Home Educatione-Learning Referral Considerations for Lung Transplantation in the Era of the Lung Allocation System
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Referral Considerations for Lung Transplantation in the Era of the Lung Allocation System

PCCSU Volume 25, Lesson 25

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Jonathan Singer, MD, MS

Dr. Singer is Clinical Instructor, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine; Department of Medicine; University of California, San Francisco; San Francisco, California.

Dr. Singer has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:

National Institutes of Health (F32 grant to study health-related quality of life and disability in recipients of a lung transplant) – grant monies

Novartis (investigator-initiated research award to study health-related quality of life and disability in recipients of a lung transplant) – grant monies

Objectives

  1. Describe the rationale for the Lung Allocation Score system of organ allocation.
  2. Understand the overarching principles behind the variables used in calculating the Lung Allocation Score.
  3. Identify the appropriate time to refer patients for lung transplantation.
  4. Identify the absolute and relative contraindications to lung transplantation.
  5. Identify modifiable contraindications to lung transplantation that are amenable to intervention before or concurrent with referral to lung transplantation.

Key words: COPD; cystic fibrosis; idiopathic pulmonary fibrosis; lung allocation score; lung transplantation; pulmonary arterial hypertension

Abbreviations: Dlco = diffusing capacity of the lung for carbon monoxide; HRQL = health-related quality of life; IPF = idiopathic pulmonary fibrosis; ISHLT = International Society for Heart and Lung Transplantation; LAS = lung allocation score; NYHA = New York Heart Association; OPTN = Organ Procurement and Transplant Network; PAH = pulmonary arterial hypertension

Gap in Clinical Practice

Lung transplantation is a rapidly evolving field of pulmonary medicine. In addition, the system of organ allocation in the United States was overhauled in 2005 and the lung allocation score (LAS), a weighted composite score of medical urgency and anticipated survival after transplant, was introduced. This overhaul changed the timing of when patients are listed for lung transplantation. It also increased the medical acuity of patients ultimately undergoing this procedure. Thorough evaluation is therefore needed to ensure that patients going through lung transplantation are medically, physically, and psychologically robust in order to withstand this intensive therapy. Appropriate timing of referral affords transplant centers the ability to provide patients and their caregivers with information on lung transplant and with the time to identify and rectify modifiable contraindications to transplant.

Introduction

Over the last three decades, lung transplantation has emerged as an accepted therapy for advanced chronic lung disease. Although the first human lung transplant is typically attributed to James Hardy in 1963, that patient survived only 18 days.1 Over the next 20 years, subsequent attempts met with similar outcomes—until 1984, when Joel Cooper performed a single lung transplant in a patient with pulmonary fibrosis.2 That patient survived 7 years, ultimately dying of renal failure. This achievement ignited new interest in lung transplantation for advanced lung disease.

Since then, evolution in surgical techniques, immunosuppressive regimens, and prevention and management of comorbidities has improved survival after transplant. As a direct result of these improvements, global demand for lung transplantation has increased. Indeed, five transplants were performed in 1985; in 2009, that number had grown to nearly 3,300.3 Today, the primary aims of lung transplantation are to improve survival and health-related quality of life.

Advances in the approaches used to identify ideal candidates for lung transplantation have paralleled the evolution in surgical techniques and medical management. Despite these advances, however, survival following lung transplantation continues to lag behind outcomes with other solid-organ transplants. In the decade 2000 to 2009, survival half-life after lung transplant (the time at which point 50% of patients are still alive) was 5.9 years; if patients survived the first year after transplant, this conditional survival half-life was 8.0 years.3 The early posttransplant period remains high risk, with 20% of patients dying within the first postoperative year. Notably, nonalloimmune factors are responsible for the majority of deaths within this first year.3,4 Also, the patients in need of lung transplantation far outnumber the available donors. Thus, appropriate selection of candidates who can be expected to derive the greatest benefit from this scarce therapy is critically important. Broadly, the evaluation of patients referred for lung transplantation includes considerations of whether an individual will be able to survive the intense perioperative time period. Candidates ultimately selected for listing must also be physiologically capable of tolerating toxic immunosuppressive medications and the comorbid conditions they cause (eg, diabetes mellitus, renal and hepatic dysfunction, hypertension, hyperlipidemia, osteoporosis), as well as the psychological stressors after transplant.

This manuscript aims to review current guidelines and their rationale for referring patients for evaluation lung transplantation in the era of the LAS. Three important points should be considered when evaluating these guidelines. First, lung transplantation is a rapidly evolving field. Improvements in donor and recipient management have allowed this intervention to be successfully provided to patients not previously considered to be candidates. Second, lung transplant remains a relatively rare intervention. As a result, robust clinical data supporting these guidelines are, at times, lacking. Especially for more rare indications, guidelines are based on expert opinion and/or published single-center experiences. Thus, in carefully selected cases, lung transplant has been successfully performed in patients who meet one or more of the absolute contraindications listed below. Third, the criteria considered when referring a patient for evaluation are often different from the criteria used to ultimately list a patient for transplant. Reflecting these three points, criteria and contraindications for listing for lung transplant vary by center and are constantly evolving; physicians are urged to discuss complicated patients with their local transplant center.

The Lung Allocation Score: A Novel System for Donor Lung Allocation

Prior to 2005, allograft allocation to wait-listed patients in the United States was seniority based.5 A patient’s position on the list was determined by the number of days spent waiting. Patients with rapidly progressive diseases, such as idiopathic pulmonary fibrosis (IPF) or pulmonary arterial hypertension (PAH) frequently died before accumulating enough time on the wait list to be prioritized. Also, through the 1990s, improved survival after lung transplantation led to an increased number of patients being placed on the waiting list. With a relatively fixed pool of donors, the result was an increase in the number of patients dying while waiting for transplantation, especially those with rapidly progressive diseases.

To address this perceived inequity and inefficiency in the system of lung allograft allocation, the Department of Health and Human Services published the Final Rule in 1998 that, among other things, recommended emphasizing medical urgency and deemphasizing wait time for organ allocation.6 The Final Rule was published in 2000 and was subsequently supported by the Institute of Medicine.7 In response to the Final Rule, an organ allocation modeling subcommittee was formed within the Organ Procurement and Transplant Network (OPTN) Thoracic Organ Transplantation Committee to study the feasibility of an “urgency”-based system of lung allocation. The committee was driven by three goals: (1) reduction of mortality among patients on the waiting list; (2) urgency-based prioritization of candidates while avoiding “futile” transplants; and (3) deemphasizing the role of waiting time and geography.

Using data from a large registry of lung transplant recipients, the OPTN lung allocation subcommittee identified clinical predictors of waiting list mortality and postoperative mortality.5 Examples of factors predictive of mortality included older age, high or low body mass index, low forced expiratory value FEV1 % predicted, low FVC % predicted, and need for oxygen. The subcommittee used the identified factors to generate regression models to assign each patient a LAS that incorporated his or her medical urgency (risk of dying on the waiting list) and his or her predicted 1-year survival after lung transplantation. The LAS is normalized to a range of 0 to 100. Candidates with higher scores are expected to derive a higher “net benefit” from lung transplantation and are therefore prioritized. On May 4, 2005, this new LAS organ allocation system was implemented in the United States. An online LAS calculator is now available through the US Department of Health and Human Services.8

Because wait list time is now wholly deemphasized in the LAS system, the timing of listing a patient for lung transplantation is now driven by a theoretical concept called the “transplant window” (Fig 1). A patient enters this window when his or her lung disease is advanced enough that the anticipated survival following transplant exceeds the anticipated survival without transplant. In this window, patients are neither too healthy for transplant nor are they too sick and debilitated to safely undergo this intense intervention. In order to ensure timely and organized evaluation, referral for lung transplant is advisable when a patient has a 2- to 3-year predicted survival of <50% or a New York Heart Association (NYHA) III or IV level of function despite maximum medical therapy.


Figure 1. Timing of referral for lung transplantation: the transplant window.


Indications for Lung Transplantation

Lung transplantation is an accepted therapy for a myriad of chronic diseases of the airways, parenchyma, and vasculature (Table 1). Transplantation is indicated when a pulmonary disease is advanced and refractory to other medical or potential surgical therapies. Of the many diseases for which transplantation is performed, COPD, IPF, and cystic fibrosis are the three leading indications. They account for fully 74.2% of transplants performed globally.3 Notably, the amount of oxygen needed at rest to maintain adequate oxygen saturation is a factor heavily weighted in the LAS. As a result of typically high oxygen needs and heightened risk of death while waiting for transplant, patients with IPF are prioritized for transplant under the LAS. Indeed, IPF is now the leading indication for transplant in the United States.9 Other common indications include α1-antitrypsin deficiency (6%), other types of pulmonary fibrosis (3%), noncystic fibrosis bronchiectasis (2.8%), and sarcoidosis (2.6%).3


Table 1Indications for Lung Transplantation by LAS Primary Diagnostic Groupings (A-D)

Obstructive Lung Disease (Group A)
COPD/emphysema
α1-Antitrypsin deficiency
Bronchiectasis
Bronchopulmonary dysplasia
Constrictive bronchiolitis
Kartagener syndrome/primary ciliary dyskinesia
Granulomatous lung disease
Lymphangioleiomyomatosis
Granulomatosis with polyangiitis (Wegener)-bronchiectasis
Inhalation burns/trauma
Sarcoidosis with mean pulmonary artery pressure ≤30 mm Hg
Tuberous sclerosis
 
Pulmonary Vascular Disease (Group B)
Pulmonary arterial hypertension
Eisenmenger syndrome
Scleroderma/CREST syndromea: pulmonary hypertension
Secondary pulmonary hypertension
 
Pulmonary veno-oclusive disease
Pulmonary thromboembolic disease
Pulmonic stenosis
 
Cystic Fibrosis or Immunodeficiency Disorders (Group C)
Cystic fibrosis
Common variable immune deficiency
Hypogammaglobulinemia
Pulmonary veno-occlusive disease
Pulmonary hypertension secondary to systemic disease
 
Restrictive Lung Disease (Group D)
Idiopathic pulmonary fibrosis
Sarcoidosis with mean pulmonary arterial pressure >30 mm Hg
Scleroderma/CREST syndrome: fibrosis
Pulmonary alveolar proteinosis
Occupational lung disease (other)
Silicosis
Amyloidosis
Wegener granuloma: restrictive
Eosinophilic granuloma
Hypersensitivity pneumonitis
Lung retransplant/graft failure
Lymphocytic insterstitial pneumonia
Idiopathic pulmonary hemosiderosis
Sjögren syndrome
Polymyositis
Systemic lupus erythematosus
ANCA-positive vasculitis
Bronchiolitis obliterans and organizing pneumonia
Bronchiolitis obliterans (non-retransplant)
Pulmonary fibrosis
Mixed connective tissue disease
Rheumatoid disease
ARDS
Fibrosing mediastinitis
Pulmonary telangiectasia: restrictive
Hermansky-Pudlak syndrome
Adenocarcinoma in situ/minimally invasive adenocarcinoma
(formerly bronchoalveolar carcinoma)

Table 1 is not an exhaustive list of all diagnoses for which lung transplantation is indicated. Diagnoses listed, however, account for >95% of transplants. Diagnostic groups (A-D) are used in calculating the LAS.5 ANCA = antineutrophil cytoplasmic antibodies.

aCREST syndrome is a form of scleroderma in which the main features are calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia.


Other less common indications for lung transplant have changed over time. PAH was previously a leading indication for transplant. As a result of improved and novel medical therapeutics, only 2% of lung transplants are now performed for this condition. Transplantation for interstitial lung diseases related to connective tissue or autoimmune diseases (eg, scleroderma, rheumatoid arthritis, dermatomyositis, and polymyositis) remains controversial given concerns about the impact of extrapulmonary organ involvement that could compromise patient or allograft function after transplant. Small case series, however, have demonstrated that short- and medium-term allograft and patient survival following transplant for these conditions are similar to those seen with more traditional indications.10,11 Enthusiasm has waned, however, for transplantation for adenocarcinoma in situ/minimally invasive adenocarcinoma (formerly called bronchoalveolar carcinoma12) after disappointing results.

Referral for Lung Transplantation: General Concepts

The number of patients waiting for lung transplantation continues to exceed the donor pool. As a result, careful attention is paid to selecting candidates most likely to derive a survival and quality-of-life benefit. Appropriate candidate selection fulfills the medical and ethical responsibilities to best serve patients, to value the altruistic gift from donor families, and to serve society as a whole.

Absolute and relative contraindications help physicians to select the patients most likely to derive a transplant benefit by identifying clinical scenarios that place candidates at increased risk for morbidity and mortality from the surgery itself or from the toxicities associated with the immunosuppressants required to maintain allograft function. The responsibilities placed on patients and their caregivers are substantial: Numerous medications must be taken daily, routine follow-up visits to the transplant center are frequent, immunosuppressants require careful monitoring and frequent titration, and complications are, unfortunately, frequent. As a result, factors that impede strict adherence to this rigorous care plan after transplantation are carefully assessed and, if deemed immutable, are considered contraindications to transplant. It is important to note that absolute contraindications are few and that decisions to ultimately list an individual patient for transplant can be driven by complex weighting of multiple relative contraindications and comorbidities.

The goals of the initial multidisciplinary lung transplant consultation are threefold: (1) Assess a patient’s indication and anticipated need for transplant; (2) identify contraindications or other barriers to transplant success that may be modifiable; (3) provide patients and their caregivers with information about the transplant process. Early referral allows this process to proceed at a pace that best serves the patient’s interests. Disease-specific guidelines for timing of referral and listing for lung transplantation are presented in Table 2.


Table 2Disease-Specific Guidelines for Referral and Listing for Lung Transplantation

COPD
Referral BODE index >5
Transplant BODE index >7 or at least 1 of the following:
      History of hospitalization for exacerbation associated with acute
    hypercapnia (Pco2 >50 mm Hg)
      Pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy
      FEV1 <20% predicted and either DLco <20% or homogeneous distribution
    of emphysema
   
IPF and NSIP
Referral At the time of diagnosis (histologic or radiographic evidence of usual interstitial pneumonia, regardless of vital capacity)
Transplant Histologic or radiographic evidence of usual interstitial pneumonia and any of the following:
      DLco <39% predicted
      ≥10% decrement in FVC during 6 mo of follow-up
      Desaturation on pulse oximetry to <88% during a 6-min walk test
      Honeycombing on high-resolution chest CT scan (fibrosis score >2)
  Histologic or radiographic evidence of NSIP and any of the following:
      DLco <35% predicted
      ≥10% decrement in FVC or 15% decrement in DLco during 6 mo of follow-up
   
Cystic Fibrosis
Referral FEV1 <30% predicted or rapidly declining FEV1, particularly in young female patients
  Exacerbation of lung disease requiring ICU admission
  Increasing frequency of exacerbations requiring antibiotic administration
  Refractory or recurrent pneumothorax
  Recurrent hemoptysis not controlled by embolization
Transplant Oxygen-dependent respiratory failure
  Hypercapnia
  Pulmonary hypertension
   
PAH
Referral NYHA functional class III or IV, irrespective of ongoing therapy
  Rapidly progressive disease
Transplant NYHA functional class III or IV with maximum medical therapy
  Low (<350 m) or declining 6-min walk test
  Failing therapy with IV epoprostenol or equivalent
  Cardiac index <2 L/min/m2
  Right atrial pressure >15 mm Hg
   
Sarcoidosis
Referral NYHA functional class III or IV
Transplant NYHA functional class III or IV and any of the following:
      Hypoxemia at rest
      Pulmonary hypertension
      Right atrial pressure >15 mm Hg
   
Lymphangioleiomyomatosis
Referral NYHA functional class III or IV
Transplant Severe impairment in lung function and exercise capacity (eg, Vo2max <50% predicted)
   
Pulmonary Langerhans Cell Histiocytosis
Referral NYHA functional class III or IV
Transplant Severe impairment in lung function and exercise capacity (eg, Vo2max <50% predicted)
  Hypoxemia at rest

BODE = body mass index, oxygen use, dyspnea, exercise capacity; NSIP = nonspecific interstitial pneumonia; Vo2max = maximal oxygen consumption. (Adapted from Orens et al.13)


 

Contraindications to Transplant

Absolute Contraindications
Absolute contraindications are those factors that would result in unacceptably high early, severe morbidity or mortality after transplant (Table 3). In 2006, the International Society for Heart and Lung Transplantation (ISHLT) Pulmonary Council published consensus guidelines for the selection of candidates for lung transplantation.13 This report updated the first “International Guidelines for the Selection of Lung Transplant Candidates”14 supported jointly by the ISHLT, American Society of Transplant Physicians, American Thoracic Society, European Respiratory Society, and the Thoracic Society of Australia and New Zealand, published in 1998. In these guidelines, absolute contraindications were highlighted. As experience increases, some centers have developed successful approaches to managing high-risk factors that are considered absolute contraindications under the ISHLT Guidelines. Again, physicians are encouraged to discuss complex cases with their local center. A list of absolute contraindications follows.

  1. Malignancy within the previous 2 years, excepting cutaneous squamous and basal cell tumors. A 5-year disease-free interval is prudent.
    Anecdotally, in highly selected cases, exceptions to this 5-year disease-free interval have been made. Also, lung transplantation has been performed in patients with certain indolent or early-stage cancers (eg, localized low-grade prostate cancer) of low early metastatic potential, with definitive cancer therapy performed after transplant.
  2. Untreatable advanced dysfunction of another major organ system (eg, heart, liver, or kidney). Coronary artery disease not amenable to percutaneous intervention or bypass grafting, or associated with significant impairment of left ventricular function.
    In carefully selected cases, combined heart-lung, lung-liver, or lung-kidney transplantation can be considered.
  3. Incurable chronic extrapulmonary infection, including chronic active hepatitis B, hepatitis C, and HIV.
    A group in Italy reported the 2-year outcome of a carefully selected patient with cystic fibrosis and well-controlled HIV and hepatitis B infection who underwent lung transplantation and had an uneventful course with stable allograft function.15
  4. Significant chest wall/spinal deformity.
  5. Documented nonadherence or inability to follow through with medical therapy or follow-up office visits.
  6. Untreatable psychiatric or psychological conditions that result in the inability to adhere to medical therapy.
  7. Absence of a consistent and reliable social support system.
  8. Substance addiction (eg, alcohol, tobacco, narcotics, illicit substances) that is active or within the last 6 months.

Table 3Contraindications to Lung Transplantation

Absolute Contraindications Relative Contraindications
Malignancy in the last 2 y, excepting cutaneous squamous and basal cell cancers Age >65 y
Untreatable advanced dysfunction of another major organ system (eg, heart, liver, or kidney); coronary artery disease not amenable to percutaneous intervention or bypass grafting, or associated with significant impairment of left ventricular function Critical or unstable clinical condition (eg, shock)
Incurable chronic extrapulmonary infection, including chronic active hepatitis B, hepatitis C, and HIV infection Severely limited functional status with poor rehabilitation potential
Significant chest wall/spinal deformity Colonization/infection with highly resistant or virulent bacteria, fungi, or mycobacteria
Documented nonadherence or inability to follow through with medical therapy or office follow-up Body mass index >30 kg/m2 or <18 kg/m2
Untreatable psychiatric or psychological conditions that would result in the inability to adhere to medical therapy Severe or symptomatic osteoporosis
Absence of a consistent and reliable social support system Mechanical ventilation or extracorporeal membrane oxygenation
Substance abuse (eg, alcohol, tobacco, narcotics, illicit substances) that is active or within the last 6 mo Poorly controlled medical conditions without end-stage organ damage, such as diabetes mellitus, systemic hypertension, peptic ulcer disease, and gastroesophageal reflux
Profound debilitation with inability to ambulate Coronary artery disease (select patients with coronary artery disease amenable to intervention may undergo percutaneous intervention prior to transplantation or coronary artery bypass grafting concurrent with transplantation)

Anecdotally, some centers have developed successful approaches to managing high risk factors (eg, certain early-stage or indolent malignancies or multiorgan disease) that are considered absolute contraindications under the ISHLT Guidelines. (Adapted from Orens et al.13)


 

Relative Contraindications
Early referral permits the time to address frequently encountered relative contraindications to transplantation that are potentially modifiable. Relative modifiable contraindications that could benefit from early referral are discussed below.

Extremes of Weight: A body mass index of >30 kg/m2 or <18 kg/m2 is associated with poorer outcomes after lung transplantation, including poorer wound healing and increased mortality.16 With adequate time, enrollment in pulmonary rehabilitation programs coupled with nutrition education can help obese patients even with advanced lung disease lose enough weight to be candidates for lung transplantation. Underweight patients can also gain enough weight with better understanding of nutritional needs or use of supplements such as high-calorie shakes, adequate pancreatic enzyme replacement in patients with cystic fibrosis, or even percutaneous tube feeding in more extreme cases.

Physical Debilitation: Most transplant centers require that patients be ambulatory and capable of standing from a seated position without aid.17 Patients who do not meet these minimum requirements are likely to experience perioperative complications and are generally excluded from consideration for listing. Early enrollment in an organized exercise program (such as pulmonary rehabilitation) prior to referral or while being considered for transplant is frequently recommended.

Substance Dependence: In general, 6 months of abstinence from cigarette use and other illicit substances is required. For many centers, significant narcotic dependence is a contraindication for which modified pain management techniques can be effective.

Social Support: When referral is being considered, an organized and reliable social support system is frequently overlooked, but it is a critical factor in a successful outcome following transplant. During an initial visit, the expectations for social support are presented to patients and their caregivers. For patients who don’t have an existing network, plans for social support including family, close friends, or community/religious organizations can be developed.

Coronary Artery Disease: Older patients in general, and those with IPF in particular, are at increased risk of flow-limiting coronary artery disease and myocardial infarction.18,19 Early identification of lesions amenable to percutaneous coronary intervention with stenting is important. Patients should have the opportunity to undergo stenting and receive the recommended 3 to 12 months of clopidogrel therapy before they need to be listed for lung transplant.

Chronic Infections: In patients with cystic fibrosis or another cause of bronchiectasis, chronic bacterial infections are common. Colonization or infection with certain bacteria before transplant is associated with an unacceptably high rate of postoperative complications and possibly increased mortality. In particular, Burkholderia cenocepacia (gemnovar III), Mycobacterium abscessus and possibly Burkholderia gladioli are contraindications to transplant at many centers.20-24 When the patient is referred early, these infections can sometimes be eradicated and transplant can be subsequently considered.

Other “High-Risk” Relative Contraindications
Older Age: While age >65 years is generally considered an arbitrary cutoff for lung transplant, many centers are frequently performing transplant for older patients.4 In fact, in 2011, 26.3% of lung transplants in the United States were performed for patients aged 65 or greater.25 A growing appreciation for considering “physiologic” age as opposed to chronologic age, coupled with the increased priority for patients with IPF under the LAS system, has affected this temporal trend. While registry-based and single-center analyses show that survival after transplant is poorer in recipients older than 65 compared with younger recipients,3,26 one study of 50 carefully selected recipients ≥65 years had equivalent survival at 3 years after transplant as a propensity-matched cohort of younger recipients.27 Individual centers have differing cutoffs for considering older patients for lung transplantation.

Respiratory Failure: Respiratory failure requiring mechanical support is a strong risk factor for mortality after transplant.28 As a result, it remains a contraindication for lung transplantation at many centers. Indeed, in the LAS era, survival at 1 year in mechanically ventilated patients was 68%, compared with 80% in similarly matched nonventilated patients.29 Notably, mechanical ventilation does not appear to be a risk factor for increased mortality in certain disease categories, such as COPD.29

In some centers, however, approaches to bridging patients with severe respiratory failure with mechanical support are emerging. Transplantation is not rare in mechanically ventilated patients, however. In the LAS era, 5.3% of lung transplants in the United States were performed in such cases.29 Extracorporeal membrane oxygenation as an alternative or adjunct to mechanical ventilation is emerging as a promising bridge to lung transplantation.30 Common to both of these mechanical bridge approaches is a focus on early freedom from sedation and ambulation, frequently using tracheotomy. Debilitation and myopathy preclude successful bridging to transplant with either of these technologies. Thus, successful bridging is dependent on early referral to transplant centers with multidisciplinary teams including physicians, nurses, mechanical circulatory support staff, and physical therapists familiar with these approaches.

Future Work

Although the LAS system has been successful in reducing deaths on the waiting list, health-related quality of life (HRQL) is not considered in current lung allocation. Indeed, despite the clinical primacy of HRQL in lung transplant, the LAS gauges “net transplant benefit” solely on survival. It is clinically accepted that some patients with end-stage lung disease would exchange quantity of life for quality of life. Notably, the National Emphysema Treatment Trial demonstrated that lung volume reduction surgery provided patients with substantial and significant improved HRQL over medical management, even after accounting for the increased risk of early mortality.31 This improvement was particularly remarkable in a subgroup of patients without demonstrable mortality benefit (upper-lobe predominant emphysema and high exercise tolerance). While a similar study evaluating the composite benefit of improved survival and HRQL from lung transplant has not yet been performed, there is increasing pressure to incorporate HRQL into policy decision-making to more comprehensively and holistically capture the net benefit of lung transplant.32,33 Efforts along these lines are underway.

Summary

The timing of referral for lung transplantation is influenced by an understanding of both the natural history of lung disease and the unique characteristics of individual patients that deviate from the “traditional” natural history. Referral for transplantation is should be made early in the “transplant window,” a window of time when a patient has 2 to 3 years of expected survival and an NYHA III or IV level of function. Referral early in the transplant window allows clinicians to identify and potentially modify any barriers to transplantation. It also provides candidates and their caregivers adequate time to learn about the intervention. Because the field of lung transplantation is evolving rapidly, referring physicians are encouraged to discuss difficult cases with their local transplant centers.


 

References

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  2. Grossman RF, Frost A, Zamel N, et al. Results of single-lung transplantation for bilateral pulmonary fibrosis. The Toronto Lung Transplant Group. N Engl J Med. 1990;322(11):727-733.
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