The Future of Lung Transplantation

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Commentary Ahead of the Curve

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The Future of Lung Transplantation Steven D. Nathan, MD, FCCP

Lung transplantation has been the last of the solid organs to gain traction as a viable therapeutic option. Due to differing standards of care and the relatively low number of lung transplants performed, it has proven difficult to orchestrate prospective multicenter studies to determine best practice and explore novel therapies. Nonetheless, there have been incremental advances in lung transplantation, including liberalization of criteria for both suitable donor organs as well as acceptable recipients. This has resulted in increasing numbers of procedures being performed, and outcomes have improved despite an expanding cohort of sicker patients undergoing lung transplantation. This review will discuss current trends and future developments with a focus on the most pertinent of the pitfalls that may accompany CHEST 2015; 147(2):309-316

lung transplantation.

AMR 5 antibody-mediated rejection; BOS 5 bronchiolitis obliterans syndrome; CLAD 5 chronic lung allograft dysfunction; EVLP 5 ex vivo lung perfusion; HLA 5 human leukocyte antigen; IPF 5 idiopathic pulmonary fibrosis; PAH 5 pulmonary arterial hypertension; PGD 5 primary graft dysfunction; R-CLAD 5 restrictive chronic lung allograft dysfunction ABBREVIATIONS:

The first human lung transplant was performed in 1962 by Hardy, but it was only in the early 1980s that the modern era of lung transplantation began, with the first successful lung transplants and heart-lung transplants being reported.1 Over the ensuing decades, candidate selection has continued to evolve, with broadening of criteria for potential recipients. The consensus guidelines for the evaluation and acceptance of prospective lung transplant candidates published in 2006 do not fully reflect current practice habits and an updated version is pending publication.2,3 In the 2006 guidelines, the age criteria cited as a relative contraindication to lung transplantation was 65 to 70 years. However, recipient age has steadily

Manuscript received July 16, 2014; revision accepted September 16, 2014. AFFILIATIONS: From the Lung Transplant and Advanced Lung Disease Program, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA. CORRESPONDENCE TO: Steven D. Nathan, MD, FCCP, Lung Transplant and Advanced Lung Disease Program, Department of Medicine, Inova

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increased with more patients . 65 years of age now being transplanted (Fig 1A).4 The new guidelines will reflect this trend, with an upper age cutoff of 75 years, beyond which lung transplantation should be avoided. Increased recipient age in the United States has been facilitated by the implementation of the lung allocation score system in 2005, which resulted in organ allocation based on disease severity and the perception of likely survival benefit. This, in turn, has contributed to idiopathic pulmonary fibrosis (IPF), a disease of the elderly, becoming the number one indication for lung transplantation. For the period subsequent to the lung allocation score system (2006 to 2012), 20% of recipients with IPF were older than 65 years, while

Fairfax Hospital, 3300 Gallows Rd, Falls Church, VA 22042; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1748

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Figure 1 – Data from the Scientific Registry of Transplant Recipients4 demonstrating growing trends in lung transplantation. A, Number of lung transplant recipients older than 65 y by year. B, Number of donors recovered in the United States by year. C, Number of lung transplant candidates added to the wait list in the United States by year vs the number of transplant performed. D, Number of older donors by year.

6.3% were 70 years or older. There are data to suggest that lung transplantation in patients . 70 years of age may result in comparable outcomes.5 Therefore, this trend is likely to continue with greater IPF disease awareness and more patients beyond 70 being considered as lung transplant candidates. It is also conceivable that other diseases, formerly considered as contraindications and relative contraindications to transplantation, will contribute proportionately more recipients. Examples include patients with scleroderma, as well as those with other connective tissue disorders. A recent analysis of the United Network for Organ Sharing Registry revealed that of the 20,135 patients transplanted between 1987 and 2011, 142 had the diagnosis of scleroderma and their outcomes were similar to that of other patients.6 Patients who tested positive for HIV might constitute another group of potential recipients, and HIV-positive status is cited as a relative contraindication in the new guidelines, as is the case for other chronic infections, such as hepatitis B and C, which were formerly regarded as absolute contraindications.3,7

Pretransplant: Improving Pretransplant Survival There have been significant advances in the medical therapy of a number of diseases for which lung transplantation is often a last resort option (Fig 2). Nowhere is this more evident than in the field of pulmonary arte310 Commentary

rial hypertension (PAH), with 13 treatments now approved and available in the United States. This has enabled patients with PAH to be maintained and their lives extended without the need for transplantation. This is apparent in the proportion of transplants performed for PAH; specifically, in 1991 11.8% of all lung transplants were for idiopathic PAH vs only 2.7% in 2011.8 There is a likelihood that a similar phenomenon could evolve for other disease conditions, such as cystic fibrosis and IPF.9-11 Whereas patients have been sustained outside of the “window of opportunity” on the front end, so too has this window been extended on the back end, with patients being supported through the more liberal implementation of extracorporeal membrane oxygenation. It appears that equivalent posttransplant results are attainable in these patients despite their increased acuity of illness pretransplant.12-15

Improving Lung Donor Availability The number of lungs deemed suitable for transplant continues to increase (Fig 1B). However, patients deemed appropriate transplant candidates have continued to outstrip the availability of suitable organs (Fig 1C). Donor criteria have evolved over the years, resulting in organs that were previously considered unacceptable now being commonly used. The terms “marginal” and, more recently, “extended criteria” organs are common lexicon in organ procurement. Table 1 contrasts the

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Figure 2 – Therapeutic advances in lung diseases for which transplantation might be an option. Included are available medications in the United States with years of approval, procedures, and anticipated approvals. Inh 5 inhaled; PAH 5 pulmonary arterial hypertension; SQ 5 subcutaneous; Trep 5 Treprostinil.

traditional criteria that defined organ suitability vs today’s common practice with extended criteria. Many of these extended-criteria lungs are due to liberalization of acceptable prior smoking history as well as increasing acceptance of lungs from older donors.16 In 2004, 13.3% of lungs were from donors aged  60 years vs 19.3% in 2013 (Fig 1D). There are a number of developments that have emerged that will continue to fuel the growth of acceptable lungs. The use of lungs donated after circulatory death is one such development that is gaining increasing acceptance. Another emerging technology is ex vivo lung perfusion (EVLP), which serves to “recondition” lungs that previously might have been unacceptable and discarded17-20 (Fig 3). There are numerous potential advantages to this, including removing lungs from the effects of a damaging cytokine milieu that often accompanies brain death. In addition, EVLP enables reexpansion of atelectatic areas, clearance of secretions through serial bronchoscopy, clot removal with the ex vivo perfusate, maintenance of normothermic metabolic function, and closer monitoring of the status of the lung through serial evaluations of radiographs, blood gases, and lung mechanics. EVLP also holds promise for pharmacologic manipulation of the lung, not only through the use of antibiotics, but also with agents to enhance fluid clearance, as well as gene therapy to promote lung repair. After standard lung procurement with cold storage and transport, EVLP might be undertaken at the transplant center or could occur in the context of regional lung reconditioning centers. EVLP may also be initiated at the time of organ harvesting through a portable system that precludes the need for lung cooling, with the lungs transported

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directly for reimplantation. EVLP might find great utility as an adjunct to lungs donated after circulatory death. An exciting new approach to the organ donor shortage issue is the emerging science of tissue engineering and the creation of bioartificial lungs. This involves repopulating a denuded lung matrix with stems cells, other appropriate cell lines, or both. If the stem cells are recipient derived, then this might abrogate issues with rejection and the inherent complications of immunosuppressive therapy.21,22 However, there are a number of hurdles that need to be overcome to further this evolving technology. Stem cell transplantation has also generated interest as a means of tolerance induction in the context of allogeneic lung transplantation.23 Despite waxing and waning enthusiasm over the years, xenotransplantation remains a promising approach to address the donor/recipient imbalance. Since unsuccessful attempts in the early 1990s at primate to human liver transplants, there have been considerable advances in the field that have increased understanding of the complexities and barriers that need to be overcome for this to become a viable alternative. The first clinical trials will likely involve a genetically modified swine lung with attempts at tolerance induction and immunosuppressive strategies that mitigate not only T cells and B cells, but also natural killer cells and macrophages, as well as the complement and coagulation cascades.24

Posttransplantation There is a paucity of robust, prospective, randomized controlled studies in lung transplant recipients evaluating the role of novel immunosuppressive medications and 311

TABLE 1

] Standard (“Ideal”) Lung Donor Criteria vs Present and Future Practice

Ideal

Current Practice

Potential Role of EVLP

Age , 55 y

Lungs older than 65 y may be acceptable in select cases, older donor lungs may be more suited to older recipients

…

Clear serial chest radiographs

Chest radiographs that are not clear may be acceptable

Might enable serial clearing

Acceptable gas exchange (PaO2 . 300 mm Hg on FIO2 1.0 with PEEP 5 cm H2O

Contralateral lung may be acceptable if unilateral infiltrate as explanation for the reduced PaO2

Oxygenation might be improved

Absence of chest trauma

Absence of significant lung contusion. Contralateral side may be acceptable

No evidence of aspiration or sepsis

Contralateral side may be acceptable

… May be able to “buy time” to treat with higher dose antibiotics

May treat through sepsis Absence of purulent secretions at bronchoscopy

May be acceptable if purulent secretions clear with serial washings

Absence of organisms on sputum gram stain

Organisms on sputum Gram stain acceptable

No history of primary pulmonary disease or active pulmonary infection

Active bacterial infections might be treatable

Tobacco history , 20 pack-y

Donors with . 20 pack-y history may be used with equivalent results

…

ABO blood group compatibility

ABO blood group compatibility

…

Prior cardiac surgery acceptable

…

No prior cardiopulmonary surgery

Allows for serial bronchoscopies with pulmonary toilet … Might enable successful ex vivo treatment of pneumonias with higher dose antibiotics

Prior lung surgery may be acceptable, including LVRS Appropriate size match

…

Bigger lungs have better long-term outcomes, lung ”trimming” in select over-sized cases

EVLP 5 ex vivo lung perfusion; LVRS 5 lung volume reduction surgery; PEEP 5 positive end-expiratory pressure.

strategies. The likelihood remains high that immunosuppressive drugs will be developed first in kidneys, liver, or heart transplantation, with extrapolation of emerging novel therapies to lung transplant recipients. However, there are a number of distinctive post-lung transplant maladies where future prospective interventional studies could have a meaningful impact on outcomes. Some are highlighted in this article.

Primary Graft Dysfunction The most immediate posttransplant conundrum remains primary graft dysfunction (PGD). This tends to affect anywhere from 1% to 57% of patients, with 28.8% developing grade 3 PGD.25 There are many determinants of PGD, including donor and recipient factors, that require further characterization. Trials thus far to ameliorate PGD, including the use of inhaled nitric oxide, inhaled surfactant, and C1-esterase-inhibition, have been met with mixed results.26-29 Aside from future 312 Commentary

attempts to risk stratify patients and prevent PGD, it is a condition that is primed for further randomized controlled trials of novel interventions.

Antibody-Mediated Rejection The advent of new solid-phase methods such as the Luminex assay (Thermo Fisher Scientific Inc) provide a more sensitive platform for the detection of donorspecific anti-human leukocyte antigen (HLA) antibodies.30 Up to 90% of patients have preformed anti-HLA antibodies, about one-third of which are donor-specific antibodies (DSAs).30 These preformed antibodies would have escaped detection with the previous standard of complement-dependent cell cytotoxicity.31 Whereas it was previously thought that antibody-mediated rejection (AMR) was a rare phenomenon in lung transplant recipients, this appears not to be the case.32,33 The definition of AMR is evolving, with the most recent recommendation from an International Society for Heart and

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burden? While this might make intuitive sense and improve the chances of a negative cross-match, there are data to suggest that this might be a fruitless and costly endeavor.35 4. What are the roles of specific B-cell-targeting agents such as bortezomib and rituximab? 5. If used post-transplant, what threshold of antibody burden warrants administration of these agents or should they only be considered for clinically overt events?

Chronic Lung Allograft Dysfunction

Figure 3 – Photo depicting the early stages of ex vivo lung perfusion. After the acellular perfusate is pumped through the pulmonary artery (yellow) and out through the left atrium (green), the lungs are warmed to 32°C, the endotracheal tube is unclamped, and protective ventilation is begun. (Reprinted with permission from Perfusix USA, Inc.)

Lung Transplantation consensus statement in 2012 suggesting a multidisciplinary approach that includes a clinical evaluation of allograft dysfunction, the presence of circulating DSAs, and consistent histopathologic findings.34 However, the spectrum of pathologic changes is broad and may result from other common posttransplant insults. The presence of positive staining for complement (usually C4d), while helpful, is not necessarily a prerequisite in the context of the multidisciplinary diagnosis. There is likely a spectrum of response to the presence of low-level DSAs. On the one end is clinically overt and potentially devastating AMR, and on the other end there are emerging data suggesting indolent occult injury. Specifically, lung transplant recipients who have any pretransplant anti-HLA II antibodies have been shown to have a greater propensity for bronchiolitis obliterans syndrome (BOS) and an increased mortality risk.30 The ability to detect low-level antibodies has resulted in many unanswered questions pertaining to their significance and management: 1. When do these low-level antibodies predispose to AMR or chronic allograft rejection? 2. When should therapy be initiated? Treatment typically includes plasmapheresis for immediate antibody reduction and B-cell-mediated therapy to reduce subsequent antibody formation. 3. Should patients with positive antibodies be desensitized prior to transplant to reduce their antibody

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Chronic lung allograft rejection remains the most common cause of long-term morbidity and mortality. Chronic rejection is manifest pathologically by bronchiolitis obliterans. The desire to avoid surgical lung biopsies to attain this diagnosis provided the impetus for the physiologic definition of BOS. BOS is defined by a permanent . 20% reduction in the FEV1 from the patient’s prior established baseline, without other identifiable cause. In recent years, there has been increasing recognition that BOS has been used as a “waste basket” term, with many designated cases accompanied by restrictive physiology and parenchymal infiltrates. This evolution was partly due to a lack of definition for chronic lung allograft dysfunction (CLAD) other than BOS. CLAD has since been recognized and defined physiologically by either a 20% reduction in the FEV1 or a 20% decline in the FVC from the prior established baseline.36,37 CLAD can broadly be divided into restrictive CLAD (R-CLAD) and obstructive CLAD, which encompasses BOS (Fig 4). The relative incidence of R-CLAD in the context of the broad category has been reported as approximately 30%.38,39 Within the group of patients with BOS, there are those that have azithromycin-responsive BOS, which likely represents a distinct phenotype. There are data from a randomized controlled study demonstrating improved BOS-free survival with initiation of therapy at time of discharge after transplantation,40 and, therefore, chronic lowdose azithromycin therapy has evolved to become widely used by many transplant centers to manage or prevent BOS. R-CLAD with concomitant decreases in the FVC and FEV1 is usually accompanied by parenchymal infiltrates and has been demonstrated to have a worse prognosis than BOS.36,38,39 Specific radiographic entities include upper lobe fibrosis, which in some cases may represent pleuroparenchymal fibrosis, as well as alveolar infiltrates and consolidation.36,38,39,41 There may be a broad range of accompanying pathologic changes, which may coexist 313

Figure 4 – Schematic of CLAD with risk factors, potential predictors, and phenotypes. Abs 5 antibodies; BOS 5 bronchiolitis obliterans syndrome; CHF 5 congestive heart failure; CLAD 5 chronic lung allograft dysfunction; GERD 5 gastroesophageal reflux disease; HFpEF 5 heart failure with preserved ejection fraction; HLA 5 human leukocyte antigen.

with or be the precursor of the fibrotic process. Further, there might be admixed bronchiolitis obliterans lesions and superimposed infection underscoring the vulnerability of these patients to multiple insults.42,43 The etiology of CLAD is likely multifactorial, with many potential culprits including viral or other infections, acute and chronic aspiration, persistent acute rejection, and AMR. The recent definition of CLAD has provided a foundation for future research into more precise characterization and staging of the various phenotypes. A greater understanding of the etiologies may enable preemptive strategies and targeted therapies for the various forms of CLAD. Refinements in CT imaging, including the use of microCT imaging, might enable more precise radiographic phenotyping of CLAD.44 Serum and BAL specimens for cellular, cytokine, proteinomic, and genomic analysis also hold promise in this regard.45-48

Tailored Therapy: The Role of Genomic and Systems Biology Morbidity and mortality after lung transplantation depend on the nature and severity of ensuing complications. The broad range of outcomes are determined by the interaction between donor and recipient characteristics, as well as extrapulmonary influences, including comorbidities, drug side effects, and other external factors. Lung transplant recipients are typically managed within the broad constraints of center-specific protocols, despite alternative choices in treatment options and preemptive strategies. Tailored therapy is invariably implemented based on subsequent complications, as well as side effects of the immunosuppressive and anti-infectious agents. The concept of tailored therapy upfront might be enabled through genomic risk stratification and the risk/benefit to tolerance/toxicity balance of the various medications. The evaluation of single nucleotide polymorphisms, proteomics, and metabollomics might also allow the 314 Commentary

earlier, less invasive diagnosis of acute rejection and enable the differentiation of the various forms of acute and chronic allograft dysfunction. In this regard, an ambitious and comprehensive approach to the complexities of CLAD has recently been undertaken through a systems-based approach.45 This 14-center study involves computational modeling with the integration of extensive clinical, environmental, and biologic markers. The purpose of this endeavor is to improve the prediction of CLAD and to develop tailored therapy based on the characteristics and interactions of the individual donor, recipient, and external factors. This broader comprehensive integrative approach might also have utility in the approach to other maladies that befall transplant recipients.

Summary The future of lung transplantation appears bright, with progress on multiple fronts. Anticipated pretransplant advances include ongoing improvements in medical management, broadening of candidate eligibility, widening of the donor pool through innovative management, and the use of alternative lung sources. Posttransplant priorities include targeted and less toxic immunosuppressive strategies, as well as improvements in the prevention and management of PGD, AMR, and CLAD. A steadfast principle as new technologies evolve is that the enthusiasm generated by innovation should not compromise the responsible use of available lungs regardless of donor type and source. Novel interventions and strategies should only be adopted with the overarching goal of improving all outcome measures associated with lung transplantation.

Acknowledgments Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Nathan has been a consultant for and received research funding from Actelion Pharmaceuticals Ltd,

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Bayer Pharmaceuticals Corp, Boehringer Ingelheim, Gilead Sciences Inc, Intermune Inc, and United Therapeutics Corp. Other contributions: The author is indebted to Allan Glanville, MD, for his comments and suggestions for this review.

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46. Kennedy VE, Todd JL, Palmer SM. Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome. Am J Transplant. 2013;13(3):552-561. 47. Greenland JR, Jewell NP, Gottschall M, et al. Bronchoalveolar lavage cell immunophenotyping facilitates diagnosis of lung allograft rejection. Am J Transplant. 2014;14(4):831-840. 48. De Vlaminck I, Valantine HA, Snyder TM, et al. Circulating cellfree DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014;6(241):241ra77

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