Keywords
Diffuse parenchymal lung disease, Interstitial lung disease, Lung disease, Lung transplantation, Parenchymal lung disease, Pulmonary Langerhans cell histiocytosis
Key Points
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For selected parenchymal lung disease (DPLD) patients who fail to respond to medical therapy and demonstrate declines in function that place them at increased risk for mortality, lung transplantation should be considered.
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Lung transplantation remains a complex medical intervention that requires a dedicated recipient and a medical team.
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Despite the challenges, lung transplantation affords appropriate patients a reasonable chance at increased survival and improved quality of life.
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Lung transplantation remains an appropriate therapeutic option for selected patients with DPLD.
There are over 120 distinct interstitial or diffuse parenchymal lung diseases (DPLDs). These diseases are often referred to as interstitial lung diseases; however, DPLD is a better term as the diseases affect the interstitium, pulmonary vasculature, small airways, and alveolar epithelial cells. DPLDs are typically associated with underlying autoimmune diseases, environmental/occupational exposures, medications, and radiation or are idiopathic in nature. A large percentage of these disorders (approximately 30–40%) are idiopathic. It is believed that previous prevalence estimates in the population have been grossly underestimated, and although DPLDs remain extremely rare in children, in adults the prevalence for parenchymal lung diseases is ∼70 per 100,000 population. Newer information indicates that the prevalence of the most common form of idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis (IPF), is likely greater than previously expected. Clinical courses and prognoses across all types of DPLD are variable and dependent on the underlying subtype of lung disease. In addition, the literature consistently estimates the median survival for patients with newly diagnosed IPF is 2–5 years. For IPF and the other DPLDs that progress despite best medical therapy, lung transplantation remains an appropriate treatment option for a select group of patients.
The first human lung transplantation was performed in 1963 at the University of Mississippi by Dr. James Hardy. The patient succumbed 19 days later from preexisting renal disease, and on postmortem examination he was noted to have no evidence of acute rejection. Multiple attempts between 1963 and 1981 ended in failure because of lack of adequate immunosuppressive therapy, which would allow allograft tolerance but would not result in multisystem organ failure from infection. The advent of cyclosporine A began a new era, and Reitz and Shumway performed the first successful heart and lung transplant at Stanford University in 1981. Subsequently, in 1983, Cooper and the Toronto Lung Transplant Group successfully performed the first single lung transplant on a patient with IPF. During the past 30 years, the number of transplants performed worldwide has increased from the single digits per year to over 3800 in 2013. The major indications for lung transplantation include chronic obstructive pulmonary disease, IPF, and cystic fibrosis. Together these three diseases account for over 75% of all lung transplants performed. Over the past decade, the proportion of transplants for IPF has consistently increased. This is most likely attributable to the change in organ allocation policies and implementation of the lung allocation score (LAS) in the United States. The LAS prioritizes organ placement; the calculation prioritizes based on risk of death while on the wait list. Prior to the LAS change, the percentage of transplant for IPF in the United States was ∼20% between 2000 and 2004. Once the change occurred, over 35% of the recipients between 2005 and 2012 had advanced lung disease due to IPF. This increase in the number of transplants differs with trends for idiopathic pulmonary arterial hypertension. With the advance of successful therapies for the treatment of pulmonary arterial hypertension, the number of transplants for this condition has significantly declined, now accounting for ∼2% of all transplants in 2014 compared with ∼13% of transplants performed in 1990. This underscores the challenge that patients with IPF face: until 2014 there was a lack of beneficial therapy for this devastating disease.
Who Should Be Referred and Be Listed for Transplant?
In 2015 the International Society for Heart and Lung Transplantation published an updated consensus report outlining appropriate guidelines for referral for transplantation and contraindications for transplantation. The document also includes guidelines for actively placing a patient on a waiting list for transplant. The balance between providing a short-term survival benefit must be weighed against the reality that donor lungs are a limited resource. Therefore it is paramount that the appropriate transplant candidate be expected to have a reasonable opportunity to attain longer-term survival. Assessment for potential long-term survival must include an appraisal of potential recipients’ comorbidities. The 2015 guideline statement outlines several absolute and relative contraindications to performing lung transplantation ( Table 9.1 ). In addition to medical considerations, lung transplant recipients must actively participate in the management of a complex medical regimen. Adherence to this treatment is central to good outcomes. As a result, a social support system that enhances adherence is beneficial, if not vital.
| Absolute Contraindications | Comments |
|---|---|
| Malignancy within past 2 years | 2-year disease-free interval with low risk of recurrence is reasonable. However, because of the effects of chronic immunosuppression on malignancy, a 5-year disease-free interval is prudent |
| Untreatable dysfunction of other organs | Unless combined organ transplantation is performed |
| Uncorrected coronary artery disease | Coronary artery disease that is not amenable to revascularization by percutaneous transluminal coronary angioplasty |
| Uncorrectable bleeding problem | |
| Acute medical instability | Associated with increased perioperative mortality |
| Significant chest wall/spinal deformity | Prevents safe removal of native or donor lungs |
| Documented nonadherence to medical therapy | Includes the need for a consistent and reliable social support system. In addition, untreatable psychiatric conditions that would impair the ability of the recipient to remain adherent are included here |
| Substance abuse | Alcohol, tobacco, marijuana, illicit substances |
| Chronic infection with resistant organisms that are poorly controlled pretransplant | Increased risk of perioperative sepsis, empyema, wound healing, and infections |
| Obesity with BMI >35 kg/m 2 | Associated with poor short- and long-term outcomes |
| Severely limited functional status with poor rehabilitation potential | Decreased exercise tolerance is associated with worse outcomes |
| Relative Contraindications | Comments |
|---|---|
| Age >65 years | There is an increased risk of worse long-term survival with higher age likely related to increased comorbidities at transplant |
| Progressive or severe malnutrition | Impairs wound healing |
| Mechanical ventilation or extracorporeal life support (ECLS) | Carefully selected candidate without other acute or chronic organ dysfunction may be successfully transplanted, however |
| Noncurable chronic extrapulmonary infections | Chronic active hepatitis B, hepatitis C, and HIV patients should have transplant done only in experienced centers for those infections |
| Other chronic comorbidities that have not resulted in end-stage organ damage | All medical conditions should be optimized before consideration for listing for transplant, including chronic management of diabetes, hypertension, epilepsy, peptic ulcer disease, and gastroesophageal reflux before transplantation |
Transplantation centers agree that the moment of referral should allow the potential recipient adequate time to consider this treatment option. The initial transplantation discussion should not occur as a last-ditch effort at improving a patient’s outcome. In this or any document, there are limitations in defining the appropriate time for referral and transplantation. Consideration of referral to a transplant center should include the referring physician’s assessment of the individual’s quality of life as well as overall life expectancy without a transplant. In addition, the potential recipient’s desire to learn more about this treatment option is a factor in considering referral. Early referral is crucial as it allows the potential recipient an opportunity to develop a relationship with the prospective transplant program. It also allows the patient an opportunity to learn about the entire process, from the surgery to the complex medical management one must adhere to after transplantation. The decision to actively list for transplant, alternatively, is based on organ allocation for a particular region, estimated risks and benefits based on the expertise of the individual transplant center, and the personal assessments of the transplant recipient.
Choice of Procedure
There are three potential procedures for the interstitial lung disease recipient. These include heart and lung, single lung, and bilateral lung transplantation. Heart and lung transplantation was initially the procedure of choice during the 1980s, and many centers continued this practice into the 1990s. After successful lung transplantation and the realization that the dilated right ventricle can remodel with good outcomes, heart and lung transplantation numbers have significantly declined. In 2013, there were only 46 heart and lung transplants worldwide. Currently, heart and lung transplantation is performed only on those patients with significant left ventricular dysfunction or nonoperable congenital abnormalities. The decision to perform single lung versus bilateral lung transplant remains controversial today. The only absolute criterion for bilateral lung transplant is suppurative lung disease. This is due to concerns that the native lung will soil the transplanted allograft in a chronically immunosuppressed host and lead to poor outcomes. In addition to this absolute indication, it is now common practice to perform bilateral lung transplant for patients with idiopathic pulmonary hypertension. This population is at high risk of developing primary graft dysfunction (PGD) or early acute lung injury after transplantation. This risk is lower in patients who undergo bilateral lung transplantation. For patients with very high pulmonary vascular resistance before transplant, the right ventricle becomes acutely unloaded with the reanastamosis of the normal allograft pulmonary vasculature. High cardiac output ensues with high flow rates that may increase the risk of endothelial injury and subsequent pulmonary edema. This impact is likely attenuated by double the vascular volume of a bilateral transplant. For patients with DPLD, it is less clear that individuals with secondary pulmonary hypertension receive an absolute benefit from bilateral lung transplantation. Several investigators have come to differing conclusions regarding the benefits of a particular procedure type in this population. Because there are no randomized controlled trials evaluating single lung versus bilateral lung transplantation for pulmonary fibrosis, there are inherent selection biases that confound any retrospective cohort. There have been numerous studies in the past that suggest there may be a potential survival benefit in patients with IPF who have undergone a bilateral lung transplant even though there is an increased risk of complications early after transplant. However, data also exist that show that there is no survival benefit for IPF patients who undergo bilateral vs. single lung transplantation. Given the conflicting data, the debate on double vs. single lung transplant for patients with IPF will continue on with preference determined by each transplant center.
Regardless of the rationale for the choice of procedure, recent data indicate that bilateral lung transplantation is increasing in frequency ( Fig. 9.1 ) . In 2013, 75% of all transplant procedures were bilateral lung transplants. During the same period, cystic fibrosis accounted for ∼15% of transplants and idiopathic pulmonary hypertension for less than 3%, and the frequency of bilateral transplantation for patients with an underlying diagnosis of IPF is similarly increasing. One report evaluating wait list mortality demonstrated a higher risk for those IPF patients listed for bilateral lung transplant as their only option. The impacts of current transplant procedure choice remain unclear on multiple variables, including its impact on the potential candidacy of a patient with DPLD, wait list mortality, and outcomes following lung transplant for all recipients.
Outcomes After Transplantation for Interstitial Lung Disease
The majority of information about outcomes after lung transplantation in DPLD comes from what is known about IPF recipients. Because the majority of DPLDs result in similar physiologic changes, with restrictive lung disease and high risk for the development of secondary pulmonary hypertension, some generalizations across the disease type are accurate. More specific disease considerations are discussed later.
Survival after lung transplantation has consistently improved by era from 1988 through June of 2013. The most striking improvements in outcome are during the perioperative period. These improvements are due to improved donor preservation, operative technique, and critical care management early after transplant. Currently, the median survival estimate for all recipients from 1994 through 2013 was 5.7 years. The 90-day survival rate was 89%. Although the impact has not been as great for long-term survival, this too is slowly improving. In the same era, unadjusted 10-year survival rates were 31%. Survival for patients with an underlying diagnosis of DPLD is generally consistent with these reported outcomes. The largest cohort of interstitial lung disease transplanted remains IPF, and the median survival for this group is slightly above 4.5 years. For those patients with sarcoidosis, median survival was 6.1 years. These unadjusted survival rates need to be evaluated cautiously because additional recipient factors have an impact on survival after lung transplantation.
Early survival after transplantation is affected by numerous factors, including recipient- and donor-specific conditions before transplantation. However, PGD immediately following transplant is the top cause of early mortality. PGD is the consequence of ischemia-reperfusion injury with resultant development of reactive oxygen species. Ultimately, this leads to acute lung injury and capillary leak. PGD is based on clinical findings early after transplantation ( Table 9.2 ). Several studies have identified pulmonary fibrosis and pulmonary hypertension as having strong associations with the development of this complication.
| Grade | Pa o 2 /Fi o 2 | Radiographic Infiltrates Consistent With Pulmonary Edema |
|---|---|---|
| 0 | >300 | Absent |
| 1 | >300 | Present |
| 2 | 200–300 | Present |
| 3 | <200 | Present |
Furthermore, the severest form of PGD (grade 3 at 72 h after transplant) affects long-term survival and pulmonary function and increases the risk for development of bronchiolitis obliterans syndrome (BOS). In addition to the recipient risk factors, there are donor factors that increase the risk of development of this complication. Currently, there are no recipient interventions to prevent its development. Further work into defining the best match for donor and recipient as well as the potential for conditioning of donor lungs may lead to improvements in the future.
Patients are on lifelong immunosuppression and are typically treated with corticosteroids, a calcineurin inhibitor (tacrolimus or cyclosporine), and an antimetabolite (mycophenolate mofetil or azathioprine). Chronic immunosuppression places patients at risk for the development of comorbidities, including hypertension, diabetes, chronic kidney disease, and malignancy ( Table 9.3 ). Notwithstanding the medical complexity, patients with DPLD who undergo lung transplantation garner a survival advantage from the procedure. In addition, quality of life is significantly improved after transplantation in several studies.
| Outcome | Within 1 year | Within 5 years |
|---|---|---|
| Hypertension | 51.5% | 80.7% |
| Renal dysfunction | 22.5% | 53.3% |
| Creatinine <2.5 mg/dL | 15.7% | 35.3% |
| Creatinine >2.5 mg/dL | 5.0% | 14.3% |
| Chronic dialysis | 1.7% | 3.0% |
| Renal transplant | 0.1% | 0.8% |
| Hyperlipidemia | 26.2% | 57.9% |
| Diabetes mellitus | 23.0% | 39.5% |
| Bronchiolitis obliterans syndrome | 9.3% | 41.1% |
The main limitation to long-term survival after lung transplantation remains the development of BOS, or chronic rejection. BOS is defined by persistent airflow obstruction in comparison to a recipient’s peak baseline values ( Table 9.4 ). Complications that affect the allograft (acute rejection, anastomosis issues, disease recurrence) must first be ruled out in addition to documenting a decline in pulmonary function. There are several probable and possible risk factors that set up the lung transplant recipient for the development of chronic small airways disease, including recurrent acute rejection, viral infections, lymphocytic bronchiolitis, donor antigen specific reactivity, and aspiration of gastroesophageal refluxate. Ultimately, chronic obstruction increases the risk of infection and sets the stage for respiratory failure. The rate of BOS varies in different series but has an estimated prevalence of ∼41% at 5 years. Treatment interventions for this syndrome are limited, but there are data that suggest the use of chronic azithromycin in these patients can help slow down the progression of disease.
| Grade | Diagnostic Criteria |
|---|---|
| BOS 0 | FEV 1 > 90% of baseline and FEF 25–75% > 75% of baseline |
| BOS 0p | FEV 1 81% to 90% of baseline and/or FEF 25–75% ≤ 75% of baseline |
| BOS 1 | FEV 1 66% to 80% of baseline |
| BOS 2 | FEV 1 51% to 65% of baseline |
| BOS 3 | FEV 1 50% or less of baseline |
Disease-Specific Considerations
Idiopathic Pulmonary Fibrosis
Over the past decade there has been an increase in disease awareness with IPF, while during the same period there has been a shift in transplantation practices where now programs are more willing to perform transplants in older patients than in the past as these patients can still garner a survival benefit. Based on these new practices it is felt that once a patient is diagnosed with IPF, he or she should be referred to a transplant center ( Box 9.1 ). The appropriate time for listing for transplantation must consider the potential survival benefit of the procedure ( Box 9.2 ). In the past decade there has been much work to define risk factors associated with worse outcomes in those with IPF before transplantation. Although the overall prognosis is grim, the disease course remains variable for individual patients. As a result, identifying patients who are at particularly high risk is most appropriate when considering listing for lung transplantation.
