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Lung transplantation: General guidelines for recipient selection

Lung transplantation: General guidelines for recipient selection
Literature review current through: Jan 2024.
This topic last updated: Oct 16, 2023.

INTRODUCTION — The most common indications for lung transplantation are interstitial lung disease (ILD), advanced chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension (PAH) [1,2]. These account for approximately 85 percent of all procedures performed worldwide. The remaining 15 percent consist of a variety of diagnoses that span the spectrum of end-stage lung disease from sarcoidosis to lymphangioleiomyomatosis (LAM) to pulmonary Langerhans cell histiocytosis [3-8].

The indications and general guidelines for recipient selection will be presented here. An overview of lung transplantation, the international guidelines for recipient selection, disease-specific indications, and choice of procedure are presented separately. (See "Lung transplantation: An overview" and "Lung transplantation: Disease-based choice of procedure".)

GENERAL GUIDELINES — Lung transplantation should be considered for patients with advanced lung disease whose clinical status has progressively declined despite maximal medical or surgical therapy. Candidates are usually symptomatic during activities of daily living and have a limited life expectancy over the next two years [9,10]. In addition, the ideal candidate should be free of any other organ dysfunction or medical problem that would substantially jeopardize the outcome of lung transplantation.

Recipient selection — The International Society of Heart and Lung Transplantation (ISHLT) guidelines for recipient selection for lung transplant have been updated and include the following description of suitable candidates [11]:

Clinically and physiologically advanced lung disease for which medical therapy is ineffective or unavailable

High risk (>50 percent) of death from lung disease without transplantation

High likelihood (>80 percent) of surviving at least five years after lung transplantation, provided graft function is adequate

Contraindications and risk factors for poor outcomes — The 2021 ISHLT guidelines, which were developed by consensus and expert opinion, advise evaluating potential candidates for the presence of risk factors for poor post-transplant outcomes [11]. Certain risk factors for a poor outcome are felt to be absolute or relative contraindications to lung transplantation and others increase the risk of a poor outcome, particularly when present in combination with other risk factors.

Absolute contraindications — Absolute contraindications include the following [11]:

Lack of patient willingness or acceptance of transplant

Septic shock; active extrapulmonary or disseminated infection; active tuberculosis infection; HIV infection with detectable viral load (see 'HIV infection' below)

Malignancy with a high risk of recurrence or death related to the cancer (see 'Malignancy' below)

Significant dysfunction of other vital organs:

Glomerular filtration rate <40 mL/min/1.73 m3 unless being considered for multiorgan transplant; acute kidney failure with rising creatinine or on dialysis with low likelihood of recovery

Stroke within 30 days or progressive cognitive impairment

Acute liver failure or cirrhosis with portal hypertension or synthetic dysfunction unless being considered for multi-organ transplant

Acute coronary syndrome or myocardial infarction within 30 days (excluding demand ischemia) or significant coronary heart disease not amenable to revascularization (see 'Coronary heart disease' below)

Untreatable hematologic disorders including bleeding diathesis, thrombophilia, or severe bone marrow dysfunction

Active substance use or dependence including current tobacco use, vaping, cannabis smoking, or intravenous drug use

Limited functional status (eg, nonambulatory) with poor potential for post-transplant rehabilitation

Repeated episodes of nonadherence without evidence of improvement (Note: Not an absolute contraindication for pediatric patients, and ongoing assessment of nonadherence should occur as they progress through different developmental stages.)

Factors with high or substantially increased risk — Patients with certain risk factors for high or substantially increased likelihood for a poor outcome may be considered for transplant at centers with special expertise in managing the particular conditions. However, when more than one of these risk factors are present, the risk may be prohibitive. These risk factors include the following [11]:

Age >70 years (see 'Recipient age' below)

Severe coronary artery disease that requires coronary artery bypass grafting at the time of transplant; reduced left ventricular ejection fraction <40 percent

Significant cerebrovascular disease

BMI ≥35 kg/m2; BMI <16 kg/m2 (see 'Nutritional status' below)

Thrombocytopenia, leukopenia, or anemia with high likelihood of persistence after transplant

Severe esophageal dysmotility

Chest wall or spinal deformity expected to cause restriction after transplant; previous thoracic surgery; previous pleurodesis (see 'Previous cardiothoracic surgery' below)

Colonization or infection with highly resistant or highly virulent bacteria, fungi, and certain strains of mycobacteria (see 'Cystic fibrosis and bronchiectasis' below)

Infection with Mycobacterium abscessus; Lomentospora prolificans (formerly Scedosporium prolificans); Burkholderia cenocepacia or gladioli

Hepatitis B or C viral infection with detectable viral load and liver fibrosis (see 'Hepatitis B or C infection' below)

Limited functional status with potential for post-transplant rehabilitation

Psychiatric, psychologic, or cognitive conditions with potential to interfere with medical adherence without sufficient support or caregiving systems; lack of understanding of disease and/or lung transplantation despite teaching

Retransplant <1 year after initial lung transplant; retransplant for restrictive chronic lung allograft dysfunction (CLAD); retransplant for antibody mediated rejection as etiology for CLAD

Unfavorable risk factors — The ISHLT identified an additional set of risk factors that have unfavorable implications for short and/or long-term outcomes [11]. Transplant programs may consider patients with these risk factors when present in isolation, but find the candidate unacceptable when multiple risk factors are present:

Age 65 to 70 years

Cardiovascular comorbidities (see 'Coronary heart disease' below):

Mild to moderate coronary artery disease

Severe coronary artery disease that can be revascularized via percutaneous coronary intervention prior to transplant

Prior coronary artery bypass grafting

Reduced left ventricular ejection fraction 40 to 50 percent

Peripheral vascular disease

Glomerular filtration rate 40 to 60 mL/min/1.73 m2

Diabetes that is poorly controlled (see 'Diabetes mellitus' below)

Osteoporosis (see 'Osteoporosis' below)

Esophageal dysmotility; severe gastroesophageal reflux disease

Nutritional risk factors: BMI 30 to 34.9 kg/m2 or BMI 16 to 17 kg/m2; hypoalbuminemia

Thrombocytopenia, leukopenia, or anemia with high likelihood of persistence after transplant

Rheumatic diseases (scleroderma, lupus, inflammatory myopathies)

HIV infection with undetectable viral load (see 'HIV infection' below); Scedosporium apiospermum infection

Frailty

Edible cannabis use

Prior thoracic surgery; prior pleurodesis

Mechanical ventilation

Retransplant for obstructive CLAD >1 year after transplantation

Timing of referral — The referral and evaluation process for transplantation takes time, and ideally this process is completed before the patient becomes critically ill or the need for transplantation becomes urgent. Thus, whenever possible, patients with a progressive lung disease should be referred to a transplant center when they are still able to undergo the standard, relatively extensive multidisciplinary evaluation to determine the potential risks and benefits of lung transplantation in their case. Early referral may identify modifiable risk factors that would influence a patient's candidacy for transplantation or their outcome after transplantation. For example, a patient with class I obesity would have more time to lose weight or a patient with deconditioning could enroll in pulmonary rehabilitation to improve their functional status before listing for transplantation.

Referral to a transplant center does not mean that the patient will necessarily be listed for transplant. Following the evaluation, the patient, patient's family, and transplant specialists will determine together whether placing the patient on the transplant list would be appropriate.

Clinical settings outlined by the ISHLT as appropriate for referral for transplantation evaluation vary based on the underlying disease and include the following [11]:

Chronic obstructive pulmonary disease (COPD) that is progressive despite smoking cessation, optimization of medications, pulmonary rehabilitation, and supplemental oxygen; a BODE (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity) index of 5 to 6 (calculator 1); or a forced expiratory volume in one second (FEV1) <25 percent of predicted. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Lung transplantation'.)

At the time of a confident radiographic diagnosis of idiopathic pulmonary fibrosis (IPF) or a histologic diagnosis of IPF or fibrosing nonspecific interstitial pneumonia (NSIP), regardless of lung function. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Indications and choice of procedure'.)

Interstitial lung disease (ILD) associated with rheumatic disease, sarcoidosis, or pulmonary Langerhans cell histiocytosis and New York Heart Association (NYHA) functional class III or IV (ie, symptoms with minimal exertion or severe limitation with symptoms at rest) or rapidly progressive respiratory impairment.

For patients with ILD, additional parameters at which a transplantation evaluation would be appropriate include a forced vital capacity (FVC) <80 percent predicted, a diffusing capacity for carbon monoxide (DLCO) <40 percent predicted, or the requirement for supplemental oxygen, at rest or with exertion.

Early consideration of referral for transplantation in patients with pulmonary arterial hypertension (PAH) is advised. The ISHLT recommends use of the European Society of Cardiology/European Respiratory Society (ESC/ERS) and the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) models to risk stratify patients [11-13]. Patients who cannot achieve a low-risk status within six months of aggressive therapy should be referred for transplant evaluation [11,13,14]. Patients with pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis should be evaluated at the time of diagnosis. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation'.)

The Cystic Fibrosis Foundation updated its guidelines for the referral of patients with CF in 2019 [15]. In general, the new guidelines recommend referral at an earlier stage in the disease course to allow patients and their families to better prepare for transplantation medically and psychologically. Early referral provides sufficient time to modify certain risk factors that may improve a patient's candidacy for transplantation or their post-transplant outcome (table 1). (See 'Cystic fibrosis and bronchiectasis' below and "Cystic fibrosis: Management of advanced lung disease", section on 'Indications for referral to a lung transplant center'.)

Evaluation of potential lung transplant candidates — Lung transplant centers evaluate potential lung transplant candidates to identify any factors that would adversely impact the success of lung transplantation or that need remediation prior to transplant listing. An example of testing that is often performed during a lung transplant evaluation is provided in the table (table 2). The specific tests vary somewhat depending on the patient's age and medical history and the particular transplant center's protocol.

Once a candidate has been accepted by a transplant program, a lung composite allocation score (CAS) is calculated (table 3). The LAS is used to determine the candidate's place on the waiting list and likelihood of benefit from lung transplantation (UNOS CAS calculator). The CAS is described in greater detail separately. (See "Lung transplantation: An overview", section on 'Lung allocation'.)

SPECIAL CONSIDERATIONS — A number of factors that may increase the risk of lung transplant or decrease the expected survival are considered on a case-by-case basis. These factors include age, ventilator dependence, previous cardiothoracic surgery, nutritional status, chronic glucocorticoid use, allosensitization, and psychosocial issues [16].

Recipient age — The ISHLT guidelines consider age >70 years to carry a high risk for poor outcome after lung transplant, although an upper age limit for recipient selection has not been established [11]. Since patients vary enormously at any chronological age, a potential transplant patient's age is not usually a contraindication by itself. Instead, age must be considered in the context of the individual patient's medical comorbidities, overall performance status, and expected outcome.

The number of lung transplant recipients older than 65 has increased annually in the US; based on Organ Procurement and Transplantation Network (OPTN) data, this age group accounted for 38 percent of all lung transplant recipients in 2020 [17,18]. A separate report found that over 40 percent of all lung transplants performed worldwide from 2006 to mid-2012 were for recipients older than 60 years of age; approximately 10 percent were for recipients older than 65 years of age; and 3 percent were for recipients over 70 years [11].

Individuals older than 60 years tend to have shorter survival following lung transplant than younger recipients [1,19-21]. However, not all studies support a worse survival for older recipients. Among 225 patients 70 years or older undergoing primary lung transplant between 2005 and 2012, the risk of mortality at one year was not greater than those age 60 to 69 (HR 1.02, 95% CI 0.71-1.46) [19]. In a separate study, survival statistics for septuagenarians (70s) and sexagenarians (60s) were compared, using data from the United Network for Organ Sharing (UNOS) [20]. Among 543 septuagenarians and 4327 sexagenarians, survivals at one year were 79 percent and 80 percent, respectively, but survival rates at three years (49 versus 64 percent, p<0.001) and five years (28 versus 48 percent, p<0.001) were significantly lower for septuagenarians.

Frailty — Frailty is characterized by physiologic decline, including features such as weight loss (≥5 percent of body weight in last year), exhaustion, weakness (decreased grip strength), slow walking speed, and decreased physical activity, that exceed what might be expected based on age alone [22]. The specific definition varies and a number of measures of frailty have been developed; one example is provided in the table (table 4). However, an optimal assessment tool has not been determined [11]. (See "Frailty".)

Among patients with advanced lung disease, frailty is associated with a greater risk of death before and after lung transplant [23-26]. In a retrospective cohort analysis of adult lung transplant recipients, 46 of 102 patients (45 percent) met criteria for frailty and had an increased risk of death, adjusted HR 2.24 (95% CI 1.22-4.19) [24]. On the other hand, measures of frailty may improve in some patients in the first six months after lung transplant [27]. Frailty is increasingly recognized as an important comorbidity that impacts waiting list and post-transplant outcomes.  

Our approach is to identify frail and pre-frail individuals using the Short Physical Performance Battery during the initial evaluation and to incorporate this assessment in determining transplant candidacy. Early identification of frailty can make it amenable to rehabilitation and nutritional support, potentially making frailty a modifiable risk factor. However, studies demonstrating an improvement in frailty indices with rehabilitation and a resultant improvement in post-transplant outcomes have not been done.  

Ventilator dependence and extracorporeal life support — Mechanical ventilation and extracorporeal membrane oxygenation (ECMO) are considered risk factors for poor post-transplant outcomes that may be acceptable at centers with special expertise (see 'Disease-based considerations' below) using these as a "bridging" strategy for lung transplant candidates who develop respiratory failure while awaiting transplant [11,28-31]. In 2019, 9.6 percent of lung transplant recipients aged 12 years or older in the United States were supported with mechanical ventilation and/or ECMO before transplant [17].

While invasive mechanical ventilation remains a significant risk factor for mortality after transplant [11], multiple reports have demonstrated that carefully selected candidates requiring invasive mechanical ventilation can have satisfactory short- and long-term outcomes after lung transplant [16,32-37]. However, unstable patients requiring mechanical ventilation before transplant have a significantly worse survival [38].

When feasible, noninvasive positive pressure ventilation is preferred over invasive ventilation because it obviates the need for sedation, and the patient can remain ambulatory and participate in pulmonary rehabilitation. Multiple studies have confirmed satisfactory outcomes after the use of noninvasive ventilation as a bridge to transplant [39-41].

ECMO is increasingly being used as a bridge to lung transplant in patients with pulmonary or cardio-pulmonary failure [11,37,42-44]. In 2019, approximately 7 percent of all lung transplant recipients in the United States were supported with ECLS before transplant [17]. Between 2016 and 2020, the 587 patients from the United States bridged to single-organ lung transplant with ECMO demonstrated higher mortality compared with nonbridged recipients (16 versus 10 percent at one year and 35 versus 24 percent at three years) [45]. However, after accounting for other patient- and donor-specific factors, the adjusted increased mortality for patients receiving ECMO was only +8 percent (95% CI -17 to +33 percent), which was not statistically significant. In a separate case series, bridging with ECMO was associated with a greater likelihood of needing postoperative ECMO use [37].

Carefully selected patients can be supported with venovenous ECMO while awake and off invasive mechanical ventilation [46]. This approach allows patients to undergo physical therapy and maintain an adequate nutritional status.

Previous cardiothoracic surgery — Previous cardiothoracic surgery, pleurodesis, or pleurectomy increases the technical difficulty of explanting the native lung and the operative risk of lung transplant but are not contraindications to lung transplantation [11,47]. Among 206 patients who underwent lung transplant after various cardiothoracic surgical procedures, survival was similar at 30 days, one year, and five years for those who had prior cardiothoracic procedures and those who did not, although intensive care unit (ICU) stays were longer for the prior surgery group [47].

Prior coronary artery bypass grafting (CABG) is considered a risk factor for unfavorable short and/or long-term outcomes following lung transplant [11]. In a series of 14,791 patients transplanted between 2004 and 2013, 292 (2 percent) had previously undergone a CABG and of these, 181 received a single right lung transplant, 68 received a single left lung transplant, and 43 received bilateral lung transplants (BLT) [48]. Prior CABG was a predictor of mortality at one, three, and five years, with an overall hazard ratio of 1.97 (95% CI, 1.23-3). However, the effect was largely due to increased mortality among those who underwent BLT.

Simple pneumothorax that was treated by closed tube thoracostomy, open lung biopsy, or uncomplicated lobectomy is not usually an impediment to transplantation, but more complex cases, such as pleurodesis, must be individually assessed.

Nutritional status — The nutritional status of lung transplant candidates can adversely affect post-transplant survival. Thus, consensus guidelines for recipient selection state that a BMI ≥35 kg/m2 or <16 kg/m2 carries a substantially increased risk for poor post-transplant outcomes [11].

Multiple studies have identified pretransplant obesity as a significant risk for mortality after transplant independent of other risk factors [49-56], including the following:

An analysis of the United Network for Organ Sharing (UNOS) database demonstrated a 15 percent higher mortality for overweight recipients (BMI = 25 to 29.9 kg/m2) and a 22 percent higher mortality for obese recipients (BMI >30 kg/m2) than normal weight recipients [53].

Among 512 adult lung transplant recipients, obesity was also an independent risk factor for development of grade 3 primary graft dysfunction within 72 hours of transplant [57].

In a multicenter study using multivariate analyses to examine the impact of BMI on one-year survival after lung transplant, recipients with class I obesity (BMI 30 to 34.9 kg/m2) had similar adjusted survival to normal weight and overweight recipients whereas those with class II or III obesity (BMI ≥35 kg/m2) had a significantly increased risk of death [58]. Importantly, this study demonstrated a poor correlation between BMI and adiposity, measured by whole-body dual X-ray Absorptiometry (DEXA), suggesting that BMI is a poor measure of obesity in lung transplant candidates.

Low BMI has not been a risk factor for mortality after transplant in the ISHLT registry, although one study found a higher mortality among recipients with a BMI <18.5 kg/m2 and another found a trend to a higher 90-day mortality among recipients with a BMI <17 kg/m2 [49,50,55,58]. Nonetheless, multiple series have shown that malnutrition is ominous, especially among patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) [53,59-62]. Aggressive attempts to improve the nutritional status are warranted, but low BMI alone generally should not preclude listing or transplantation.

Allosensitization — Antibodies to human leukocyte antigens (HLA), a manifestation of allosensitization, are most commonly induced by blood transfusions, pregnancy, and previous transplant, although some allosensitized patients have no history of such sensitizing events. Allosensitization can make it difficult to find a compatible donor, increasing the waiting time and risk of death on the waiting list [11,63].

Lung transplant candidates are screened for pre-existing anti-HLA antibodies using solid-phase immunoassays that are highly sensitive and specific. If HLA antibodies are present, there is a risk of hyperacute rejection if the donor expresses the reactive HLA. In addition, even low-level donor-specific anti-HLA antibodies (DSA) that don't result in hyperacute rejection increase the risk of chronic rejection and death after transplant [64]. The methodology of assays used in histocompatibility testing are discussed separately. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing" and "Evaluation and treatment of antibody-mediated lung transplant rejection".)

Previous studies suggest that recipients who have a panel reactive antibody (PRA) greater than 25 percent before transplant have an increased risk of death, especially in the early postoperative period [65]. However, improved management techniques appear to have reduced the mortality risk of higher PRA levels, perhaps because more specific and sensitive assays are used to avoid the reactive HLA [65]. In a single-center study of 304 transplants performed from 2006 to 2012, pretransplant allosensitization was not associated with an increased risk of adverse outcomes after transplantation when the reactive HLA were avoided in the donor [66].

While some centers report poor post-transplant survival among allosensitized recipients [66-69], other centers report comparable overall and chronic lung allograft dysfunction (CLAD)-free survival [66,69,70]. This variability may reflect differences in sensitivity of the assays used to detect HLA antibodies. The optimal tests for identifying and measuring donor-specific antibodies and thresholds for organ acceptance have not been determined [11]. At our center, only donors who do not have the reactive HLA are accepted for allosensitized patients. Although this approach mitigates any risk of allosensitization on post-transplant outcomes, it is associated with a longer waiting time and an increased risk of death on the waitlist for highly allosensitized patients [63,66].

Regimens to deplete anti-HLA antibodies have been tried in patients waiting for lung transplant, but have not demonstrated consistent benefit [71,72].

In one study, 18 patients with a calculated PRA ≥80 percent were treated prior to lung transplant with a desensitization protocol consisting of plasmapheresis, methylprednisolone, bortezomib, rituximab, and intravenous immune globulin (IVIG) in an attempt to deplete anti-HLA antibodies and increase the donor pool before transplant, but there were no significant changes in the PRA [71]. Nine of the 18 patients were transplanted during the study period; among these, four received organs from donors who did not have the reactive HLA, three from donors with typing that matched low-level HLA antibodies, and two from donors with reactive HLA based only on past antibody testing. Survival after transplant was comparable to allosensitized recipients who were not treated with this regimen [71].

A subsequent study used a desensitization protocol at the time of transplant, rather than before donor organ acceptance [72]. The protocol consisted of plasmapheresis and IVIG intraoperatively and anti-thymocyte globulin postoperatively. Fifty-three patients who had DSA before transplant were treated with this regimen and had similar clinical outcomes as patients who were not allosensitized and those who were allosensitized but did not have DSA. However, only five of the 53 patients who had DSA had a positive direct crossmatch suggesting that the antibody detection threshold may be overly sensitive, and these antibodies may not be clinically significant.

Psychosocial assessment — All lung transplant candidates undergo screening for psychological conditions that might interfere with their post-transplant care [16]. Patients are evaluated for a history of psychiatric problems, substance addiction (eg, alcohol, tobacco, narcotics), and other issues that might cause nonadherence to the medical regimen. A reliable social support system is essential to the success of transplantation. Multiple instruments to assess psychosocial status before transplantation are available, including the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) and the Transplant Evaluation Rating Scale (TERS) [73-75]. These may identify modifiable risk factors that would benefit from intervention before or after transplantation.

ASSESSMENT OF COMORBID DISEASE — The presence of certain comorbid diseases may increase the likelihood of peritransplant complications or adversely affect the anticipated benefit of lung transplantation. Thus, an important component of the transplant candidate evaluation is to assess the potential contribution of any comorbid diseases to peritransplant complications and long-term survival. An example of testing done during a lung transplant evaluation is provided in the table (table 2). Lung transplant centers generally prefer to do most of this testing at the transplant center.

Coronary heart disease — Many lung transplant candidates are at risk for coronary artery disease because of their age, smoking history, or other risk factors. One series of 453 adults undergoing lung transplant demonstrated an incidence of clinically important coronary artery disease of 21 percent, and 15 percent required revascularization either before or at the time of transplant [76]. Candidates should therefore be screened for occult coronary disease during their pretransplant evaluation.

At our center, essentially all patients over the age of 45 years undergo angiography. This practice is not uniform among transplant programs. Some employ a noninvasive, provocative test for cardiac ischemia as a screen; if this is negative, coronary angiography is not done. (See "Evaluation of cardiac risk prior to noncardiac surgery".)

Noninvasive screening tests for coronary disease have a high false positive rate in patients with end-stage lung disease [77]. Some experts have advocated reserving angiography for patients with multiple risk factors since the majority without risk factors will have normal coronary arteries [78,79]. However, the value of a negative angiogram should not be underestimated, especially in the perioperative period, when hemodynamics are unstable and nonspecific chest pain, positive troponin values from intraoperative cardiac manipulation, and electrocardiographic abnormalities are common.

Coronary artery disease is a risk factor for unfavorable outcomes following lung transplant. Carefully selected patients with advanced coronary disease and left ventricular dysfunction may be candidates for heart-lung transplant [16]. Alternatively, percutaneous or surgical revascularization may be an option in selected patients with preserved left ventricular function [76]. Several series have documented satisfactory results with percutaneous revascularization before transplant or concomitant bypass surgery at the time of transplant [76,80,81].

Diabetes mellitus — A history of diabetes mellitus (DM) is common among patients with end-stage lung disease. While it is not considered a contraindication to lung transplantation, poorly controlled DM is a risk factor for poor post-transplant outcomes. Most programs require that blood sugars be under good control (eg, a hemoglobin A1C level of 7 percent or less) and significant end-organ disease may be considered a contraindication. (See "Measurements of chronic glycemia in diabetes mellitus", section on 'Glycated hemoglobin (A1C)'.)

Several studies have found reduced survival in patients with comorbid DM [82-85], particularly among patients with poor glycemic control [86]. In a ten-year study of 386 consecutive transplants, DM was associated with a significantly increased risk of mortality (HR 3.96, 95% CI 2.85-5.51) [85]. A retrospective study of 267 lung transplant recipients found that pretransplant diabetes mellitus increased the risk of mortality (1.82-fold increase; 95% CI 1.08-3.06) despite an organized DM management program [87].

HIV infection — HIV infection with a detectable viral load is considered an absolute contraindication to lung transplant [11]. However, lung transplantation may be acceptable for patients who have an undetectable HIV viral load (<20 copies/mL), a CD4+ lymphocyte count above 200/mm3, no current AIDS-defining illness, and demonstrated adherence to antiretroviral therapy [11]. Special expertise is needed to avoid post-transplant drug-drug interactions between immunosuppressive therapy and antiretroviral therapy.

Hepatitis B or C infection — Infection with hepatitis B (HBV) or C (HCV) viruses with a detectable viral load and liver fibrosis places a patient at high or substantially increased risk for poor post-transplant outcomes [11,88]. Antiviral therapies for HBV are effective and safe, so HBV infection does not limit lung transplantation in the absence of cirrhosis. Similarly, direct-acting combination antiviral therapy for HCV is effective. It is preferable to treat and cure HCV prior to lung transplant, but patients with detectable HCV without significant liver fibrosis can be treated after transplant [11,89].

Notably, two small studies have reported good outcomes after lung transplant from hepatitis C viremic donors into uninfected recipients when the recipients were treated with direct-acting antivirals after transplant [90,91]. This suggests that post-transplant treatment of a viremic recipient may also be curative, but experience with this approach has been limited to date. (See "Infection in the solid organ transplant recipient", section on 'HIV, HTLV, and hepatitis viruses'.)

Malignancy — Age-appropriate and disease-specific screening for cancer should be part of every pre-transplant evaluation [11]. For patients with a previous malignancy, the risk of cancer recurrence affects the appropriateness and timing of lung transplant. Malignancy with a high risk of recurrence or death is an absolute contraindication to lung transplant. In contrast, lung transplant may be an option in patients where the risk of recurrence is deemed to be very low based on the type and stage of cancer and with negative metastatic evaluation [92,93]. A five-year disease-free interval is prudent for most patients with a prior malignancy, particularly hematologic malignancy, sarcoma, melanoma, or cancer of the breast, bladder, or kidney, although a shorter disease-free interval may be appropriate for certain malignancies depending on the stage [92]. Localized non-melanoma skin cancer is generally not considered a contraindication to transplantation. The American Society of Transplantation and International Transplant Skin Cancer Collaborative have offered guidelines for the following cancers based on stage and clinical characteristics [92-94]:

Breast cancer (table 5)

Colorectal cancer (table 6 and table 7)

Prostate cancer (table 8)

Renal cell carcinoma (table 9)

Bladder cancer (table 10)

Gynecological cancer (table 11)

Lung cancer (table 12)

Nonmelanoma skin cancer (table 13)

Melanoma (table 14)

Hematologic malignancies (table 15 and table 16)

Although we consider the recommendations offered by these guidelines, we tend to be slightly more conservative in practice. Additional caution is appropriate for lung transplantation, as lung recipients historically carry the greatest risk of cancer recurrence due to high levels of post-transplant immunosuppression. (See "Malignancy after solid organ transplantation" and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Malignancy'.)

The effect of prior malignancy on lung transplant outcomes has been examined in observational series, such as the following:

Experience with prior hematopoietic and solid organ malignancies – Among 13,613 lung transplant recipients in the International Society of Heart and Lung Transplantation (ISHLT) registry, proportionate hazard modeling found that pretransplant malignancy was not associated with an increased hazard of mortality at five years; no specific malignancy was associated with a change in the hazard of mortality [95]. These observations suggest that current selection techniques for choosing which patients with pretransplant malignancy are transplanted are successful.

Among 111 heart and lung transplant recipients with a prior malignancy, almost 50 percent were due to hematopoietic malignancies. Recurrences were noted in 23 recipients with the majority occurring in those with less than five years since treatment of the tumor [96]. Among eight lung recipients with tumors found incidentally in the explanted lung, six were fatal. This high recurrence rate contrasts with other cases in which unsuspected T1N0M0 non-small cell cancers discovered in the excised native lungs of transplant recipients did not recur [97,98].

Lung adenocarcinoma-in-situ – In an analysis of the UNOS registry of lung transplantation as a treatment for adenocarcinoma-in-situ (AIS: previously called bronchioloalveolar cell carcinoma), the five-year survival of 29 patients transplanted for AIS over a 23-year period was similar to the general lung transplant cohort, suggesting that lung transplantation may be a treatment option for carefully selected patients with AIS [99]. Nonetheless, because experience is limited and predictors of a good outcome are unclear, many transplant centers consider AIS a contraindication to lung transplantation.

Respiratory failure due to prior treatment of acute leukemia – Children can develop bronchiectasis or bronchiolitis obliterans following treatment of acute leukemia with chemotherapy and radiation, and these pulmonary complications can eventually progress to end-stage lung disease. The experience with lung transplantation in such patients is limited, but one small series noted similar outcomes when patients transplanted following treatment of malignancy were compared with those without a history of malignancy [100].

Osteoporosis — Severe, symptomatic osteoporosis, often a complication of glucocorticoid use, is a risk factor for unfavorable outcomes following lung transplant, particularly if it limits post-transplant mobility and rehabilitation [16]. (See "Screening for osteoporosis in postmenopausal women and men".)

DISEASE-BASED CONSIDERATIONS — Certain features or comorbidities of the underlying lung disease may influence lung transplant candidacy decisions.

Chronic obstructive pulmonary disease (COPD) — Patients with emphysema may be considered for lung volume reduction surgery (LVRS), lung transplantation, or both. A discussion of the general indications for lung transplantation in COPD and potential alternative interventions is provided separately. (See 'Timing of referral' above and "Management of refractory chronic obstructive pulmonary disease", section on 'Lung Volume Reduction, in select patients with dyspnea' and "Management of refractory chronic obstructive pulmonary disease", section on 'Lung transplantation'.)

Patients with advanced COPD, such as those with BODE scores (calculator 1) in the range of 5 to 6 and a forced expiratory volume in one second (FEV1) in the range of 20 to 25 percent predicted, may benefit from referral to a transplant center for initial consultation [11]. Additional but less well-validated factors that may warrant a referral include an increase in BODE index score >1 over the preceding 24 months and an enlarged pulmonary artery diameter with a pulmonary artery-to-aorta diameter >1 on computed tomography (CT).

Increasing experience with patients who have previously undergone LVRS indicates that subsequent successful lung transplant is possible [101-104]. Among 117 lung transplant recipients at a single center, 52 had previous LVRS; in-hospital mortality was 10 percent with or without prior LVRS [104]. Median survival after transplant was 86 months (95% CI 56-116) among those without prior LVRS and 107 months (95% CI 77-137) with prior LVRS (p = 0.6). (See "Lung volume reduction surgery in COPD".)

Pulmonary fibrosis associated with telomeropathy — General parameters for referral of patients with idiopathic pulmonary fibrosis (IPF) are discussed above and separately. (See 'Timing of referral' above and "Treatment of idiopathic pulmonary fibrosis", section on 'Indications and choice of procedure' and "Dyskeratosis congenita and other telomere biology disorders".)

The short telomere syndromes are caused by variants in the genes responsible for maintaining telomere length (eg, TERT, TERC, PARN, DKC1, TINF2, RTEL1). These variants are associated with IPF and also with dyskeratosis congenita and hematologic manifestations, such as myelodysplasia. Lung transplant recipients with telomerase mutations appear to be at greater risk for post-transplant hematologic abnormalities, such as anemia and thrombocytopenia, and this may cause greater need for transfusions and adjustment of the immunosuppressive regimen [105-107]. Lung recipients with short telomeres also have an increased risk of serious CMV infection post-transplant, as described separately. (See "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'Risk factors'.)

While long-term survival following lung transplant in these patients appears feasible, careful assessment of hematologic status is appropriate prior to lung transplant. The effect of telomerase mutations on lung transplantation is discussed separately. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Factors that may increase the risk of transplantation'.)

Interstitial lung diseases other than IPF — Advanced interstitial lung disease (ILD) due to idiopathic interstitial lung disease (IIP) accounts for approximately 40 percent of lung transplants [108]. Consistent clinical predictors of mortality in non-IPF ILDs include FVC and DLCO decline, hospitalization, frailty, oxygen use, and symptoms; thus, timing of referral and listing for lung transplant should take these factors into account.

Interstitial lung disease with extrapulmonary manifestations — Carefully selected patients whose lung disease has extrapulmonary manifestations, such as sarcoidosis, lymphangioleiomyomatosis (LAM), and pulmonary Langerhans cell histiocytosis (PLCH) have had satisfactory results after lung transplant. Recurrent disease in the allograft has been reported (eg, lymphangioleiomyomatosis, PLCH, sarcoidosis), but in general, this has not been clinically significant [7,8,109]. However, in one report of three patients with systemic lupus erythematosus, two patients who had anticardiolipin antibodies died early after transplantation because of recurrent vasculitis [110]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Lung transplantation' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Lung transplantation' and "Pulmonary Langerhans cell histiocytosis", section on 'Lung transplantation'.)

Systemic sclerosis is often complicated by esophageal dysmotility and gastroesophageal reflux, which predispose lung transplant recipients to aspiration and accelerated graft loss. While carefully selected patients with systemic sclerosis and esophageal dysmotility have had satisfactory results after lung transplant [111-113], ISHLT guidelines consider severe esophageal dysmotility to be a risk factor associated with high or substantially increased risk of a poor outcome, and some centers will not offer lung transplant to these patients [11]. (See 'Factors with high or substantially increased risk' above and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Lung transplantation'.)

Cystic fibrosis and bronchiectasis — The timing of referral of patients with cystic fibrosis (CF) for an evaluation for possible lung transplant is described separately; the appropriate timing for referral of patients with noncystic fibrosis bronchiectasis has not been formally determined. Guidance from the Cystic Fibrosis Foundation emphasizes beginning the process of lung transplant referral well before a patient reaches end-stage lung disease (table 1) [15]. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Indications for referral to a lung transplant center'.)

Chronic infection is a special issue in patients with bronchiectasis, especially those with cystic fibrosis [114]. Aspergillus species, nontuberculous mycobacteria (NTM), and multidrug-resistant bacteria are frequently cultured from the sputum of patients with end-stage CF [115-117]. In addition, multiple studies have reported infection early after transplantation with the same organisms that were cultured from the recipients' airways before transplantation [115,118-120]. Depending on the organism, pretransplant antimicrobial therapy may be indicated to suppress or eradicate the organism. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Lung transplant evaluation'.)

Aspergillus and ScedosporiumAspergillus species are isolated in sputum cultures from 20 to 50 percent of patients with CF awaiting transplantation. In addition, those colonized with Aspergillus before transplantation have a higher risk of Aspergillus tracheobronchitis and anastomotic infections after transplantation. Therefore, most centers initiate antifungal suppressive therapy when Aspergillus is isolated before or after transplantation [121]. (See "Fungal infections following lung transplantation", section on 'Prophylaxis'.)

Scedosporium infection, while less common than Aspergillus species, is also associated with poor outcomes after lung transplant, and some centers consider lung infection with Scedosporium to be a contraindication to lung transplantation [15,122]. Life-long prophylaxis after lung transplant may be prudent [122]. (See "Treatment of Scedosporium and Lomentospora infections".)

Nontuberculous mycobacteria – NTM infections occur in about 10 to 20 percent of lung transplant recipients [15,115]. CF patients with NTM cultured from sputum before transplantation are at increased risk of infection after transplantation, and the risk was highest among those infected with Mycobacterium abscessus [115]. Thus, all patients with CF who are referred for lung transplantation should be evaluated for NTM [15]. Attempts to eradicate these pathogens before transplantation are prudent, and persistently positive cultures on antimycobacterial treatment are a relative contraindication to transplantation [15,16]. (See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients", section on 'Prevention'.)

Multidrug-resistant bacteria – The prevalence of infection or colonization with multidrug-resistant bacteria (eg, Burkholderia species) among patients with CF coming to lung transplantation may be increasing; one series found that over 50 percent harbored at least one pan-resistant organism [123,124]. In addition, those with multidrug-resistant Pseudomonas aeruginosa isolated from the sputum have a more rapid decline in lung function and are more likely to need transplantation [125]. Although several series found no statistically significant difference in survival after transplantation between those with resistant organisms and those with sensitive ones, one multicenter study reported that recipients infected with pan-resistant organisms before transplantation had a significantly worse survival after transplantation than those infected with sensitive organisms [123,126-128].

Burkholderia species – Infection with Burkholderia cepacia complex (Bcc) or Burkholderia gladioli is considered a relative contraindication to lung transplantation [15,16]. Many transplant centers consider infection with any Bcc an absolute contraindication to transplantation due to the high risk of recurrent and often lethal infection post-transplant; others consider transplant if there is reasonable expectation of pre- and postoperative control of the infection. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Indications for referral to a lung transplant center'.)

Bcc infection is associated with accelerated decline in lung function, making it even more prevalent among transplant candidates [129-132]. Certain genomovars, or subspecies, may have greater virulence than others. Patients infected with Bcc, subspecies Burkholderia cenocepacia in particular, have significantly worse survival after transplantation compared with uninfected patients with CF, and the increased mortality is directly attributable to Bcc infection. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Burkholderia cepacia complex'.)

Lung disease due to COVID-19 — Some patients with severe coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) and are subsequently unable to wean from mechanical ventilation or extra-corporeal membrane oxygenation (ECMO) support. Other patients with milder initial disease may develop fibrotic interstitial lung disease and long-term oxygen dependence. A number of lung transplants have been performed for such patients [133-140].

For those with ARDS, some groups have reported challenges due to severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements, with the early post-transplant course notable for increased bleeding, high rates of primary graft dysfunction, and prolonged intensive care unit (ICU) length of stay [135-137]; however one-year mortality and graft survival appear to be similar to that of patients transplanted due to other conditions [139,140]. In addition to screening for other contraindications and adverse risk factors, candidates should be evaluated to ensure that COVID-19 infection has cleared, sufficient time has elapsed for recovery, and the patient is likely to tolerate transplant surgery and immunosuppression. (See 'Contraindications and risk factors for poor outcomes' above.)

Centers that have managed lung transplants in patients with chronic fibrosis post-COVID-19 advise a pretransplant evaluation that includes the following: assessment for ILD predating COVID-19, underlying rheumatic disease, and evidence of progression or lack of improvement in pulmonary function tests, six-minute walk tests, and CT [133]. Patients should participate in pulmonary rehabilitation, and reversable causes of ILD should be treated.

Two groups have analyzed overlapping cohorts of approximately 400 patients who underwent lung transplantation in the United States for COVID-19-associated end-stage lung disease between March 2020 and August 2022, comprising almost 9 percent of all lung transplants performed during this time period [139,140]. These patients were evenly divided in terms of indication (COVID-ARDS and post-COVID fibrosis). Not surprisingly, those who underwent transplantation for COVID-19-related lung disease were generally younger, more likely to be in the ICU, and more likely to need mechanical ventilation or ECMO support before transplantation than other transplant recipients. Despite longer hospital stays, overall survival over the first 12 months was similar to that seen in patients who received lung transplantation for other causes.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)

SUMMARY AND RECOMMENDATIONS

Common diagnoses for lung transplant – Advanced chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension (PAH) are the most common diseases that lead to lung transplantation. (See 'Introduction' above.)

Multidisciplinary evaluation – Patients with progressive lung disease should be referred to a transplant center when they are still able to undergo the relatively extensive, multidisciplinary evaluation to determine the potential risks and benefits of lung transplantation in their case (table 2). Referral may identify modifiable risk factors that would influence a patient's candidacy for transplantation or outcome after transplant. (See 'Timing of referral' above.)

Guidelines for recipient selection – A consensus document outlining recommendations for recipient selection for lung transplantation have been developed by the International Society of Heart and Lung Transplantation (ISHLT). This consensus document includes consideration of the severity of the underlying lung disease, likelihood of benefit from lung transplantation, presence of comorbid diseases, age of the candidate, ability to participate in an exercise program, nutritional status, and psychosocial support. (See 'General guidelines' above.)

Risk factors for poor outcomes – A number of clinical characteristics and comorbidities are recognized as risk factors for poor outcomes after lung transplantation; some are considered absolute contraindications to lung transplantation, some may be acceptable at centers with special expertise in managing the particular condition, and others may be acceptable unless the patient has more than one of these risk factors. (See 'Contraindications and risk factors for poor outcomes' above.)

Mechanical ventilation and extracorporeal life support (ECLS) were historically considered relative contraindications to lung transplantation but are increasingly used as a "bridging" strategy for lung transplant candidates who develop respiratory failure while awaiting transplant. (See 'Ventilator dependence and extracorporeal life support' above.)

A body mass index (BMI) ≥35 kg/m2 or <16 kg/m2 carries a substantially increased risk for poor post-transplant outcomes. Attention to nutrition may be able to modify this risk factor prior to transplantation. (See 'Nutritional status' above.)

Many lung transplant candidates have risk factors for coronary heart disease. The value of noninvasive testing, such as exercise testing, may be limited because of the underlying lung disease. We obtain coronary angiography in all candidates age 45 years or older. Good outcomes have been achieved in selected patients who can be revascularized prior to or at the time of lung transplant. (See 'Coronary heart disease' above.)

Significant dysfunction of other vital organs, as might occur with systemic diseases like systemic sclerosis or sarcoidosis, may contribute to increased risk of poor outcomes post-transplant. Certain other special considerations, like prior cardiothoracic surgery, glucocorticoid use, chronic infection, and allosensitization also influence decisions on appropriateness for lung transplantation. (See 'Special considerations' above.)

Disease-specific considerations – Additional disease-specific considerations include the following:

Carefully selected patients whose advanced lung disease has extrapulmonary manifestations, such as sarcoidosis, lymphangioleiomyomatosis (LAM), and pulmonary Langerhans cell histiocytosis have had satisfactory results after lung transplantation. (See 'Interstitial lung disease with extrapulmonary manifestations' above.)

Guidance from the Cystic Fibrosis Foundation emphasizes beginning the process of lung transplant referral well before a patient with CF with reaches end-stage lung disease (table 1). (See 'Cystic fibrosis and bronchiectasis' above.)

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Topic 4658 Version 48.0

References

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