebo-controlled, multicenter study of rabbit ATG in the prophylaxis of acute rejection in lung transplantation.
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.
Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients.
Similarly, standard and extended release tacrolimus requires higher dosing to maintain similar levels in individuals with CF compared to those without CF.
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
Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis.
Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients.
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.
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.
; 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.
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.
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.
References
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.
02283-X&id=gr1.jpg){kind=link}