Despite improvement in median life expectancy and overall health, some children with cystic fibrosis (CF) progress to end-stage lung or liver disease and become candidates for transplant. Transplants for children with CF hold the promise to extend and improve the quality of life, but barriers to successful long-term outcomes include shortage of suitable donor organs; potential complications from the surgical procedure and immunosuppressants; risk of rejection and infection; and the need for lifelong, strict adherence to a complex medical regimen. This article reviews the indications and complications of lung and liver transplantation in children with CF.
Key points
- •
Despite improvement in median life expectancy and overall health, some children with cystic fibrosis (CF) progress to end-stage lung or liver disease and become candidates for transplant.
- •
Lung and liver transplants have the potential to extend life and improve the quality of life, but require strict adherence to a complex medical regimen.
- •
Chronic lung allograft dysfunction continues to be a major barrier to the success of lung transplants.
- •
Determining the optimal time to move forward with a liver transplant in CF remains controversial.
Lung transplantation
Introduction
In the second decade of the twenty-first century clinicians are witnessing a revolution in the care of patients with cystic fibrosis (CF). The introduction of genetic modulators has for the first time allowed clinicians to directly target the basic defect in CF. However, for some children, these therapies have come along too late in the course of the disease to be of significant benefit. In those cases, lung transplant (LTx) is a potential life-extending therapy.
Indications
General indications for LTx in children were published by the American Society of Transplantation in 2007. The transplantation community was quick to recognize the potential utility of survival models to aid in determining appropriate timing for referral and listing for LTx. Kerem and colleagues’ criteria were one of the first such models. Patients with a forced expiratory volume in 1 second (FEV 1 ) less than 30% of predicted, a Pa o 2 less than 55 mm Hg, or a Pa co 2 greater than 50 mm Hg had 2-year mortalities more than 50%, with younger female patients doing the worst for any given FEV 1 . Several other investigators have studied models that include more variables, but none of these models are any more precise than Kerem and colleagues’ criteria.
The number of children and young adults with CF who have received lung or liver transplants are listed in Table 1 . Consensus criteria have been established for when patients with CF should be referred to a transplant center ( Box 1 ). In general, early referral is preferred. Importantly, early referral does not mean early transplant or even early listing, but it does provide the child and family the opportunity to establish a relationship with the transplant team. It gives the patient time to understand the process and commitment required and allows the center to put into place any necessary measures to optimize the posttransplant outcome.
| Age (y) | 2012 | 2013 | 2014 |
|---|---|---|---|
| Lung/Liver | Lung/Liver | Lung/Liver | |
| 5–9 | 0/0 | a /5 | a / a |
| 10–14 | a / a | 15/ a | 6/5 |
| 15–19 | 17/7 | 23/ a | 16/7 |
Lung function
- •
FEV 1 less than or equal to 30% predicted
- •
Rapid rate of lung function decline (especially in a female patient)
- •
Six-minute walk distance less than 400 m
- •
Need for noninvasive positive pressure ventilation
Pulmonary hypertension
- •
Systolic PAP greater than 35 mm Hg on echocardiography
- •
Or mean PAP greater than 25 mm Hg on cardiac catheterization
Infection
- •
Increasing antibiotic resistance
- •
Poor clinical recovery from pulmonary exacerbations
Nutrition
- •
Worsening nutritional status despite supplementation and appetite stimulants
Other clinical signs or symptoms
- •
Pneumothorax
- •
Life-threatening hemoptysis
- •
Diabetes
Abbreviation: PAP, pulmonary artery pressure.
In addition, all candidates should at the least possess:
- 1.
An adequate array of family support, including 2 care providers
- 2.
Adequate access to transplant services and medications
- 3.
Adequate evidence of an ability to adhere to the complex posttransplant regimen
Contraindications
There is a great deal of variability among LTx centers in the contraindications for transplant. The reasons for this variability include:
- 1.
The list of contraindications is not static over time. The introduction of newer techniques or therapies may yield meaningful improvements in outcome to change how a particular condition is viewed.
- 2.
Center-specific experience.
- 3.
Center-specific interpretation of published data.
The common thread is that contraindications place patients at greater risk for a poor outcome. Contraindications are usually divided into absolute versus relative. Among transplant centers, there is variability as to which contraindications are in which category. What is considered an absolute contraindication at one center may only be a relative contraindication at another ( Box 2 ).
Absolute
- •
Infectious
- ○
Burkholderia cenocepacia
- ○
Mycobacterium abscessus
- ○
Active tuberculosis
- ○
Sepsis
- ○
- •
Malignancy
- ○
Less than 2 years disease free (many centers use up to 5 years)
- ○
- •
Multi-organ dysfunction
- •
Neurologic
- ○
Severe neuromuscular disease
- ○
Poor rehabilitation potential
- ○
- •
Psychosocial
- ○
Lack of adequate social support system
- ○
Documented, refractory nonadherence
- ○
- •
Body habitus
- ○
Severe scoliosis
- ○
Severe chest wall deformity
- ○
Relative
- •
Infectious
- ○
Multidrug-resistant organisms
- ○
- •
Previous surgery
- ○
Pleurodesis
- ○
Multiple thoracotomies
- ○
- •
Immunologic
- ○
Sever immunodeficiency syndromes
- ○
Active collagen vascular disease
- ○
High circulating human leukocyte antigen antibody titers
- ○
Of particular interest in patients with CF is the microbiology of the airway. Patients with CF are chronically infected with a variety of pathogens. Some of these microorganisms are known to lead to a more rapid decline in lung function before transplant. However, some of those same organisms are associated with poor outcomes after LTx. The posttransplant management of patients infected with Burkholderia cenocepacia highlights this quandary. B cenocepacia is associated with higher morbidity and mortality in CF, but, in general, posttransplant survival rates are very poor for those infected with this organism. As a result, most transplant centers view infection with B cenocepacia as an absolute contraindication. Importantly, patients infected with other Burkholderia cepacia complex (BCC) organisms, apart from Burkholderia dolosa , have outcomes that are just as acceptable as those of patients not infected with BCC organisms. Other organisms that raise concern in the transplantation community include Burkholderia gladioli , a non-BCC organism, and Mycobacterium abscessus . For more detail, readers are referred to the excellent review article by Lobo and Noone.
Referring centers must also be aware that documented, refractory nonadherence does not portend a good posttransplant outcome. Referring centers must be transparent with the transplant center and the patient when referring patients for consideration. This requirement is not meant to be punitive, but is meant to optimize the potential for a good outcome, and allows for a dialogue to occur and plans to be put into place to give the patients the best opportunity to succeed.
Timing of Transplant
Timing of the transplant is critically important because 5-year survival rates after pediatric LTx remain at about 50% ( Fig. 1 ). Results from mathematical modeling before the advent of the lung allocation score (LAS) in the United States suggested that children with CF derived no survival benefit from LTx. However, the validity of the conclusion has been challenged because the data set used covariates that were obtained well before the transplant.
There is an optimal window during which patients are sick enough to derive benefit from a transplant, but not so sick so that they are at greater risk for a poor outcome. The LAS makes it more likely that the sickest patients get offered a transplant first and, in addition to blood type, height, and geographic proximity of the donor, is used to determine priority on the transplant waiting list for patients 12 years of age and older ( Box 3 ). Prioritization of the transplant list in children less than 12 years of age is based on wait time but also on urgency within a tiered system ( Box 4 ).
Blood Type
Diagnosis
Forced vital capacity
Need for supplemental oxygen
P co 2 and change in P co 2
Need for mechanical ventilation
Six-minute walk distance
Age
Body mass index
New York Heart Association functional score
Pulmonary arterial pressure
Creatinine
Bilirubin and change in bilirubin
Diabetes
Must have one of the following:
- •
Be on continuous mechanical ventilation
- •
Requiring more than 50% fraction of inspired oxygen to maintain oxyhemoglobin saturations greater than or equal to 90%
- •
An arterial or capillary P co 2 greater than 50 mm Hg
- •
A venous P co 2 greater than 56 mm Hg
- •
Pulmonary vein stenosis involving at least 3 vessels
- •
A cardiac index less than 2 L/min/m 2
- •
Syncope
- •
Hemoptysis
- •
Suprasystemic pulmonary artery pressure
Surgery
Detailed discussion of the surgical procedure is beyond the scope of this article and is described elsewhere. The most common procedure involves a clamshell incision with bilateral sequential LTx. Of note is that the lymphatics, bronchial circulation, and nervous system are not reanastomosed, which leads to potential limitations in a recipient’s ability to clear pulmonary edema or airway secretions.
Living donor LTx lost favor in the United States with the advent of the LAS and the removal of time spent on the list as a criterion. Reasons for the decline in this procedure include the risk to the physical and emotional well-being of the 2 normal donors with no additional benefit in terms of recipient outcomes between living donor and deceased donor transplant.
Posttransplant Management
Immunosuppression
Immediately posttransplant, most pediatric LTx programs in the United States use induction therapy with lympholytic agents or interleukin (IL)-2 receptor antagonists to decrease the risk of acute rejection. Maintenance immunosuppression consists of a 3-drug regimen that usually comprises a calcineurin inhibitor, a cell cycle toxin, and prednisone or prednisolone ( Table 2 ). These agents have many potential side effects and the risk of toxicity can be monitored by following trough concentrations and other laboratory tests ( Box 5 ). However, in any individual patient, these concentration levels correlate poorly with the relative degree of immunosuppression.
| Medication | Potential Adverse Effect |
|---|---|
| Corticosteroids | Hyperglycemia/diabetes Hypertension Osteopenia Glaucoma Infection |
| Tacrolimus | Renal dysfunction Hypertension Infection (fungal, viral, parasitic) Diabetes/impaired glucose tolerance Dyslipidemia Neurotoxicity (headaches, tremors, seizures, PRES) Malignancy (cutaneous, lymphoid, others) |
| Cyclosporine | Renal dysfunction Hypertension Infection Neurotoxicity Hirsutism Gingival hyperplasia Malignancy |
| Mycophenolate mofetil | GI symptoms (nausea, vomiting, diarrhea, abdominal pain) Neutropenia Teratogenicity |
| Sirolimus | Impaired wound healing Myelosuppression (anemia, neutropenia, thrombocytopenia) Hyperlipidemia Proteinuria Pneumonitis Hepatic artery thrombosis? |
| Azathioprine and 6-MP | Myelosuppression (especially leukopenia) Malignancy (eg, hepatosplenic T-cell lymphoma [very rare]) Hepatotoxicity (transaminase level increase) Pancreatitis GI symptoms (nausea, vomiting [rare]) |
Bloodwork
- •
Complete blood count with differential
- •
Comprehensive metabolic panel, including electrolytes, renal function
- •
Tacrolimus and mycophenolate concentrations
- •
Donor-specific antibody assay
- •
Uric acid, lactate dehydrogenase
- •
Cholesterol and fasting lipid panel
- •
Prothrombin time and partial thromboplastin time
- •
Cytomegalovirus and Epstein-Barr virus polymerase chain reaction (PCR)
- •
Hemoglobin A1c
- •
Pregnancy test if appropriate
- •
Pulmonary function testing
- •
Spirometry
- •
Lung volumes
- •
Diffusion capacity
- •
Imaging
- •
Chest radiograph
- •
High-resolution chest computed tomography
- •
Ventilation/perfusion scan
- •
Bronchoscopy
- •
Evaluation of the anastomoses
- •
Bronchoalveolar lavage for cultures, stains, or PCR (bacterial, acid fast, fungal, and viral)
- •
Transbronchial biopsy
- •
Unlike other solid organ transplant recipients, pediatric LTx recipients rarely ever wean entirely off any of these medicines. It is essential that patients’ home CF centers be aware that there are multiple potential drug interactions and to communicate with the transplant center before initiating any new therapies ( Table 3 ).
| CYP3A4 Inhibitors (Increase CNI Blood Levels) | CYP3A4 Inducers (Decrease CNI Blood Levels) |
|---|---|
| Antimicrobials (fluconazole, ketoconazole, erythromycin, clarithromycin) | Antimicrobials (rifampin, rifabutin) |
| HIV protease inhibitors (nelfinavir, ritonavir, saquinavir, indinavir) | HIV protease inhibitors (nevirapine, efavirenz) |
| HCV protease inhibitors (telaprevir, boceprevir) | Antiepileptics (carbamazepine, phenytoin, phenobarbital) |
| Others: cimetidine, sertraline, grapefruit juice | Others: St John’s wort |
Antimicrobials
Patients receive antibiotic and antifungal therapy based on their previous native airway cultures and susceptibilities. The donor organ is also cultured before transplant. At our center we perform a bronchoscopy with bronchoalveolar lavage (BAL) within the first 24 hours both to assess the anastomoses and to obtain cultures. Antimicrobial therapies are adjusted based on the results.
Antifungal prophylaxis strategy varies between centers. Candida prophylaxis is routinely administered in the form of oral nystatin or clotrimazole troches. Pneumocystis jiroveci prophylaxis is routinely administered shortly after transplant; trimethoprim/sulfamethoxazole is the treatment of choice.
For patients who are cytomegalovirus (CMV) seropositive or for those who receive an organ from a CMV seropositive donor, prophylaxis with ganciclovir is given. The length and mode of therapy vary among different transplant centers. Longer courses of up to 12 months have benefits. Herpes simplex virus (HSV) prophylaxis with acyclovir should be considered when the recipient is not receiving CMV prophylaxis.
Adolescents
Although there are anatomic similarities between adults and adolescents, teenagers present a well-described separate set of challenges for health care teams. Adolescents must cope with their emerging autonomy and need to fit in among their peers. They are more likely to indulge in risk-taking behaviors. Increased incidence of late rejection, graft failure, and death is well described in the adolescent transplant literature.
Results from a recent retrospective study of United Network for Organ Sharing (UNOS) data showed improved survival (half-life 4.6 vs 2.5 years) in adolescent LTx recipients transplanted at high-volume pediatric centers compared with those transplanted at adult LTx centers. Multivariable analysis showed that being transplanted at an adult center was an independent risk factor for graft failure in adolescents, with a hazard ratio of 1.5 ( P <.001). It is the investigators’ opinion that any adult center choosing to offer transplants to adolescents must at a minimum have on-site involvement of pediatric care providers such as pediatric pulmonologists, psychologists, child life specialists, coordinators, and social workers to optimize the children’s posttransplant outcomes.
Complications
When considering the differential diagnosis in a transplant recipient, it is useful to consider that complications tend to occur along a posttransplant timeline. The immediate posttransplant complications are listed in Box 6 .
Surgery related
Bleeding
Vascular anastomotic stenosis
Dehiscence of the airway anastomosis
Airway anastomotic stenosis
Phrenic nerve injury
Vocal cord paralysis
Atrial arrhythmias
Gastrointestinal paresis
Distal ileal obstruction syndrome
Primary graft dysfunction
Infection
Bacterial
Fungal
Viral
Immunologic
Hyperacute rejection
Acute rejection
Early posttransplant (1–6 months)
Infection
Patients with CF come to transplant with chronic airway infection of not only their lower airways but also of their sinuses and trachea. The risk of infection is increased by immunosuppression. Data to support the use of sinus surgery to promote Pseudomonas eradication has overall been disappointing. However, in a single center, when combined with daily nasal douching, a reduction in pseudomonal airway colonization was achieved.
Fungi are typically considered opportunistic organisms, but, because patients with CF may be chronically colonized before transplant, fungal infection may be seen early. Risk factors include acute cellular rejection (ACR), pretransplant colonization, tacrolimus-based immunosuppression, and CMV-positive donor, but not CF. Pulmonary fungal infection is associated with 1-year mortality (hazard ratio, 3.9). Possible therapies include voriconazole, amphotericin (intravenous or inhaled), or echinocandins. Each has its own set of advantages and disadvantages based on mode of delivery, drug interactions, and the specific fungus to be treated.
CMV was a significant pathogen associated with increased mortality within the first year after transplant as well as with the development of chronic lung allograft dysfunction (CLAD). However, effective prophylactic regimens have resulted in decreased incidence of infection.
Because this is a time of maximal immunosuppression, even respiratory viral infections (RVIs) may be life threatening. RVIs are also associated with the development of CLAD. Therefore, many pediatric LTx centers treat children infected with respiratory syncytial virus (RSV) with ribavirin, although practices are not uniform.
Immunologic
At this stage rejection may be cellular or antibody mediated. Both forms are associated with the later development of CLAD. The incidence of ACR is between 18% and 50%. ACR may be clinically silent and therefore many transplant centers perform routine surveillance transbronchial biopsies (TBBs) at scheduled intervals within the first 6 to 12 months posttransplant. In experienced hands, TBB can provide important diagnostic information with a good safety profile in even very young children.
Patients can present with clinical symptoms, decreased lung function, and/or radiographic infiltrates that are identical to those of a patient with an infection, which highlights the importance of performing appropriate diagnostic testing, including bronchoscopy with BAL and TBB.
When found, ACR is typically treated with 3 days of high-dose methylprednisolone (10–20 mg/kg/d). If ACR is persistent, a second course of methylprednisolone may be given. If ACR is still present, patients then may receive lympholytic therapy with antithymocyte globulin. The primary risk of augmenting immunosuppression is infection. Patients are frequently treated concurrently with antimicrobials.
Antibody-mediated rejection (AMR) may also occur in this phase. AMR in LTx recipients has proved to be both a diagnostic as well as a therapeutic challenge. The evaluation of a patient with clinical allograft dysfunction includes an assessment for the presence of circulating donor-specific antibodies (DSAs), lung biopsy evidence of capillaritis, and capillary endothelial complement (C4d) deposition. The evidence suggests that LTx patients with CF are at higher risk for developing DSA than those without CF. The diagnostic effort is complicated by the potential for autoantibodies, antibodies to self-antigens, to contribute to the development of CLAD. Therefore, the absence of a DSA is not enough to rule out the diagnosis of AMR.
The presence of AMR portends a very poor prognosis and is associated with the development of CLAD. Treatment with a variety of different agents have been described in single case reports, with the most promising perhaps being the addition of bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells. The treatment protocol at our center combines therapy with plasmapheresis, rituximab, intravenous immunoglobulin, and bortezomib; however, the results have been disappointing.
Anastomotic
Anastomotic complications can relate to either airway or vascular anastomoses. Vascular anastomotic complications are usually seen in the immediate posttransplant phase. The risk of airway anastomotic stenosis is not associated with the size of the airway, but it is associated with pretransplant BCC, posttransplant fungal pulmonary infection, and days mechanically ventilated. Airway stenosis is treated by balloon dilatation.
Immunosuppression
In addition to the increased risk of infection, immunosuppressants commonly used after LTx are associated with a host of potential complications (see Table 2 ). Patients with CF are at increased risk of developing diabetes even without transplant. However, both tacrolimus, a calcineurin inhibitor (CNI), and systemic steroids are known to increase the risk of diabetes. CNIs are also associated with nephrotoxicity, which is more of a problem among patients with CF who, by the time they arrive for transplant, have probably had years of exposure to aminoglycosides and other nephrotoxic antibiotics. CNIs may also cause seizures, headaches, and sleep disturbances.
Late postoperative (greater than 6 months)
Infection
Although immunosuppression is decreased over time in patients who have not experienced ACR, infection remains a problem throughout the posttransplant course. Pediatric LTx recipients typically stay on triple-drug immunosuppression and therefore are not only at risk for opportunistic infections but also at risk for complications from community-acquired infections.
Immunologic
Patients continue to be at risk for either ACR or AMR in this phase. Importantly, CLAD begins to emerge as an important complication affecting up to 10% of LTx recipients by the first year and 50% by 3 years from transplant. CLAD is a fairly new term meant to take into consideration that not all patients with allograft dysfunction have obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS). Some may have neutrophil reversible allograft dysfunction (NRAD), whereas others may present with decrease in lung function that is more restrictive, or restrictive allograft syndrome (RAS). CLAD encompasses all of these entities.
Obliterative bronchiolitis/bronchiolitis obliterans syndrome
OB is an inflammatory injury to the small airways, which is presumed to result from chronic rejection in LTx. OB is a histopathologic diagnosis. Because the process is initially patchy and inhomogeneous, TBB is often inadequate to make the diagnosis. Open lung biopsy is the gold standard. Therefore, a corresponding clinical syndrome, termed BOS ( Table 4 ), was defined that corresponds with OB. However, BOS is not specific to the diagnosis of OB. BOS constitutes most CLAD.
| BOS 0 | FEV 1 90% of baseline and FEF 25%–75% 75% of baseline |
| BOS 0-p | FEV 1 81%–90% of baseline and/or FEF 25%–75% 75% of baseline |
| BOS 1 | FEV 1 66%–80% of baseline |
| BOS 2 | FEV 1 51%–65% of baseline |
| BOS 3 | FEV 1 50% of baseline |
Risk factors for BOS include recurrent acute rejection or a single episode of severe acute rejection. Other risk factors for BOS include lymphocytic bronchiolitis, primary graft dysfunction (PGD), gastroesophageal reflux (GER), RVIs, and the development of anti–human leukocyte antigen (anti-HLA) antibodies.
Chest radiographic findings may be normal or may reveal hyperinflation. High-resolution chest computed tomography scan may show bronchiectasis, decreased vascular markings, and air trapping. Ventilation scan may show retention of xenon. On histology, OB is characterized by a proliferation of fibroblasts into the airway lumen, ultimately forming intraluminal granulation tissue and total obliteration.
The reality is that no intervention in the armamentarium can be expected to do anything more than halt further deterioration in lung function. The exception seems to be in patients with NRAD. They have airway neutrophilia and experience an improvement in lung function when on azithromycin. Therapies that, in some cases, can at least stabilize function for some period of time include antithymocyte globulin, fundoplication for patients with GER, change in immunosuppression from cyclosporine A to tacrolimus, and photopheresis.
Photopheresis is seemingly one of the more promising approaches to treating patients with OB/BOS. A retrospective review of 60 adult LTx recipients showed a slowing in the rate of decline in the FEV 1 .
Restrictive allograft syndrome
RAS is characterized by a symmetric decline in forced vital capacity and FEV 1 with a decrease in total lung capacity. On histology, inflammation and fibrosis are typically seen.
Posttransplant lymphoproliferative disease
The use of immunosuppressive agents places LTx recipients at increased risk for malignancies after their transplants. The most common such malignancy in children is posttransplant lymphoproliferative disease. The spectrum of disease severity varies, with the most severe being true malignancy. Primary infection with Epstein-Barr virus after transplant is the primary risk factor. Pediatric LTx recipients are at high risk.
Potential therapies include reducing immunosuppression, treatment with anti–B-cell antibodies (eg, rituximab), interferon-alpha with or without intravenous immunoglobulin, surgical resection, radiotherapy, and cytotoxic chemotherapy.
Immunosuppression
These complications are discussed earlier. In addition, osteopenia may begin to emerge as more of a problem because LTx recipients are rarely able to come off prednisone.
Outcomes
Patients with CF do as well after LTx as any other group (see Fig. 1 ). However, long-term outcomes continue to disappoint. Changes in surgical technique and early postoperative critical care management have resulted in improved early outcomes. However, the inability to adequately prevent or treat CLAD continues to limit long-term success ( Fig. 2 ).
Future
Newer techniques and strategies to either address the organ shortage or extend life and optimize clinical state while the patients are waiting on the list are being studied or adopted. These include the following:
Extracorporeal membrane oxygenation (ECMO)
- •
Ambulatory ECMO is increasingly used as a bridge to LTx. It provides patients in respiratory failure with the potential for ambulation and continued rehabilitation, maximizing the odds for a good transplant outcome.
Donation after cardiocirculatory death (DCD)
- •
In an attempt to increase the donor pool, some transplant programs accept DCD donors. The outcomes from these donors do not significantly differ from outcomes from donors with brain death.
Ex-vivo lung perfusion (EVLP)
- •
Donor lungs that do not meet criteria for suitability are never used. EVLP provides an opportunity to assess and improve the function of these lungs. It is essentially a circuit that allows for careful monitoring of oxygenation, compliance, and other parameters. It also allows for the possibility of introducing therapies to the donor lung before transplant. Long-term outcomes of transplanting lungs using EVLP are promising.
Basic science and translational research are focused on improving the understanding of CLAD.
Lung transplantation
Introduction
In the second decade of the twenty-first century clinicians are witnessing a revolution in the care of patients with cystic fibrosis (CF). The introduction of genetic modulators has for the first time allowed clinicians to directly target the basic defect in CF. However, for some children, these therapies have come along too late in the course of the disease to be of significant benefit. In those cases, lung transplant (LTx) is a potential life-extending therapy.
Indications
General indications for LTx in children were published by the American Society of Transplantation in 2007. The transplantation community was quick to recognize the potential utility of survival models to aid in determining appropriate timing for referral and listing for LTx. Kerem and colleagues’ criteria were one of the first such models. Patients with a forced expiratory volume in 1 second (FEV 1 ) less than 30% of predicted, a Pa o 2 less than 55 mm Hg, or a Pa co 2 greater than 50 mm Hg had 2-year mortalities more than 50%, with younger female patients doing the worst for any given FEV 1 . Several other investigators have studied models that include more variables, but none of these models are any more precise than Kerem and colleagues’ criteria.
The number of children and young adults with CF who have received lung or liver transplants are listed in Table 1 . Consensus criteria have been established for when patients with CF should be referred to a transplant center ( Box 1 ). In general, early referral is preferred. Importantly, early referral does not mean early transplant or even early listing, but it does provide the child and family the opportunity to establish a relationship with the transplant team. It gives the patient time to understand the process and commitment required and allows the center to put into place any necessary measures to optimize the posttransplant outcome.
| Age (y) | 2012 | 2013 | 2014 |
|---|---|---|---|
| Lung/Liver | Lung/Liver | Lung/Liver | |
| 5–9 | 0/0 | a /5 | a / a |
| 10–14 | a / a | 15/ a | 6/5 |
| 15–19 | 17/7 | 23/ a | 16/7 |
Lung function
- •
FEV 1 less than or equal to 30% predicted
- •
Rapid rate of lung function decline (especially in a female patient)
- •
Six-minute walk distance less than 400 m
- •
Need for noninvasive positive pressure ventilation
Pulmonary hypertension
- •
Systolic PAP greater than 35 mm Hg on echocardiography
- •
Or mean PAP greater than 25 mm Hg on cardiac catheterization
Infection
- •
Increasing antibiotic resistance
- •
Poor clinical recovery from pulmonary exacerbations
Nutrition
- •
Worsening nutritional status despite supplementation and appetite stimulants
Other clinical signs or symptoms
- •
Pneumothorax
- •
Life-threatening hemoptysis
- •
Diabetes
Abbreviation: PAP, pulmonary artery pressure.
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