Lung Transplantation

Number: 0598

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses lung transplantation.

Medical Necessity
1. Aetna considers lung transplantation medically necessary for any of the following qualifying conditions for members who meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, members must meet both the general selection criteria (see section on general selection criteria) and any applicable disease-specific selection criteria (see disease-specific selection criteria accompanying the list of qualifying conditions below), plus not have any of the contraindications to lung transplantation listed in I.B. below:
  1. Qualifying Conditions for Lung Transplantation (not an all-inclusive list)
    1. Alpha1-antitrypsin deficiency: Persons who meet the emphysema/alpha1-antitrypsin deficiency disease-specific selection criteria below
    2. Bronchopulmonary dysplasia
    3. Congenital heart disease (Eisenmenger's defect or complex): Persons who meet the disease-specific criteria for Eisenmenger's below
    4. Cystic fibrosis: Persons who meet the disease-specific selection criteria for cystic fibrosis
    5. Graft-versus-host disease or failed primary lung graft
    6. Lymphangioleiomyomatosis (LAM) with end-stage pulmonary disease
    7. Obstructive lung disease (e.g., bronchiectasis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), emphysema): For persons with pulmonary fibrosis, see the disease-specific selection criteria for pulmonary fibrosis below
    8. Primary pulmonary hypertension: Persons who meet the disease-specific selection criteria for primary pulmonary hypertension.
    9. Restrictive lung disease (e.g., allergic alveolitis, asbestosis, collagen vascular disease, desquamative interstitial fibrosis, eosinophilic granuloma, idiopathic pulmonary fibrosis, post-chemotherapy, sarcoidosis, and systemic sclerosis [scleroderma]): For persons with sarcoidosis, see the disease-specific selection criteria below.
  2. Disease-Specific Selection Criteria
    1. Lung transplant for cystic fibrosis (CF) is considered medically necessary for persons who meet the general selection criteria for lung transplantation and exhibit at least 2 of the following signs and symptoms of clinical deterioration:
      1. Cycling intravenous antibiotic therapy
      2. Decreasing forced expiratory volume in 1 second (FEV1)
      3. Development of carbon dioxide (CO₂) retention (pCO₂ greater than 50 mm Hg)
      4. FEV1 less than 30% predicted
      5. Increasing frequency of hospital admission
      6. Increasing severe exacerbation of CF – especially an episode requiring hospital admission
      7. Initiation of supplemental enteral feeding by percutaneous endoscopic gastrostomy or parenteral nutrition
      8. Non-invasive nocturnal mechanical ventilation
      9. Recurrent massive hemoptysis
      10. Worsening arterial-alveolar (A-a) gradient requiring increasing concentrations of inspired oxygen (FiO₂)
      11. Recurrent pneumothorax.
    2. Lung transplant for emphysema (including alpha 1-antitrypsin deficiency) is considered medically necessary for persons who meet the general selection criteria for lung transplantation and both of the following clinical criteria:
      1. Hospitalizations for exacerbation of COPD associated with hypercapnia in the preceding year. Hypercapnia is defined as pCO₂ greater than or equal to 50 mm Hg with hospitalizations and/or the following associated factors:
        
        Declining body mass index
        
        Increasing oxygen requirements
        
        Reduced serum albumin
        
        Presence of cor pulmonale (defined as clinical diagnosis by a physician or any 2 of the following):
        
        Enlarged pulmonary arteries on chest X-ray
        
        Mean pulmonary artery pressure by right heart catheterization of greater than 25 mm Hg at rest or 30 mm Hg with exercise
        
        Pedal edema or jugular venous distention
        
        Rright ventricular hypertrophy or right atrial enlargement on EKG
      2. BODE index of 7 or above (indicating 2 years or less survival) (see Appendix).
    3. Lung transplant for Eisenmenger's complex is considered medically necessary for persons who meet the general criteria for lung transplantation and any of the following disease-specific criteria:
      1. Marked deterioration in functional capacity (New York Heart Association (NYHA) Class III)
      2. Pulmonary hypertension with mean pulmonary artery pressure by right heart catheterization greater than 25 mm Hg at rest or 30 mm Hg with exercise
      3. Signs of right ventricular failure – progressive hepatomegaly, ascites.
    4. Lung transplant for pulmonary fibrosis is considered medically necessary for persons who meet the general criteria for lung transplantation and any of the following disease-specific criteria:
      1. Diffusing capacity for carbon monoxide (DLCO) less than 60% predicted
      2. Presence of cor pulmonale (indicative of severe pulmonary fibrosis) or pulmonary hypertension
      3. Total lung capacity (TLC) less than 70% predicted.
    5. Lung transplant for pulmonary hypertension is considered medically necessary for persons who meet the general criteria for lung transplantation plus any of the following criteria, and valvular disease has been excluded by echocardiography:
      1. Persons who are NYHA III, failing conventional vasodilators (calcium channel blockers or endothelin receptor antagonists)
      2. Persons who are NYHA III, and have initiated or being considered for initiation of parenteral or subcutaneous vasodilator therapy
      3. Pulmonary hypertension with mean pulmonary artery pressure by right heart catheterization of greater than 25 mm Hg at rest or 30 mm Hg with exercise, or pulmonary artery systolic pressure of 50 mm Hg or more defined by echocardiography or pulmonary angiography.
      Note: NYHA Class III for heart failure is defined as follows: Persons with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity (i.e., mild exertion) causes fatigue, palpitation, dyspnea, or anginal pain.
    6. Lung transplant for sarcoidosis is considered medically necessary for persons who meet the general criteria for lung transplantation plus any of the following disease-specific criteria:
      1. DLCO less than 60% predicted
      2. Presence of cor pulmonale (indicative of severe pulmonary fibrosis) or pulmonary hypertension
      3. Total lung capacity less than 70 % predicted.
  3. General Selection Criteria
    
    The member must meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, all of the following selection criteria must be met, and none of the contraindications listed below should be present:
    1. Absence of acute or chronic active infection (pulmonary or non-pulmonary) that is not adequately treated; and
    2. Adequate cardiac status (e.g., no angiographic evidence of significant coronary artery disease, ejection fraction greater than 40%, no myocardial infarction in last 6 months, negative stress test). Persons with any cardiac symptoms may require heart catheterization to rule out significant heart disease; and
    3. Adequate functional status. Under established guidelines, active rehabilitation is considered important to the success of transplantation. Mechanically ventilated or otherwise immobile persons are considered poor candidates for transplantation; however, short-term mechanical ventilation (less than 2 weeks) or bridge to transplant with ambulatory ECMO does not, in itself, rule out candidacy for lung transplantation; and
    4. Adequate liver and kidney function, defined as a bilirubin of less than 2.5 mg/dL and a creatinine clearance of greater than 50 ml/min/kg; and
    5. Limited life expectancy of less than 2 years; and
    6. No active alcohol or chemical dependency that interferes with compliance to a strict treatment regimen. Persons with a history of drug or alcohol abuse must be abstinent for at least 3 months before being considered an eligible transplant candidate; and
    7. No uncontrolled and/or untreated psychiatric disorders that interfere with compliance to a strict treatment regimen; and
    8. Absence of inadequately controlled HIV/AIDS infection, defined as
      1. CD4 count greater than 200 cells/mm³ for greater than 6 months; and
      2. HIV-1 RNA (viral load) undetectable; and
      3. No other complications from AIDS, such as opportunistic infection (e.g., aspergillus, tuberculosis, coccidioidomycosis, resistant fungal infections) or neoplasms (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma); and
      4. On stable antiviral therapy greater than 3 months.
2. Lung transplantation is considered not medically necessary for persons with any of the following contraindications to lung transplant surgery because the safety and effectiveness of lung transplantation in persons with these contraindications has not been established:
  1. Malignancy involving the lung (primary or metastatic). Persons with a history of non-pulmonary cancer must be in remission before being considered a lung transplant candidate.
    Note: Lung transplantation is considered medically necessary in persons with bronchioloalveolar carcinoma who are good surgical candidates.
  2. Multi-system disease. Persons with potentially multi-system diseases such as systemic sclerosis (scleroderma), other collagen vascular diseases such as systemic lupus erythematosus, or sarcoidosis must be carefully evaluated to ensure that their disease is primarily confined to the lung. Persons with diabetes must be carefully evaluated to rule out significant diabetic complications such as nephropathy, neuropathy or retinopathy.
  3. Other effective medical treatments or surgical options are available.
  4. Presence of gastrointestinal disease (e.g., bleeding peptic ulcer, chronic hepatitis, diverticulitis).
  5. Refractory uncontrolled hypertension.
  6. Single-lung transplantation is contraindicated in persons with chronic pulmonary infections (e.g., bronchiectasis, chronic bronchitis, and cystic fibrosis).
  7. Smoking. Persons with a history of smoking must be abstinent for 6 months before being considered eligible for lung transplantation.
3. Aetna considers lobar (from living-related donors or cadaver donors) lung transplantation medically necessary for persons with end-stage pulmonary disease when general selection criteria are met.
4. Aetna considers anti-thymocyte globulin (thymoglobulin) medically necessary for the treatment of acute cellular rejection in lung transplant recipients.
Experimental and Investigational
1. The following procedures are considered experimental and investigational because there is either insufficient evidence in the peer-revised literature, or its effectiveness for the indication has not been established:
  1. Alemtuzumab for antibody induction therapy and the treatment of acute cellular rejection in lung transplant (see CPB 0764 - Alemtuzumab (Campath));
  2. AlloSure (donor-derived cell-free DNA testing) for monitoring acute rejection following lung transplantation;
  3. Ex-vivo lung perfusion for lung transplantation;
  4. Lung xenotransplantation (e.g., porcine xenografts) for any pulmonary conditions;
  5. Prophylactic anti-reflux surgery to improve lung function and survival in lung transplant recipients without gastroesophageal reflux disease;
  6. TransMedics Organ Care System for preservation and transport of donor lungs.
Related Policies
- CPB 0597 - Heart-Lung Transplantation
- CPB 0764 - Alemtuzumab (Campath)

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
CPT codes covered if selection criteria are met:
32850	Donor pneumonectomy(s) (including cold preservation), from cadaver donor
32851	Lung transplant, single; without cardiopulmonary bypass
32852	with cardiopulmonary bypass
32853	Lung transplant, double (bilateral sequential or en bloc); without cardiopulmonary bypass
32854	with cardiopulmonary bypass
34714	Open femoral artery exposure with creation of conduit for delivery of endovascular prosthesis or for establishment of cardiopulmonary bypass, by groin incision, unilateral (List separately in addition to code for primary procedure)
CPT codes not covered for indications listed in the CPB:
Allosure (Donor-derived cell-free DNA testing)- no specific code
0494T	Surgical preparation and cannulation of marginal (extended) cadaver donor lung(s) to ex vivo organ perfusion system, including decannulation, separation from the perfusion system, and cold preservation of the allograft prior to implantation, when performed.
0495T	Initiation and monitoring marginal (extended) cadaver donor lung(s) organ perfusion system by physician or qualified health care professional, including physiological and laboratory assessment (eg, pulmonary artery flow, pulmonary artery pressure, left atrial pressure, pulmonary vascular resistance, mean/peak and plateau airway pressure, dynamic compliance and perfusate gas analysis), including bronchoscopy and X ray when performed; first two hours in sterile field.
0496T	Initiation and monitoring marginal (extended) cadaver donor lung(s) organ perfusion system by physician or qualified health care professional, including physiological and laboratory assessment (eg, pulmonary artery flow, pulmonary artery pressure, left atrial pressure, pulmonary vascular resistance, mean/peak and plateau airway pressure, dynamic compliance and perfusate gas analysis), including bronchoscopy and X ray when performed; each additional hour (List separately in addition to code for primary procedure).
43257	Esophagogastroduodenoscopy, flexible, transoral; with delivery of thermal energy to the muscle of lower esophageal sphincter and/or gastric cardia, for treatment of gastroesophageal reflux disease
43280	Laparoscopy, surgical; esophagogastric fundoplasty (e.g., Nissen, Toupet procedures) [not covered if patient is asymptomatic]
43281	Laparoscopy, surgical, repair of paraesophageal hernia, includes fundoplasty, when performed; without implantation of mesh [not covered if patient is asymptomatic]
43282	Laparoscopy, surgical, repair of paraesophageal hernia, includes fundoplasty, when performed; with implantation of mesh [not covered if patient is asymptomatic]
43325	Esophagogastric fundoplasty with fundic patch (Thal-Nissen procedure) [not covered if patient is asymptomatic]
43327	Esophagogastric fundoplasty partial or complete; laparotomy [not covered if patient is asymptomatic]
43328	Esophagogastric fundoplasty partial or complete; thoracotomy [not covered if patient is asymptomatic]
43332	Repair paraesophageal hiatal hernia, via laparotomy except neonatal; without implantation of mesh or other prosthesis [not covered if patient is asymptomatic]
43333	Repair paraesophageal hiatal hernia, via laparotomy except neonatal; with implantation of mesh or other prosthesis [not covered if patient is asymptomatic]
43334	Repair paraesophageal hiatal hernia, via thoracotomy, except neonatal; without implantation of mesh or other prosthesis [not covered if patient is asymptomatic]
43335	Repair paraesophageal hiatal hernia, via thoracotomy, except neonatal; with implantation of mesh or other prosthesis [not covered if patient is asymptomatic]
43336	Repair paraesophageal hiatal hernia, via thoracoabdominal incision, except neonatal; without implantation of mesh or other prosthesis [not covered if patient is asymptomatic]
43337	Repair paraesophageal hiatal hernia, via thoracoabdominal incision, except neonatal; with implantation of mesh or other prosthesis [not covered if patient is asymptomatic]
HCPCS codes covered if selections criteria are met:
J7504	Lymphocyte immune globulin, antithymocyte globulin, equine, parenteral, 250 mg
J7511	Lymphocyte immune globulin, antithymocyte globulin, rabbit, parenteral, 25 mg
HCPCS codes not covered for indications listed in the CPB:
J0202	Injection, alemtuzumab, 1 mg
ICD-10 codes covered if selection criteria are met:
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [good surgical candidates]
C96.6	Unifocal Langerhans-cell histiocytosis [eosinophilic granuloma]
D86.0	Sarcoidosis of lung [must be carefully evaluated to ensure diseases is primarily confined to lung]
D89.810 - D89.813	Graft-versus-host disease
E84.0 - E84.9	Cystic fibrosis [contraindicated for single-lung transplant]
E88.01	Alpha-1-antitrypsin deficiency
I27.0	Primary pulmonary hypertension
I27.83	Eisenmenger's syndrome
J41.8	Mixed simple and mucopurulent chronic bronchitis [contraindicated for single-lung]
J42	Unspecified chronic bronchitis [bronchiolitis obliterans]
J43.0 - J43.9	Emphysema
J44.0 - J44.9	Chronic obstructive pulmonary disease [contraindicated for single-lung]
J47.0 - J47.9	Bronchiectasis [contraindicated for single-lung]
J61	Pneumoconiosis due to asbestos and other mineral fibers
J67.4 - J67.9	Allergic alveolitis (extrinsic)
J84.10	Pulmonary fibrosis, unspecified
J84.111 - J84.117	Idiopathic interstitial pneumonia
J84.81	Lymphangioleiomyomatosis [with end-stage pulmonary disease]
J84.89	Other specified interstitial pulmonary diseases
J99	Respiratory disorders in diseases classified elsewhere
M31.0	Hypersensitivity angitis [must be carefully evaluated to ensure diseases is primarily confined to lung]
M34.81	Systemic sclerosis with lung involvement [must be carefully evaluated to ensure diseases is primarily confined to lung]
P27.0 - P27.9	Chronic respiratory disease arising in the perinatal period [bronchopulmonary dysplasia]
Q33.0	Congenital cystic lung
Q33.3	Agenesis of lung
Q33.4	Congenital bronchiectasis
Q33.6	Congenital hypoplasia and dysplasia of lung
T86.810 - T86.819	Complications of lung transplant
ICD-10 codes contraindicated for this CPB (not all-inclusive):
A00.0 - B99.9	Infectious and parasitic diseases [acute or chronic active infection not adequately treated including HIV/AIDS and complications such as aspergillus, tuberculosis, coccidoidomycosis, or fungal]
C34.00 - C34.92	Malignant neoplasm of bronchus and lung
C46.0 - C46.9	Kaposi's sarcoma [complication from AIDS]
C82.00 - C85.99	Non-Hodgkin's lymphoma [complication from AIDS]
D02.0	Carcinoma in situ of larynx
E10.21 - E10.29 E11.21 - E11.29 E13.21 - E13.29	Diabetes mellitus with renal complications
E10.311 - E10.39 E11.311 - E11.39 E13.311 - E13.39	Diabetes mellitus with ophthalmic complications
E10.40 - E10.49 E10.610 E11.40 - E11.49 E11.610 E13.40 - E13.49 E13.610	Diabetes mellitus with neurologic complications
F01.50 - F99	Mental and behavioral disorders [uncontrolled and/or untreated that interfere with compliance including alcohol, chemical, or tobacco dependency]
I10 - I16.2	Hypertensive disease [refractory uncontrolled]
I21.01 - I22.9	ST elevation (STEMI) and non-ST (NSTEMI) myocardial infarction [in last 6 months]
I25.1 - I25.9	Atherosclerotic heart disease of native coronary artery [significant]
K25.0 - K25.9	Gastic ulcer
K57.00 - K57.93	Diverticular disease of intestine
K73.0 - K73.9	Chronic hepatitis, not elsewhere classified
M32.0 - M32.9	Systemic lupus erythematosus (SLE) [must be carefully evaluated to ensure diseases is primarily confined to lung]
*There is no specific code for the TransMedics Organ Care System*:

Background

Lung transplantation (LTX) has become a viable treatment option for carefully selected patients with end-stage pulmonary disease (ESPD). Single, double, and lobar-lung transplantation have all been performed successfully for a variety of diseases. Single-LTX appears to be most effective for patients with end-stage pulmonary fibrosis, while double-LTX is most effective for patients with end-stage chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) in whom cardiac function has been preserved. Lobar-LTX (from living donors or cadaver donors) is usually reserved for children or adolescents who are appropriate candidates for LTX and will not survive waiting for cadaver lungs. Indications for LTX in pediatric patients include pulmonary vascular disease, bronchiolitis obliterans, broncho-pulmonary dysplasia, graft failure due to viral pneumonitis, and CF.

Chronic obstructive pulmonary disease and alpha 1-antitrypsin deficiency, the 2 principal causes of emphysema, are responsible for approximately 60 % of all single-LTX performed. Other indications for single-LTX include primary pulmonary hypertension, Eisenmenger's syndrome, as well as a variety of interstitial lung diseases (e.g., interstitial pulmonary fibrosis).

Cystic fibrosis, emphysema, and alpha 1-antitrypsin deficiency are the most common indications for double-LTX, also known as bilateral single-LTX (sequential replacement of both lungs). Comparing patients who have undergone en bloc double-LTX to patients who have undergone bilateral single-LTX, studies have shown a better outcome for those who have undergone the bilateral sequential procedure. The latter is generally considered the procedure of choice for patients with any pulmonary disorder complicated by chronic airway infection, such as bronchiectasis, CF, and chronic bronchitis. The possibility of spillover of infection from the native lung to the allograft precludes single-LTX in such patients.

Although LTX offers acceptable prospects for 5-year survival, chronic rejection and donor shortage remain to be major problems. To address the problem of donor shortage, living-donor lobar-LTX has been performed with satisfactory intermediate survival and functional results. In lobar-LTX, a lobe of the donor's lung is excised, sized appropriately for the recipient, and transplanted. Common indications for living-donor bilateral lobar-LTX are CF and severe primary pulmonary hypertension. Based on available scientific evidence, there is no significant difference in effectiveness between living-donor lobar-LTX and cadaver lobar-LTX.

There are currently 2 surgical therapies for the treatment of end-stage emphysema: LTX and lung volume reduction surgery (LVRS) (see CPB 0160 - Lung Volume Reduction Surgery). Ideal candidates for LVRS are those with hyper-inflation, heterogeneous distribution of disease, forced expiratory volume in 1 second (FEV1) of more than 20 %, and normal PCO2. Patients with diffuse disease, low FEV1, hypercapnia, and associated pulmonary hypertension are directed toward transplantation. Moreover, LTX provides more satisfactory results than LVRS for patients with emphysema due to alpha1-antitrypsin deficiency. Combinations of LTX and LVRS, simultaneously or sequentially, are feasible but rarely indicated.

Complications of LTX include re-implantation response and airway complications. Rejection may occur in the hyper-acute, acute, or chronic settings and requires judicious management with immunosuppression. Infection and malignancy remain potential complications of the commitment to lifelong systemic immunosuppression. Obese (greater than 20 % of ideal body weight), cachectic (less than 80 % of ideal body weight), mechanically ventilated or otherwise immobile patients are considered poor candidates for transplantation.

Advanced bronchoalveolar carcinoma (BAC) carries a poor prognosis, with median survival of approximately 1 year. More extended survivals have been reported after lung transplantation for BAC; however, fewer than 50 patients have been reported. To compare outcomes of lung transplantation for advanced BAC, Ahmad, et al. (2012) studied this population in a compulsory, prospectively maintained database. The United Network for Organ Sharing (UNOS) database was queried for patients undergoing lung transplant from 1987 to 2010 for the diagnosis of BAC or cancer. Pathology reports of explanted specimens were reviewed. The investigators reported that 29 patients underwent lung transplantation for BAC, representing 0.13% of the 21,553 lung transplants during the study period. BAC patients had better forced expiratory volume in 1 second percent predicted (60% vs 35%, p<0.0001) and received more double-lung transplants (79% vs 54%, p=0.006). Pure BAC was present in only 52% of the explants, whereas 41% had some degree of invasive tumor, and 7% had pure adenocarcinoma. The BAC and general lung transplantation cohorts had similar 30-day mortality (10% vs 7%, p=0.44) and 5-year survival (57% vs 50%, p=0.66). The investigators concluded that survival after lung transplantation for BAC appears to be consistent with that of lung transplantation for other diagnoses and is better than that reported with chemotherapy. The investigators stated that further study is warranted to identify the subgroup of patients with lung cancer who will have a maximum survival advantage after lung transplantation.

There is a steadily increasing need for a greater supply of lung donors. Xenotransplantation offers the possibility of an unlimited supply of lungs that could be readily available when needed. However, antibody-mediated mechanisms cause the rejection of pig organs transplanted into non-human primates, and these mechanisms provide key immunological barriers that have yet to be overcome. Although porcine hearts have functioned in heterotopic sites in non-human primates for periods of several weeks, no transplanted porcine lung has functioned for even 24 hours. Currently, lung xenotransplantation is not a clinically applicable option, and is therefore considered an experimental and investigational procedure.

Amital and colleagues (2008) noted that LTX impairs surfactant activity, which may contribute to primary graft dysfunction (PGD). In an open, randomized, controlled prospective study, these researchers examined if the administration of surfactant during transplantation serves as an effective preventive measure. A total of 42 patients scheduled for single (n = 38) or double (n = 4) LTX were randomly assigned to receive, or not, intra-operative surfactant treatment. In the treated group, bovine surfactant was administered at a dose of 20 mg phospholipids/kg body weight through bronchoscope after the establishment of bronchial anastomosis. The groups were compared for oxygenation (PaO2/FiO2), chest X-ray findings, PGD grade, and outcome. Compared with the untreated group, patients who received surfactant were characterized by better post-operative oxygenation mean PaO2/FiO2 (418.8 +/- 123.8 versus 277.9 +/- 165 mm Hg, p = 0.004), better chest radiograph score, a lower PGD grade (0.66 versus 1.86, p = 0.005), fewer cases of severe PGD (1 patient versus 12, p < 0.05), earlier extubation (by 2.2 hrs; 95 % confidence interval (CI): 1.1 to 4.3 hrs, p = 0.027), shorter intensive care unit stay (by 2.3 days; 95 % CI: 1.47 to 3.74 days, p = 0.001), and better vital capacity at 1 month (61 % versus 50 %, p = 0.022). One treated and 2 untreated patients died during the first post-operative month. The authors concluded that surfactant instillation during LTX improves oxygenation, prevents PGD, shortens intubation time, and enhances early post-transplantation recovery. Moreover, they stated that further, larger studies are needed to evaluate if surfactant should be used routinely in LTX.

In LTX recipients, gastro-esophageal reflux disease (GERD) is associated with increased incidence of acute rejection, earlier onset of chronic rejection, and higher mortality. Surgical treatment of GERD in LTX recipients seems to prevent early allograft dysfunction and improve overall survival. A total (360 degrees) fundoplication is shown to be a safe and effective method for treating GERD in LTX recipients for this high-risk patient population. The principal goal should be to minimize reflux of enteric contents that may lead to micro- or macro-aspiration events in this complicated group of patients. Peri-operative care should involve a multi-disciplinary approach, including physicians and other health care providers familiar with the complexities of LTX recipients (Hartwig et al, 2005).

Molina et al (2009) identified outcomes in LTX recipients with clinical evidence of GERD. Retrospective review of 162 LTX recipients at the authors' institution between January 1994 and June 2006 was performed. Gastro-esophageal reflux disease was confirmed in symptomatic patients by esophago-gastro-duodenoscopy (EGD) and/or esophagography. Occurrence of biopsy-proven obliterative bronchiolitis (OB) and bronchiolitis obliterans syndrome (BOS) were analyzed. Kaplan-Meier analysis of survival and Cox proportional hazard analysis of risk factors were performed. Gastro-esophageal reflux disease was diagnosed in 21 (13 %) of patients, usually following LTX (71 %). There was no difference in mean survival (1,603 +/- 300 versus 1,422 +/- 131 days; log rank p > 0.05), or development of OB (5 % versus 6 %, respectively; p > 0.05) in patients with GERD compared with patients without GERD. However, there was correlation between GERD and BOS (p = 0.01). The authors concluded that symptomatic GERD is increased following LTX. Patients with symptomatic GERD demonstrated an increased incidence of BOS, but survival was not affected in this study. They stated that more sensitive and specific diagnostic tools should be implemented in all LTX recipients to investigate the impact of symptomatic and silent GERD and thus improve outcomes after LTX.

Burton et al (2009) stated that GERD in LTX recipients has gained increasing attention as a factor in allograft failure. There are few data on the impact of fundoplication on survival or lung function, and less on its effect on symptoms or quality of life. Patients undergoing fundoplication following LTX from 1999 to 2005 were included in the study. Patient satisfaction, changes in GERD symptoms, and the presence of known side effects were assessed. The effect on lung function, body mass index, and rate of progression to the BOS were recorded. A total of 21 patients (13 males), in whom reflux was confirmed on objective criteria, were included, with a mean age of 43 years (range of 20 to 68). Time between transplantation and fundoplication was 768 days (range of 145 to 1,524). The indication for fundoplication was suspected micro-aspiration in 13 and symptoms of GERD in 8. There was 1 peri-operative death, at day 17. There were 3 other late deaths. Fundoplication did not appear to affect progression to BOS stage 1, although it may have slowed progression to stage 2 and 3. Forced expiratory volume-1 % predicted was 72.9 (20.9), 6 months prior to fundoplication and 70.4 (26.8), 6 months post-fundoplication, p = 0.33. Body mass index decreased significantly in the 6 months following fundoplication (23 kg/m(2) versus 21 kg/m(2), p = 0.05). Patients were satisfied with the outcome of the fundoplication (mean satisfaction score 8.8 out of 10). Prevalence of GERD symptoms decreased significantly following surgery (11 of 14 versus 4 of 17, p = 0.002). Fundoplication does not reverse any decline in lung function when performed at a late stage post-LTX in patients with objectively confirmed GERD. It may, however, slow progression to the more advanced stages of BOS. Reflux symptoms were well-controlled and patients were highly satisfied. The authors stated that whether performing fundoplication early post-LTX in selected patients can prevent BOS and improve long-term outcomes requires formal evaluation.

King et al (2009) examined the relationship between BOS and GERD measured by esophageal impedance. After the initiation of routine screening for GERD, 59 LTX recipients underwent ambulatory esophageal impedance monitoring. Exposure to acid reflux and non-acid liquid reflux was recorded. Clinical outcomes were reviewed to analyze any effect of reflux on the time to development of BOS. A total of 37 patients (65 %) had abnormal acid reflux and 16 (27 %) had abnormal non-acid reflux. There was no relationship between acid reflux and BOS. The hazard ratio (HR) for development of BOS in the presence of abnormal non-acid reflux was 2.8 (p = 0.043). The HR for development of BOS increased to 3.6 (p = 0.022) when the number of acute rejection episodes was also taken into account. The authors concluded that GERD is prevalent in LTX recipients and may represent a modifiable risk factor for BOS. This study found non-acid reflux, measured by esophageal impedance to be associated with the development of BOS. They stated that prospective studies are now needed to investigate a causal association between GERD and the development of BOS and to establish the role of surgery for GERD in preventing progression to BOS.

Robertson et al (2010) noted that LTX is an accepted treatment strategy for end-stage lung disease; however, BOS is a major cause of morbidity and mortality. These investigators reviewed the role of GERD in BOS and the evidence suggesting the benefits of anti-reflux surgery in improving lung function and survival. There is a high prevalence of gastro-esophageal reflux in patients post-LTX. This may be due to a high pre-operative incidence, vagal damage and immunosuppression. Reflux in these patients is associated with a worse outcome, which may be due to micro-aspiration. Anti-reflux surgery is safe in selected LTX recipients; however there has been 1 report of a post-operative mortality. Evidence is conflicting but may suggest a benefit for patients undergoing anti-reflux surgery in terms of lung function and survival; there are no controlled studies. The precise indications, timing, and choice of fundoplication are yet to be defined, and further studies are required.

Zheng et al (2011) examined the safety and possible benefits of laparoscopic anti-reflux surgery in pediatric patients following LTX and heart-lung transplantation. An Institutional Review Board-approved retrospective chart review was performed to evaluate the outcomes and complications of laparoscopic anti-reflux surgery in pediatric LTX and heart-lung transplant patients. Spirometry data were collected for BOS staging using BOS criteria for children. A total of 25 LTX and heart-lung transplants were performed between January 2003 and July 2009. Eleven transplant recipients, including 6 double-lung and 5 heart-lung, with a median age of 11.7 years (range of 5.1 to 18.4 years), underwent a total of 12 laparoscopic Nissen fundoplications at a median of 427 days after transplant (range of 51 to 2310 days). The diagnosis of GERD was made based upon clinical impression, pH probe study, gastric emptying study, and/or esophagram in all patients. Three patients already had a gastrostomy tube in place and 2 had one placed at the time of fundoplication. There were no conversions to open surgery, 30-day re-admissions, or 30-day mortalities. Complications included 1 exploratory laparoscopy for free air 6 days after laparoscopic Nissen fundoplication for a gastric perforation that had spontaneously sealed. Another patient required a revision laparoscopic Nissen 822 days following the initial fundoplication for a para-esophageal hernia and recurrent GERD. The average length of hospital stay was 4.4 +/- 1.7 days. Nine of the 12 fundoplications were performed in patients with baseline spirometry values prior to fundoplication and who could also complete spirometry reliably. One of these 9 operations was associated with improvement in BOS stage 6 months after fundoplication; 7 were associated with no change in BOS stage; and 1 was associated with a decline in BOS stage. The authors concluded that it is feasible to perform laparoscopic Nissen fundoplication in pediatric LTX and heart-lung transplant recipients without mortality or significant morbidity for the treatment of GERD. The real effect on pulmonary function can not be assessed due to the small sample size and lack of reproducible spirometry in the younger patients. The authors stated that additional studies are needed to elucidate the relationship between anti-reflux surgery and the potential for improving pulmonary allograft function and survival in children that has been previously observed in adult patients.

Robertson et al (2012) evaluated the safety of fundoplication in LTX recipients and its effects on quality of life. Between June 1, 2008 and December 31, 2010, a prospective study of LTX recipients undergoing fundoplication was undertaken. Quality of life was assessed before and after surgery. Body mass index (BMI) and pulmonary function were followed-up. A total of 16 patients, mean +/- SD age of 38 +/-11.9 yrs, underwent laparoscopic Nissen fundoplication. There was no peri-operative mortality or major complications. Mean +/- SD hospital stay was 2.6 +/- 0.9 days; 15 out of 16 patients were satisfied with the results of surgery post-fundoplication. There was a significant improvement in reflux symptom index and DeMeester questionnaires and gastro-intestinal quality of life index scores at 6 months. Mean BMI decreased significantly after fundoplication (p = 0.01). Patients operated on for deteriorating lung function had a statistically significant decrease in the rate of lung function decline after fundoplication (p = 0.008). The authors concluded that laparoscopic fundoplication is safe in selected LTX recipients. Patient benefit is suggested by improved symptoms and satisfaction. Thye stated that this procedure is acceptable, improves quality of life and may reduce deterioration of lung function. These preliminary findings need to be validated by well-designed studies.

Fisichella and colleagues (2012) hypothesized that laparoscopic anti-reflux surgery (LARS) alters the pulmonary immune profile in LTX patients with GERD. In 8 LTX patients with GERD, these researchers quantified and compared the pulmonary leukocyte differential and the concentration of inflammatory mediators in the broncho-alveolar lavage fluid (BALF) 4 weeks before LARS, 4 weeks after LARS, and 12 months after LTX. Freedom from BOS (graded 1 to 3 according to the International Society of Heart and Lung Transplantation guidelines), FEV1 trends, and survival were also examined. At 4 weeks after LARS, the percentages of neutrophils and lymphocytes in the BALF were reduced (from 6.6 % to 2.8 %, p = 0.049, and from 10.4 % to 2.4 %, p = 0.163, respectively). The percentage of macrophages increased (from 74.8 % to 94.6 %, p = 0.077). Finally, the BALF concentration of myeloperoxide and interleukin-1-beta tended to decrease (from 2,109 to 1,033 U/mg, p = 0.063, and from 4.1 to 0 pg/mg protein, p = 0.031, respectively), and the concentrations of interleukin-13 and interferon-gamma tended to increase (from 7.6 to 30.4 pg/mg protein, p = 0.078 and from 0 to 159.5 pg/mg protein, p = 0.031, respectively). These trends were typically similar at 12 months after transplantation. At a mean follow-up of 19.7 months, the survival rate was 75 % and the freedom from BOS was 75 %. Overall, the FEV1 remained stable during the first year after transplantation. The authors concluded that these preliminary findings indicated that LARS can restore the physiologic balance of pulmonary leukocyte populations and that the BALF concentration of pro-inflammatory mediators is altered early after LARS. These results suggested that LARS could modulate the pulmonary inflammatory milieu in LTX patients with GERD.

There is great disparity between the supply of donor lungs and the number of potential lung transplant recipients. The shortage of donor lungs for transplantation demands optimal utilization of the donor organ. For many years hypothermic preservation has been the universal standard for organ preservation. Although limited in terms of the duration of preservation, hypothermic preservation has had the major advantages of simplicity, portability and affordability. Recently, organ preservation and transportation by normothermic perfusion has been reported to be superior over static cold storage in experimental settings; however, all devices examined were non-portable. The Organ Care System (TransMedics, Inc., Andover, MA) is a portable device for preservation and transport of donor lungs. However, its role in lung transplantation has not yet been established.

Van Raemdonck et al (2010) noted that the critical organ shortage has forced lung transplant teams to extend their donor criteria, thereby compromising a good early outcome in the recipient. Better preservation solutions for longer storage are welcomed to further reduce incidence of primary graft dysfunction. New ex-vivo techniques to assess and to condition lungs prior to transplantation are hoped to increase the number of available pulmonary grafts. Although no prospective clinical trial has been carried out so far, clinical and experimental evidence suggest that an extracellular solution is currently the preservation fluid of choice for lung transplantation. The combination of an antegrade and retrograde pulmonary flush and technique to control reperfusion and ventilation are becoming common practice, although the evidence to support this method is low. Ex-vivo lung perfusion to assess and to re-condition lungs has been demonstrated to be well-tolerated and effective in small clinical series. The author concluded that new extracellular preservation solutions have contributed in decreasing the incidence of primary graft dysfunction over the last decade leaving more room to extend the donor criteria and ischemic time. Ex-vivo lung perfusion is now on the horizon as a potential method to prolong the preservation time and to resuscitate lungs of inferior quality.

Warnecke et al (2012) stated that cold flush and static cold storage is the standard preservation technique for donor lungs before transplantations. Several research groups have assessed normothermic perfusion of donor lungs but all devices investigated were non-portable. In a pilot study, these investigators reported first-in-man experience of the portable Organ Care System (OCS) Lung device for concomitant preservation, assessment, and transport of donor lungs. Between Feb 18, and July 1, 2011, 12 patients were transplanted at 2 academic lung transplantation centers in Hanover, Germany and Madrid, Spain. Lungs were perfused with low-potassium dextran solution, explanted, immediately connected to the OCS Lung, perfused with Steen's solution supplemented with 2 red-cell concentrates. These researchers assessed donor and recipient characteristics and monitored extended criteria donor lung scores; primary graft dysfunction scores at 0, 24, 48, and 72 hrs; time on mechanical ventilation after surgery; length of stays in hospital and the intensive-care unit after surgery; blood gases; and survival of grafts and patients. Eight donors were female and 4 were male (mean age of 44.5 years, range of 14 to 72). Seven recipients were female and 5 were male (mean age of 50.0 years, range of 31 to 59). The pre-harvest donor ratio of partial pressure of oxygen (PaO(2)) to fractional concentration of oxygen in inspired air (F(I)O(2)) was 463.9 (SD 91.4). The final ratio of PaO(2) to F(I)O(2) measured with the OCS Lung was 471.58 (127.9). The difference between these ratios was not significant (p = 0.72). All grafts and patients survived to 30 days; all recipients recovered and were discharged from hospital. The authors concluded that lungs can be safely preserved with the OCS Lung, resulting in complete organ use and successful transplantation in this series of high-risk recipients. In November, 2011, the authors began recruitment for a prospective, randomized, multi-center trial (INSPIRE) to compare preservation with OCS Lung with standard cold storage.

Also, an UpToDate review on "Lung transplantation: Donor lung preservation" (Cypel et al, 2012) states that "The cold static preservation system described above was developed in an era with younger organ donors and good-quality organs. However, in order to increase the availability of donor organs, older and sometimes injured donor organs are being used. The use of suboptimal donor lungs and difficulties assessing lung function in donation after cardiac death have made it necessary to explore alternative preservation techniques. Hypothermic preservation inhibits cellular metabolism and eliminates the possibility of substantial reparative processes occurring after donor organ injury. For this reason, normothermic (37ºC) or near-normothermic (25 to 34ºC) ex vivo perfusion is becoming popular as a preservation alternative in kidney and liver transplantation. Attempts at using a ventilating and perfusing machine for lung preservation have failed in the past, largely due to the development of lung edema and increases in pulmonary vascular resistance. However, investigators have used an animal model to develop a perfusion system that allows evaluation of lung function ex vivo. A key part of ex vivo perfusion is the identification of a specific solution (Steen^® solution) that allows for ex vivo perfusion of lungs without development of pulmonary edema. In an animal model and a single human case, after a short period (60 to 90 minutes) of ex vivo evaluation, lungs were successfully transplanted. An acellular, ex vivo lung perfusion (EVLP) technique that can maintain donor lungs for at least 12 hours at body temperature without inducing injury has been tested in porcine and human lungs. After prolonged EVLP, lung function after transplantation was excellent. Using this acellular perfusion technique also allowed evaluation of lung function ex viv. However, another animal model of EVLP was less successful; six hours of EVLP resulted in impaired lung function, manifest by increased pulmonary vascular resistance (PVR) and increased airway pressures towards the end of the procedure. A clinical trial is underway using normothermic ex vivo lung perfusion as a method to reassess and optimize donor lungs that are initially unsuitable for transplantation".

TransMedics is currently conducting a clinical trial "International Randomized Study of the TransMedics Organ Care System (OCS Lung) for Lung Preservation and Transplantation (INSPIRE)", which compares preservation of donor lungs using OCS-Lung perfusion device to cold flush and storage (last verified December 2012).

Warnecke et al (2018) noted that severe PGD3 is a common serious complication following lung transplantation. In a randomized, open-label, non-inferiority, phase-III clinical trial (INSPIRE), these researchers examined physiological donor lung preservation using the OCS Lung device compared with cold static storage. Subjects (aged 18 years or older) were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of PaO2 to FiO2 of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by center, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness end-point was absence of PGD3 within the first 72 hours after transplant and 30-day survival in the per-protocol population, with a stringent 4 % non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety end-point was the mean number of lung graft-related serious adverse events (SAEs) within 30 days of transplant. These investigators performed analyses in the per-protocol and intention-to-treat (ITT) populations. Between November 17, 2011 and November 24, 2014, these researchers randomly assigned 370 patients, and 320 (86 %) underwent transplantation (n = 151 OCS and n = 169 control); follow-up was completed in November 24, 2016. The primary end-point was met in 112 (79.4 %) of 141 patients (95 % CI: 71.8 to 85.8) in the OCS group compared with 116 (70.3 %) of 165 patients (62.7 to 77.2) in the control group (non-inferiority point estimate -9.1 %; 95 % CI: -∞ to -1.0; p = 0.0038; and superiority test p = 0.068). Patient survival at day 30 post-transplant was 135 (95.7 %) of 141 patients (95 % CI: 91.0 to 98.4) in the OCS group and 165 patients (100 %; 97.8 to 100.0) in the control group (p = 0.0090) and at 12 months was 126 (89.4%) of 141 patients (83.1 to 93.9) for the OCS group compared with 146 (88.1 %) of 165 patients (81.8 to 92.8) for the control group. Incidence of PGD3 within 72 hours was reported in 25 (17.7 %) of 141 patients in the OCS group (95 % CI: 11.8 to 25.1) and 49 (29.7 %) of 165 patients in the control group (22.8 to 37.3; superiority test p = 0·015). The primary safety end-point was met (0.23 lung graft-related SAEs in the OCS group compared with 0.28 events in the control group [point estimate -0.045 %; 95 % CI: -∞ to 0.047; non-inferiority test p = 0.020]). In the ITT population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n = 2 for OCS versus n = 7 for control), cardiac causes (n = 4 versus n = 1), vascular or stroke (n = 3 versus n = 0), metabolic coma (n = 0 versus n = 2), and generalized sepsis (n = 0 versus n = 1). The authors concluded that the INSPIRE trial met its primary safety and effectiveness end-points; the OCS Lung device is a potential model for shifting technology in lung transplantation. These researchers stated that although no short-term survival benefit was reported, further research is needed to examine if the reduced incidence of PGD3 within 72 hours of a transplant might translate into earlier recovery and improved long-term outcomes following lung transplantation. They noted that longer-term follow-up of the INSPIRE trial patients (protocol amendment has been filed for collection of 5-year outcomes), is underway to assess the long-term survival and incidence of chronic lung allograft dysfunction in the trial population. Additionally, a prospective OCS Thoracic Organ Perfusion registry is being developed to further expand prospective clinical evidence with the OCS Lung technology. The OCS Lung device might also enable new therapeutic approaches to be applied ex-vivo in the future, promising a new era in lung transplantation.

The authors stated that one limitation of the study was its unblinded nature, with clinical personnel involved in donor retrieval and transplant procedures potentially having introduced bias. Another limitation was the transient interruption in supply of the OCS Lung Solution, which led to greater use of the commercially available potassium dextran solution than these researchers had originally anticipated.

Loor and colleagues (2019) noted that donor lung use for transplantation is the lowest among solid organ transplants because of several complex and multi-factorial reasons; one area that could have a substantial role is the limited capabilities of cold ischemic storage. The objective of the EXPAND trial was to examine the efficacy of normo-thermic portable OCS Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. In a single-arm study carried out in 8 institutions across the U.S., Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of PaO2 to FiO2 in the donor lung of 300 mm Hg or less; expected ischemic time longer than 6 hours; donor age of 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy end-point was a composite of patient survival at day 30 post-transplant and absence of the International Society for Heart & Lung Transplantation PGD grade-3 (PGD3) within 72 hours post-transplantation, with a pre-specified objective performance goal of 65 %. The primary analysis population was all transplanted recipients. Between January 23, 2014, and October 23, 2016, a total of 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung; 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation; 2 lungs were excluded for logistical reasons, hence 79 (87 %) of eligible lungs were transplanted. The primary end-point was achieved in 43 (54 %) of 79 patients and did not meet the objective performance goal; 35 (44 %) of 79 patients had PGD3 within the initial 72 hours; 78 (99 %) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related SAEs (respiratory failure and major pulmonary-related infection) was 0 to 3 events per patient (SD 0.5). The authors concluded that despite missing the objective primary end-point, the portable OCS Lung resulted in 87 % donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centers were successfully transplanted using this new technology, which implied its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. Moreover, these researchers stated that longer follow-up of EXPAND trial patients is underway to examine the long-term survival and prevalence of BOS. In addition, a prospective OCS Thoracic Organ Perfusion registry has been developed to further expand prospective clinical evidence with the OCS Lung technology in the post-market setting.

The authors stated that one of the limitations of the EXPAND trial was the single-arm design, chosen because of the ethical and patient safety challenges of allowing extended-criteria donor lungs to be randomly assigned to cold storage. Importantly, the single-arm design avoided any potential donor selection bias based on presence or absence of the OCS Lung at the donor center after randomization. Therefore, these researchers did not know how recipients who might have received lungs from extended-criteria donors and donors after circulatory death after cold ischemic storage would have responded after transplant. Indeed, some of these extended-criteria donor lungs might well have been transplanted successfully without ex-vivo lung perfusion. However, many donor lungs in the EXPAND trial had multiple extended criteria, increasing the recipient’s risk when being transplanted directly. Portable ex-vivo lung perfusion provided an extra safety tool to screen out donor lungs that might not do well after transplantation. Some centers now successfully use lung transplants from donors after circulatory death without ex-vivo lung perfusion as reported by the ISHLT registry; however, these centers use strict selection criteria to maintain good clinical outcomes. It would be ethically and clinically challenging to accept lungs from donors after circulatory death with average cross-clamp times of 10 hours and from donors older than 55 years or with a low initial PaO2:FiO2 ratio. These were the types of donor lungs that were placed on the OCS Lung for recruitment and functional assessment before final acceptance, and used successfully in the EXPAND trial. It was agreed that the best alternative was to use INSPIRE standard-criteria donor lung transplants as a comparator group for bench-marking. Moreover, these investigators stated that another issue was the inherent limitation of the overall ex-vivo lung perfusion strategy because it was associated with open air leak and severe lung contusions. For example, of the 12 donor lungs that were rejected for transplantation after OCS Lung assessment, 6 were rejected because of open air leak from either lung contusion or surgical laceration during retrieval, resulting in perfusate leak into the bronchoalveolar tree creating bloody froth and compromising oxygenation capacity of the donor lung. Open air leak and lung contusion remain a contra-indication for OCS Lung and represents an area of potential research using novel modalities to potentially further increase the use of these donor lungs for transplantation. Moreover, the study protocol described BOS rather than chronic lung allograft dysfunction as a pre-specified secondary study outcome. Therefore, FEV1 values were reviewed for presence or absence of BOS without differentiating between restrictive allograft syndrome, BOS, or chronic lung allograft dysfunction.

Uhlving and co-workers (2012) stated that BO following allogeneic hematopoietic SCT (HSCT) is a serious complication affecting 1.7 to 26 % of the patients, with a reported mortality rate of 21 to 100 %. It is considered a manifestation of chronic graft-versus-host disease (cGVHD), but its etiology and pathogenesis is still unclear. Diagnostic criteria are being developed, and will allow more uniform and comparable research activities between centers. At present, no randomized controlled trials have been completed that could demonstrate an effective treatment. Steroids in combination with other immunosuppressive drugs still constitute the mainstay of the treatment strategy, and results from the authors and other centers suggested that monthly infusions of high-dose pulse intravenous methylprednisolone might stabilize the disease and hinder progression.

Vogl and associates (2013) noted that BO is a detrimental late pulmonary complication after allogeneic HSCT associated with cGVHD. When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for LTX. These researchers presented 7 patients undergoing LTX for severe refractory BO after HSCT. Evaluation for LTX was initiated after failure of a median of 4 immunosuppressive regimens. Between 1996 and 2012, a total of 7 patients with severe refractory BO were evaluated for LTX. The median time from HSCT to diagnosis of chronic lung GVHD was 8.2 months (range of 3.7 to 16.6). At a median time of 18.1 months (range of 6 to 120) after diagnosis of BO, 6 patients received a bilateral sequential LTX, and 1 patient received a single LTX. Six post-operative courses were uneventful; the patient with single LTX died from septic multi-organ failure. Three LTX recipients had a mild acute rejection after 1 to 3 months after LTX, and 1 patient experienced fatal chronic rejection and hemolytic uremic syndrome; 3 (43 %) LTX recipients remained alive at a median observation time of 26 months (range of 1 month to 16 years) after LTX. The median overall survival from LTX was 24 months (95 % CI: 0.5 to 78); the median overall survival time after allogeneic HCT was 98 months (95 % CI: 46 to 198). The authors concluded that the findings of this case series illustrated that LTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.

Soubani and colleagues (2014) stated that non-infectious pulmonary complications following HSCT are major cause of morbidity and mortality with limited treatment options. Lung transplantation has been rarely reported as a treatment option for selected HSCT recipients with these problems. These researchers described the outcome of HSCT recipients who underwent LTX. A total of 2 cases of LTX following HSCT from the authors’ institution were presented. Cases reported in literature were identified using English language PubMed/Medline with keywords hematopoietic stem cell transplantation, bone marrow transplantation or bronchiolitis obliterans cross-referenced with lung transplantation. These investigators extracted data on baseline characteristics and survival data following LTX. A total of 84 patients were analyzed. Median age at time of LTX was 22 years (range of 1 to 66); 79 patients were recipients of allogeneic HSCT. The indications for LTX were BOS (n = 63), pulmonary fibrosis (n = 13), BOS/pulmonary fibrosis (n = 5), and GVHD of lung (n = 3). The median time between HSCT and LTX was 52.3 months (range of 6 to 240). The median follow-up after LTX was 36 months (range of 0 to 168). During this time, BOS was documented in 25 patients. Relapse of hematological malignancy was reported in 2 patients and new malignancy developed in 4 patients. At the end of follow-up, 60 patients were alive and 24 patients died. The probability of survival following LTX at 24 and 36 months was 0.88 (95 % CI: 0.78 to 0.93) and 0.79 (95 % CI: 0.67 to 0.87), respectively. The authors concluded that LTX is a potential therapeutic option in selected patients with severe chronic pulmonary disease following HSCT. Moreover, they stated that further studies are needed to determine the appropriate timing and the outcome of this approach.

In an exploratory analysis, Schaffer et al (2015) compared outcomes in single- and double-LTX recipients since the Lung Allocation Score was implemented. Adults with idiopathic pulmonary fibrosis (IPF) or COPD who underwent LTX in the United States between May 4, 2005, and December 31, 2012, were identified in the UNOS thoracic registry, with follow-up to December 31, 2012. Post-transplantation graft survival was assessed with Kaplan-Meier analysis. Propensity scores were used to control for treatment selection bias. A multi-variable flexible parametric prognostic model was used to characterize the time-varying hazard associated with single- versus double-LTX. Main outcome measures were composite of post-transplant death and graft failure (re-transplantation). Patients with IPF (n = 4,134, of whom 2,010 underwent single-lung and 2,124 underwent double-LTX) or COPD (n = 3,174, of whom 1,299 underwent single-LTX and 1,875 underwent double-LTX) were identified as having undergone LTX since May 2005. Median follow-up was 23.5 months. Of the patients with IPF, 1,380 (33.4 %) died and 115 (2.8 %) underwent re-transplantation; of the patients with COPD, 1,138 (34.0 %) died and 59 (1.9 %) underwent re-transplantation. After confounders were controlled for with propensity score analysis, double-LTX were associated with better graft survival in patients with IPF (adjusted median survival, 65.2 months [interquartile range {IQR}, 21.4 to 91.3 months] versus 50.4 months [IQR, 17.0 to 87.5 months]; p < 0.001) but not in patients with COPD (adjusted median survival, 67.7 months [IQR, 25.2 to 89.6 months] versus 64.0 months [IQR, 25.2 to 88.7 months]; p = 0.23). The interaction between diagnosis type (COPD or IPF) and graft failure was significant (p = 0.049). Double-LTX had a time-varying association with graft survival; a decreased instantaneous late hazard for death or graft failure among patients with IPF was noted at 1 year and persisted at 5 years post-operatively (instantaneous hazard at 5 years, HR, 0.67 [95 % CI: 0.52 to 0.84] in patients with IPF and 0.89 [95 % CI: 0.71 to 1.13] in patients with COPD). The authors concluded that in an exploratory analysis of registry data since implementation of a medical need-based lung allocation system, double-LTX was associated with better graft survival than single-LTX in patients with IPF. In patients with COPD, there was no survival difference between single- and double-LTX recipients at 5 years.

Anti-Fungal Prophylaxis

Pilarczyk and colleagues (2016)stated that LTX recipients are at high risk of invasive Aspergillus infections (IAI). However, no randomized-controlled trials (RCT) or international guidelines on anti-fungal prophylaxis (AFP) in the LTX population exist. These investigators performed a meta-analysis to determine whether AFP reduces the rate of IAI after LTX. A total of 6 eligible observational studies (5 with no prophylaxis, 1 with targeted prophylaxis, 3 studies including heart/lung transplantation) with a total of 748 patients were included. The pooled odds ratio (OR) for IAI (62 IFI in the intervention arm, and 82 in the control group) was 0.234 (95 % CI: 0.097 to 0.564, p = 0.001, z = -3.237). Pooled studies were characterized by substantial heterogeneity (I2 = 66.64 %); number needed to treat was 6.8. A subgroup analyses with exclusion of heart transplant recipients also showed a statistically significant reduction in IAI with AFP (OR 0.183, 95 % CI: 0.0449 to 0.744, p = 0.018). The authors concluded that the findings of this study suggested that universal anti-fungal prophylaxes reduced incidence of IAI after LTX. However, included studies were limited by small sample size, single-center structure without randomization, mixed population (including heart/heart-lung transplant), and heterogeneity due to variations in immunosuppression, type, and duration of AFP. Thus, there is a clear need for an adequately powered RCT.

Intraoperative Extracorporeal Membrane Oxygenation (ECMO)

Ius and associates (2012) stated that patients requiring extracorporeal cardio-respiratory support during lung transplantation can be treated with conventional cardiopulmonary bypass (CPB) or veno-arterial extracorporeal membrane oxygenation (ECMO). In a retrospective analysis, these investigators compared the post-operative course and outcomes of patients treated using these approaches. Between August 2008 and September 2011, a total of 92 consecutive patients underwent lung transplantation with extracorporeal support (CPB group, n = 46; and, since February 2010, ECMO group, n = 46) at the authors’ institution. They evaluated survival, secondary organ failure, bleeding complications, and the need for blood and platelet transfusions in these 2 patient populations. Intra-operatively, the CPB group required more packed red blood cell (RBC) transfusions (12 ± 11 versus 7 ± 9 U; p = 0.01) and platelet concentrates (2.5 ± 1.6 versus 1.5 ± 1 U; p < 0.01) than the ECMO group. In-hospital mortality (39 % versus 13 %; p = 0.004), the need for hemodialysis (48 % versus 13 %; p < 0.01), and new post-operative ECMO support (26 % versus 4 %; p < 0.01) were greater in the CPB group than in the ECMO group, respectively. After propensity score analysis, multi-variate analysis identified re-transplantation (OR, 7; 95 % CI: 1 to 43; p = 0.034) and transplantation with CPB support (OR, 4.9; 95 % CI: 1.2 to 20; p = 0.026) as independent risk factors for in-hospital mortality. The survival rate at 3, 9, and 12 months was 70 %, 59 %, and 56 % in the CPB group, and 87 %, 81 %, and 81 % in the ECMO group (p = 0.004). The authors concluded that intra-operative ECMO allowed for better peri-procedural management and reduced post-operative complications and conferred a survival benefit compared with CPB, mainly because of lower in-hospital mortality. They stated that it is now the standard of care in their lung transplantation program.

In a retrospective, single-center study, Hoechter and co-workers (2015) analyzed transfusion requirements, coagulation parameters, and outcome parameters in patients undergoing lung transplantation (LuTx) with intra-operative extracorporeal circulatory support, comparing CPB and ECMO. Over a 3-year period, 49 of a total of 188 LuTx recipients were identified being set intra-operatively on either conventional CPB (n = 22) or ECMO (n = 27). Intra- and post-operative transfusion and coagulation factor requirements as well as early outcome parameters were analyzed. LuTx patients on CPB had significantly higher intra-operative transfusion requirements when compared with ECMO patients, that is, packed RBCs (9 units [5 to 18] versus 6 units [4 to 8], p = 0.011), platelets (3.5 units [2 to 4] versus 2 units [0 to 3], p = 0.034), fibrinogen (5 g [4 to 6] versus 0 g [0 to 4], p = 0.013), prothrombin complex concentrate (3 iU [2 to 5] versus 0 iU [0 to 2], p = 0.001), and tranexamic acid (2.5 mg [2 to 5] versus 2.0 mg [1 to 3], p = 0.002). Also, ventilator support requirements (21 days [7 to 31] versus 5 days [3 to 21], p = 0.013) and lengths of ICU stays (36 days [14 to 62] versus 15 days [6 to 44], p = 0.030) were markedly longer in CPB patients. There were no differences in 30-day and 1-year mortality rates. The authors concluded that these findings indicated a peri-operative advantage of ECMO usage with low-dose heparinization over conventional CPB for extracorporeal circulatory support during LuTx; however, long-term outcome is not affected.

In a meta-analysis, Hoechter and colleagues (2017) stated that extracorporeal circulation is an invaluable tool in lung transplantation. Over the past years, an increasing number of centers changed their standard for intra-operative extracorporeal circulation from CPB to ECMO with differing results. These investigators reviewed the existing evidence. An online literature research on Medline, Embase, and PubMed has been performed; 2 persons independently judged the papers using the ACROBAT-NRSI tool of the Cochrane collaboration. Meta-analyses and meta-regressions were used to determine whether veno-arterial ECMO resulted in better outcomes compared to CPB. A total of 6 papers -- all observational studies without randomization -- were included into the analysis. All were considered to have serious bias due to heparinization as co-intervention. Forest plots showed a beneficial trend of ECMO regarding blood transfusions (packed red blood cells with an average mean difference of -0.46 units [95 % CI: -3.72 to 2.80], fresh-frozen plasma with an average mean difference of -0.65 units [95 % CI: -1.56 to 0.25], platelets with an average mean difference of -1.72 units [95 % CI: -3.67 to 0.23]). Duration of ventilator support with an average mean difference of -2.86 days [95 % CI: -11.43 to 5.71] and intensive care unit (ICU) length of stay with an average mean difference of -4.79 days [95 % CI: -8.17 to 1.41] were shorter in ECMO patients; ECMO treatment tended to be superior regarding 3-month mortality (odds ratio [OR] = 0.46, 95 % CI: 0.21 to 1.02) and 1-year mortality (OR = 0.65, 95 % CI: 0.37 to 1.13). However, only the ICU length of stay reached statistical significance. Meta-regression analyses showed that heterogeneity across studies (sex, year of ECMO implementation and underlying disease) influenced differences. The authors concluded that these data indicated a benefit of the intra-operative use of ECMO as compared to CPB during lung transplant procedures regarding short-term outcome (ICU stay). However, there was no statistical significant effect regarding blood transfusion needs or long term outcome. They stated that the superiority of ECMO in lung transplantation patients remains to be determined in larger multi-center randomized trials.

Ex-Vivo Lung Perfusion

Popov and colleagues (2016) stated that LTX remains the gold standard for patients with ESPD. However, the number of suitable donor lungs for the increasing number of patients on the waiting list necessitates alternative tools to expand the lung donor pool. Modern preservation and lung assessment techniques could contribute to improved function in previously rejected lungs. Ex-vivo lung perfusion (EVLP) already demonstrated its value in identification of transplantable grafts from the higher risk donor pool. Moreover, lungs from EVLP did not show significantly different post-operative results compared to standard criteria lungs. This could be explained by the reduction of the ischemia-reperfusion injury through EVLP application. The authors concluded that the usage of ELVP resulted in raising the amount of lung transplants by determining grafts from the suboptimal donor pool whose performance is considered equal to those regarded standard. Since EVLP is being utilized more extensively and new ways of therapy are being adapted for the clinical environment, its application promises a new era in LTX. They stated that advancing the development of this technique might result in extending the safe ex-vivo perfusion time and treatment of different pathologies besides pulmonary edema.

In a multi-center, un-blinded, non-randomized, non-inferiority, observational study, Fisher and associates (2016) compared transplant outcomes between EVLP-assessed and standard donor lungs. Participants included patients aged greater than or equal to 18 years with advanced lung disease who were accepted onto the lung transplant waiting list. The study intervention was EVLP assessment of donor lungs before determining suitability for LTX. The primary outcome measure was survival during the first 12 months following LTX; secondary outcome measures were patient-centered outcomes that were influenced by the effectiveness of LTX and that contribute to the health-care costs. Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34 %) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95 % CI: 0.40 to 0.83] for the EVLP arm and 0.80 (95 % CI: 0.74 to 0.85) for the standard arm. The HR for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95 % CI: 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade-3 PGD in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for ECMO support was higher in the EVLP arm (7/18, 38.8 %) than in the standard arm (6/184, 3.2 %). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants was approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life (QOL) on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that included EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP could increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for LTX. Study limitations included small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. The authors concluded that 1/3 of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experienced a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limited the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. They noted that EVLP using a Lund protocol has the potential to offer an increased chance of achieving effective LTX in patients at high risk of death on the waiting list. Moreover, they stated that although the overall findings of the DEVELOP-UK study were not what was hoped for, and did not allow the original research question to be definitively answered, there are still a significant number of factors to consider that will help to direct further research in the area of EVLP.

Loor and associates (2017) reported the ability to extend lung preservation up to 24 hours (24H) by using autologous whole donor blood circulating within an EVLP system. This approach facilitated donor lung re-conditioning in a model of extended normo-thermic EVLP. These researchers analyzed comparative responses to cellular and acellular perfusates to identify these benefits. A total of 12 pairs of swine lungs were retrieved after cardiac arrest and studied for 24H on the Organ Care System (OCS) Lung EVLP platform; 3 groups (n = 4 each) were differentiated by perfusate:

isolated red blood cells (RBCs) (current clinical standard for OCS);
whole blood (WB); and
acellular buffered dextran-albumin solution (analogous to STEEN solution).

Only the RBC and WB groups met clinical standards for transplantation at 8 hours; primary analysis at 24H focused on perfusion with WB versus RBC. The WB perfusate was superior (versus RBC) for maintaining stability of all monitored parameters, including the following mean 24H measures: pulmonary artery pressure (6.8 versus 9.0 mm Hg), reservoir volume replacement (85 versus 1607 ml), and PaO2:FiO2 ratio (541 versus 223). Acellular perfusion was limited to 6 hours on the OCS system due to prohibitively high vascular resistance, edema, and worsening compliance. The authors concluded that the use of an autologous whole donor blood perfusate allowed 24 hours of preservation without functional deterioration and was superior to both RBC, and buffered dextran-albumin solution for extended lung preservation in a swine model using OCS Lung. They stated that this finding represented a potentially significant advance in donor lung preservation and re-conditioning.

In a pilot study, Luc and co-workers (2017) reported their initial experience with the use of portable EVLP with the OCS Lung device for evaluation of donation after circulatory death (DCD) lungs. These researchers performed a retrospective review of the DCD LTX experience at a single-center through the use of a prospective database. From 2011 to 2015, a total of 208 LTX were performed at the University of Alberta, of which 11 were DCD LTX with 7 (64 %) that underwent portable EVLP. DCD lungs preserved with portable EVLP had a significantly shorter cold ischemic time (161 ± 44 versus 234 ± 60 mins, p = 0.045), lower grade of PGD at 72 hours after LTX (0.4 ± 0.5 versus 2.1 ± 0.7, p = 0.003), similar mechanical ventilation time (55 ± 44 versus 103 ± 97 hrs, p = 0.281), and hospital length of stay (29 ± 11 versus 33 ± 10 days, p = 0.610). All patients were alive at 1-year follow-up after LTX with improved functional outcomes and acceptable QOL compared with before LTX, although there were no inter-group differences. The authors concluded that in their pilot cohort, portable EVLP was a feasible modality to increase confidence in the use of DCD lungs with validated objective evidence of lung function during EVLP that translates to acceptable clinical outcomes and QOL after LTX. They stated that further studies are needed to validate these initial findings in a larger cohort.

D'Cunha and Rojas (2018) noted that EVLP has emerged as a new technology with the potential of re-conditioning human donor lungs previously unsuitable for transplantation. Since the first successful transplant of a lung treated using EVLP in the year 2000, multiple clinical trials had demonstrated, in several transplant centers around the word, the feasibility and the potential of EVLP to increase the total number of lungs available for transplant.

Sales and co-workers (2018) stated that despite the increment in LTX rates, in 2016 the overall mortality while on waiting list in Italy reached 10 %, whereas only 39 % of the wait-list patients were successfully transplanted. A number of approaches, including protective ventilatory strategy, accurate management of fluid balance, administration of a hormonal resuscitation therapy have been reported to improve lung donor performance before organ retrieval. These approaches, in conjunction with the use of EVLP technique contributed to expand the lung donor pool, without affecting the harvest of other organs and the outcomes of lung recipients. But the efficacy of issues related to the EVLP technique, such as the optimal ventilation strategy, the ischemia-reperfusion induced lung injury management, the prophylaxis of germs transmission from donor to recipient and the application of targeted pharmacologic therapies to treat specific donor lung injuries are still to be explored.

Himmat and associates (2018) stated that normo-thermic EVLP is an evolving technology to evaluate function of donor lungs to determine suitability for transplantation. These researchers hypothesized that hypoxic pulmonary vasoconstriction (HPV) during EVLP will provide a more sensitive parameter of lung function to determine donor lung quality for LTX. A total of 8 porcine lungs were procured, and subsequently underwent EVLP with autologous blood and STEEN solution for 10 hours. Standard physiologic parameters including dynamic compliance, peak airway pressure, and pulmonary vascular resistance (PVR) remained stable (p = 0.055), mean oxygenation (PO2 /FiO2 ) was 400 ± 18 mm Hg on average throughout perfusion. Response to hypoxia resulted in a robust increase in PVR (ΔPVR) up to 4 hours of perfusion, however the HPV response then blunted beyond 6 hours (p < 0.01). The decrease in HPV response inversely correlated to cytokine concentrations of interleukin-6 and tumor necrosis factor-α (p < 0.01). The authors concluded that despite acceptable lung oxygenation and standard physiologic parameters during 10 hours of EVLP, there was a subclinical deterioration of lung function. They stated that HPV challenges can be performed during EVLP as a simple and more sensitive index of PVR.

Hsin and colleagues (2018) identified potential biomarkers during EVLP using metabolomics approach. EVLP perfusate taken at 1- and 4 hr-perfusion were collected from 50 clinical EVLP cases, and submitted to untargeted metabolic profiling with mass spectrometry. The findings were correlated with early LTX outcomes. Following EVLP, 7 cases were declined for LTX. In the remaining transplanted cases, 9 cases developed PGD 3. For the metabolic profile at EVLP-1hr, a logistic regression model based on palmitoyl-sphingomyelin, 5-aminovalerate, and decanoylcarnitine yielded a receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.987 in differentiating PGD 3 from non-PGD 3 outcomes. For the metabolic profile at EVLP-4hr, a logistic regression model based on N2-methylguanosine, 5-aminovalerate, oleamide, and decanoylcarnitine yielded a ROC curve with AUC 0.985 in differentiating PGD 3 from non-PGD 3 outcomes. The authors concluded that metabolomics of EVLP perfusate revealed a small panel of metabolites highly correlated with early LTX outcomes, and may be potential biomarkers that can improve selection of marginal lungs on EVLP. Moreover, they stated that further validation studies are needed to confirm these findings.

Luo et al (2019) stated that ex-vivo lung perfusion (EVLP) is a relatively new technique that can be used to evaluate and repair the donor lungs, increasing the use of high-risk lungs. However, its effect on outcomes of lung transplantation (LTx) patients is uncertainty. In a meta-analysis, these researchers examined the impact of EVLP on donor lungs and outcomes of recipients compared with the standard lung transplantation. They systematically searched for studies comparatively analyzing the effectiveness of EVLP and standard cold storage in LTx. The hazard ratio (HR), relative risk (RR), and weighted mean difference (WMD) were used as the effect size (ES) to examine the survival outcomes, categorical variables, and continuous variables, respectively. A total of 20 published articles (including 2,574 donors and 2,567 recipients) were eligible. The chest X-ray manifestations and PaO₂/FiO₂ 100 % were more deficient in the EVLP group than the standard group. EVLP improved the function of high-risk donor lungs with the conversion rate ranging from 34 % to 100 %. The EVLP group had a lower incidence of primary graft dysfunction (PGD) grade-3, but longer intensive care unit (ICU) stay. Other clinical outcomes between the 2 groups were similar. The authors concluded that the pooled results indicated that EVLP could be used to evaluate and improve high-risk donor lungs and had non-inferior post-operative outcomes compared with the standard cold storage. EVLP not only increased the use of marginal donors, but also could extend preservation time and reduce the total ischemia time of donors.

Tian et al (2020) noted that EVLP is reportedly a useful strategy that permits marginal donor lungs to be evaluated and reconditioned for successful LTx. In a systematic review and meta-analysis, these investigators examined the outcomes of EVLP conducted for marginal donor lungs. They searched PubMed, the Cochrane Library, and Embase to select studies describing the results of LTx following EVLP for marginal donor lungs compared with standard LTx without EVLP. These researchers carried out a meta-analysis to examine donor baseline characteristics, recipient baseline characteristics, and post-operative outcomes. Of 1,380 studies, 8 studies involving 1,191 patients met the inclusion criteria. Compared with the non-EVLP group (i.e., standard LTx without EVLP), the EVLP group (i.e., EVLP of marginal donors following LTx) had similar donor age and sex and recipient baseline age, sex, body mass index (BMI), bridge by ventilator/extracorporeal life support (ECLS)/extracorporeal membrane oxygenation (ECMO), and rate of double LTx but more abnormal donor lung radiographs (p = 0.0002), a higher smoking history rate (p = 0.03), and worse donor arterial oxygen tension/inspired oxygen fraction (p < .00001). However, there were no significant differences in outcomes between the EVLP and non-EVLP groups with respect to the length of post-operative intubation, post-operative ECLS/ECMO use, length of ICU stay, hospital length of stay (LOS), 72-hour PGD of grade-3, 30-day survival, or 1-year survival (all p values > 0.05). The authors concluded that post-transplant outcomes were similar between EVLP-treated LTx and standard LTx without EVLP, although the quality of donor lungs was worse with EVLP-treated LTx.

Garijo and Roscoe (2020) stated that EVLP has been developed to expand the donor pool for LTx recipients. These investigators examined the role of EVLP in organ preservation, evaluation and potential re-conditioning. EVLP has been shown to significantly increase the use of donor lungs for LTx. Evidence suggested that patient outcomes from EVLP lungs are comparable to standard procurement technique. Novel strategies are being developed to treat and re-condition injured donor lungs. EVLP may also prove to be a tool for translational research of lung diseases. The authors concluded that EVLP has been shown to be an effective system to expand donor pool for LTx without detriment to recipients. Future potential ex-vivo developments may further improve patient outcomes as well as increasing availability of donor organs.

Iske et al (2021) stated that allogeneic lung transplantation (LTx) is considered the treatment of choice for a broad range of advanced, progressive lung diseases resistant to conventional treatment regimens. Ischemia reperfusion injury (IRI) occurring upon re-perfusion of the explanted, ischemic lung during implantation remains a crucial mediator of PGD and early allo-immune responses. EVLP displays an advanced technique aiming at improving lung procurement and preservation. Indeed, previous clinical trials have demonstrated a reduced incidence of PGD following LTx using EVLP, while long-term outcomes are yet to be evaluated. Mechanistically, EVLP may alleviate donor lung inflammation via re-conditioning the injured lung and diminishing IRI through storing the explanted lung in a non-ischemic, perfused, and ventilated status. The authors examined potential mechanisms of EVLP that may attenuate IRI and improve organ quality. Moreover, they dissected experimental treatment approaches during EVLP that may further attenuate inflammatory events deriving from tissue ischemia, shear forces or allograft rejection associated with LTx.

Ahmad et al (2022) noted that the number of waitlisted LTx candidates exceeds the availability of donor organs. Barriers to utilization of donor lungs include suboptimal lung allograft function, long ischemic times due to geographical distance between donor and recipient, and a wide array of other logistical and medical challenges. EVLP is a modality that allows donor lungs to be evaluated in a closed circuit outside of the body and extends lung donor assessment before final acceptance for transplantation. EVLP was first employed successfully in 2001 in Lund, Sweden. Since its initial use, EVLP has facilitated hundreds of LTx that would not have otherwise happened. EVLP technology continues to evolve and improve, and currently there are multiple commercially available systems, and more under investigation worldwide. Although barriers to universal use of EVLP exist, the possibility for more widespread adaptation of this technology abounds. Not only does EVLP have diagnostic capabilities as an organ monitoring device but also the therapeutic potential to improve lung allograft quality when specific issues are encountered. Expanded treatment potential includes the use of immunomodulatory treatment to reduce PGD, as well as targeted anti-microbial therapy to treat infection. The authors concluded that although use of EVLP remains in its early phase, multiple studies have showed its feasibility and utility. Increasing use of commercially available and investigational EVLP systems demonstrated the potential of EVLP to further revolutionize LTx. With the passage of time and ongoing investigation, additional advances and potential benefits of EVLP are assured. In the short-term, EVLP represents a viable pathway to increase the lung donor pool and potentially reduce transplant waitlist time and mortality. However, this technology holds promise to modulate long-term post-lung transplant outcomes as well. The optimal EVLP system(s) for a particular transplant center depends on individual center practices and resources; therefore, the availability of distinct EVLP models is critical. Expanded capacity for diagnostic testing to guide lung allograft acceptance and transplantation holds great promise, but perhaps most exciting for the future of EVLP is the emergence of therapeutic options for infection control and immunomodulation. With continued evolution and expanded utility, EVLP may provide the major leap needed to improve and extend allograft function in LTx.

Boffini et al (2022) stated that EVLP is a relevant procedure to increase the lung donor pool but could potentially increase the airway tree ischemic injury risk. These researchers examined the direct effect of EVLP on the airway tree by evaluating bronchial cell vitality and tissue signs of injury on a series of 117 bronchial rings collected from 40 conventional and 19 EVLP-treated lung grafts. Bronchial rings and related scraped bronchial epithelial cells were collected before the EVLP procedure and surgical anastomosis. The pre-implantation interval was significantly increased in the EVLP graft group (p < 0.01). Conventional grafts presented cell viability percentages of 47.07 ± 23.41 and 49.65 ± 21.25 in the 1st and 2nd grafts which did not differ significantly from the EVLP group (1st graft 50.54 ± 25.83 and 2nd graft 50.22 ± 20.90 cell viability percentage). No significant differences in terms of histopathological features (edema, inflammatory infiltrate, and mucosa ulceration) were observed comparing conventional and EVLP samples. A comparison of bronchial cell viability and histopathology of EVLP samples retrieved at different time intervals revealed no significant differences. Accordingly, major bronchial complications after LTx were not observed in both groups. The authors concluded that based on these data, these researchers observed that EVLP did not significantly impact bronchial cell vitality and airway tissue preservation nor interfere with bronchial anastomosis healing, further supporting it as a safe and useful procedure.

An UpToDate review on "Lung transplantation: An overview" (Hachem, 2023) states that "Studies suggest that ex vivo lung perfusion and reconditioning may ameliorate lung injury in some cases and allow transplantation from donors previously deemed unsuitable".

Furthermore, an UpToDate review on "Lung transplantation: Donor lung procurement and preservation" (Hartwig and Klapper, 2023) states that "Ex vivo lung perfusion (EVLP) is an emergent and promising technique to increase the number and quality of available allografts. Two systems have been approved by the US Food and Drug Administration (FDA): (1) XVIVO Perfusion System (XPS) for otherwise unacceptable lungs and (2) Organ Care System (OCS) for standard organ preservation as well as extended criteria organs".

There is an open-label, multi-center, phase-II clinical trial entitled "Extending Preservation and Assessment Time of Donor Lungs Using the Toronto EVLP System™ at a Dedicated EVLP Facility" (last updated December 2, 2020).

Vanderbilt University Medical Center’s webpage on "EVLP Technology Enters Clinical Trials" notes that "In 2019, Matthew Bacchetta, M.D., an associate professor of thoracic surgery at Vanderbilt University Medical Center, performed the first successful lung transplant using EVLP. Now, Bacchetta is a principal investigator on a trial designed to increase the number of lungs eligible for the procedure. "We’re trying to find ways to improve the durability and range of interventional capabilities of organ support systems".

Alemtuzumab for Antibody Induction Therapy and the Treatment of Acute Cellular Rejection

Li and colleagues (2018) stated that heart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab is increasingly used for induction therapy compared with conventional agents. However, there has been no systematic review comparing its efficacy with traditional therapeutic drugs. PubMed and Embase were searched to October 1, 2017, for articles on alemtuzumab in cardiothoracic transplant surgery. Of the 433 studies retrieved, 8 were included in the final meta-analysis. In lung transplantation, alemtuzumab use was associated with lower odds of acute cellular rejection (ACR) compared with anti-thymocyte globulin (ATG) (OR, 0.21; 95 % CI: 0.11 to 0.40; p < 0.001), lower acute rejection rates (OR, 0.12; 95 % CI: 0.03 to 0.55; p < 0.01), and infection rates (OR, 0.69; 95 % CI: 0.35 to 1.36; p = 0.33) when compared with basiliximab. Multi-variate meta-regression analysis found that mean age, male sex, single lung transplant, double lung transplant, cytomegalovirus or Epstein-Barr virus (EBV) status, CF, IPF, and mean ischemic time did not significantly influence acute rejection outcomes. For heart transplantation, alemtuzumab use was associated with lower acute rejection rates when compared with tacrolimus (OR, 0.44; 95 % CI: 0.30 to 0.66; p < 0.001). The authors concluded that alemtuzumab use was associated with lower rejection rates when compared with conventional induction therapy agents (ATG, basiliximab, and tacrolimus) in heart and lung transplantation. However, these researchers stated that this was based on observational studies; and RCTs are needed to verify its clinical use.

Computed Tomography-Based Body Composition Measures in Lung Transplantation Candidates

Cho and associates (2019) stated that abnormal body composition is an important modifiable risk factor in LTX; thus. precise quantification of different body components, including muscle and fat, may play an important role in optimizing outcomes in LTX patients. In a retrospective, single-center study, these investigators examined the prognostic significance of muscle and subcutaneous fat mass measured on chest CT with regard to LTX survival and other post-transplant outcomes. This study included 45 consecutive adult LTX recipients (mean age of 47.9 ± 12.1 years; 31 men and 14 women) between 2011 and 2017. Pre-operative cross-sectional areas (CSA) of muscle and subcutaneous fat were semi-automatically measured on axial CT images at the level of the 12th thoracic vertebra (T12). Additional normalized indexed parameters, adjusted for either height or weight, were obtained. Associations of quantitative parameters with survival and various other post-transplant outcomes were evaluated. Of the 45 patients included in this study, 10 mortalities were observed during the follow-up period. Patients with relative sarcopenia (RS) classified based on height-adjusted muscle area with a cut-off value of 28.07 cm²/m² demonstrated worse post-operative survival (log-rank test, p = 0.007; HR, 6.39:1) despite being adjusted for age, sex, and BMI (HR, 8.58:1; p = 0.022). Weight-adjusted parameters of muscle area were negatively correlated with duration of ventilator support (R = -0.54, p < 0.001) and ICU stay (R = -0.33, p = 0.021). The authors concluded that patients with RS demonstrated worse survival after LTX than those without RS. Furthermore, quantitative parameters of muscles measured at the T12 level on chest CT were associated with the duration of post-lung transplant ventilator support and duration of stay in the ICU. Moreover, these researchers stated that further research is needed to establish a sex-specific threshold for sarcopenia, to examine longitudinal changes in body composition, and validate their prognostic significance in larger, more diverse study populations.

The authors stated that this study had several drawbacks. First, the small number of patients (n = 45) included, which markedly restricted the ability to perform more flexible subgrouping and reduced the power of the statistical analyses. However, due to the restricted exclusion criteria, all but 6 of the 51 adult LTX performed in the authors’ institution during the 6-year period were included in the current study, and the influence of selection bias would have been weakened. Second, this was a retrospective, single-center study. Quantitative muscle and subcutaneous fat measurements were carried out during the pre-operative period, and longitudinal changes in body composition could not be evaluated; thus, alterations in body composition during the ICU care and long-term post-transplant recovery could not be examined. For the purpose of survival analysis, the study population was divided into 2 groups based on the value of muscle-height index (MHI), and sex-specific cut-off values for sarcopenia or adipopenia were not evaluated in the present study. One previous study proposed possible cut-off values for sarcopenia measured at the T12 level on chest CT; however, the study was based on a non-Asian population with cardiovascular disease and the authors used reference values obtained from elderly oncological patients. Therefore, direct application of such cut-off values to the current study population, which exclusively comprised Asian patients with end-stage lung disease (ESLD), would have been unsuitable. Although the cut-off value adopted in the present study could not be applied to the general population, the value was sufficient to examine the influence of being relatively sarcopenic on survival after LTX in a small number of patients. An additional drawback of the present study was the fact that only subcutaneous fat, and not visceral fat, was analyzed. Finally, transplant candidates did not undergo examinations for muscular function, and its relative importance with regard to LTX outcomes, in comparison with muscle mass, was not evaluated.

Rozenberg and colleagues (2020) noted that computed tomography (CT) is gaining increased recognition in the assessment of body composition in LTX candidates as a prognostic marker of post-transplant outcomes. In a systematic review, these investigators examined the methodology of CT measures of body composition used in LTX patients and its association with post-transplant outcomes. A total of 6 databases were searched (inception to April 2020) for studies of adult LTX patients with thoracic or abdominal CT measures (muscle CSA and/or adiposity); 13 articles were included with 1,911 LTX candidates, 58 % men, mean age range of 48 to 61 years, and BMI of 21.0 to 26.1 kg/m2. Several methods were used: thoracic or abdominal CT scans to evaluate skeletal muscle (n = 11) and adiposity (n = 4) at various anatomic locations (carina, thoracic, and lumbar vertebrae), differing muscle groups, and adipose tissue compartments. Low muscle mass was associated with adverse outcomes in 6/11 studies, including longer mechanical ventilation days (n = 2), intensive care (n = 2) and hospital stay (n = 2), and mortality (n = 4). Greater subcutaneous and mediastinal fat were associated with increased risk of primary graft dysfunction (n = 2); however, implications of adiposity on survival were variable across 4 studies. The authors concluded that further standardization of CT body composition evaluations is needed to examine the prognostic utility of these measures on LTX outcomes.

Anti-Thymocyte Globulin (Thymoglobulin) for the Treatment of Acute Cellular Rejection in Lung transplant Recipients

In a review on the management of rejection after LTx, Parulekar and Kao (2019) stated that the management of asymptomatic minimal acute rejection (grade A1) remains controversial, despite its association with the development of BOS. Bronchoscopy may be carried out to follow-up acute rejection (AR) to evaluate response to therapy or if untreated, rule out progression to a higher grade. Studies of the value of follow-up biopsies have shown that 26 % to 44 % of patients with moderate ACR have persistent rejection. There is no accepted, standardized regimen for treatment of persistent or refractory acute rejection. Reported approaches include additional intravenous (IV) glucocorticoids, ATG, alemtuzumab, total lymphoid radiation, and extracorporeal photopheresis (ECP).

January et al (2019) noted that chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the 1st year following LTx. Several treatments have been used to prevent the progression or reverse the effects of CLAD. Cytolytic therapy with rabbit ATG (rATG) has previously shown to be a potential option. However, the effect on patients with restrictive allograft syndrome (RAS) versus BOS and the effect of cumulative dosing are unknown. The charts of LTx patients treated with rATG at Barnes-Jewish Hospital from 2009 to 2016 were retrospectively reviewed. The primary outcome was response to rATG; patients were deemed responders if their FEV1 improved in the 6 months after rATG treatment. Safety endpoints included incidence of serum sickness, cytokine release syndrome (CRS), malignancy, and infectious complications. A total of 108 patients were included in this study; 43 (40 %) patients were responders who experienced an increase in FEV1 after rATG therapy. No predictors of response to rATG therapy were identified. Serum sickness occurred in 22 % of patients, 15 % experienced CRS, and 19 % developed an infection after therapy. The authors concluded that 40 % of patients with CLAD have an improvement in lung function after treatment with rATG although the improvement was typically minimal.

Kotecha et al (2021) stated that CLAD is the major factor limiting survival following LTx with limited effective therapeutic options. These investigators reported their 12-year experience ATG as 2nd-line CLAD therapy. Clinical and lung function data were collected on LTx recipients receiving ATG. Rate of FEV1 decline (ml/day) was calculated before and after ATG. Partial response (PR) to ATG was defined by rate of FEV1 decline improving 20 %; and complete response (CR) was defined by an absolute improvement or stability in baseline FEV1. A total of 76 patients received ATG for CLAD. Of these, 5 patients who had a clinical diagnosis of antibody-mediated rejection and were treated with plasmapheresis before or after ATG were excluded from analysis; 16 (23 %) were complete responders, 29 (40 %) were partial responders, and 26 (37 %) did not respond. Those with CLAD stage 2 or 3 and younger age were more likely to respond. Partial responders had a 65 % lower risk of death or re-transplant (HR, 0.35; p = 0.003), whereas complete responders reduced their risk by 70 % (HR, 0.30; p = 0.006). The authors concluded that ATG appeared to stabilize or attenuate lung function decline in CLAD, which may lead to improved retransplant-free survival. Although certain predictors of response have been identified in this large single-center review, these findings need to be confirmed by a multi-center RCT to determine predictors of response to ATG for CLAD.

Iribarnegaray et al (2021) noted that CLAD is the leading cause of mortality after the 1st year of transplantation and treatments can have little impact on CLAD progression in some cases. These researchers examined the safety and effectiveness of ATG in LTx recipients with CLAD. They reviewed all patients from their center who had undergone a LTx between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (FEV1) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. These investigators followed and recorded survival during the 12 months after treatment. A total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in 50 % of the patients. Most patients (71 %) who responded well to ATG were in CLAD stage 1 to 2. The fall slope FEV1 was better after treatment. The median survival was 27 months, and these researchers found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and non-rapid decliners. The authors concluded that ATG treatment could play a role in patient with CLAD who did not respond to conventional therapies. The effect of cytolytic therapy with ATG was clearly better in those patients in early stages, with little effect in those in CLAD stage 3.

AlloSure (Donor-Derived Cell-Free DNA Testing) for Monitoring Acute Rejection Following Lung Transplantation

Tanaka et al (2018) stated that donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors; however, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. These researchers examined the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection (AR) early after living-donor lobar LT (LDLLT). Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p = 0.022) and at 72 hours (p = 0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with AR (median of 12.0 %) than in those with infection (median of 4.2 %) (p = 0.028) or in a stable condition (median of 1.1 %) (p = 0.001). The authors concluded that measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of AR after LT.

The authors stated that this study had several drawbacks. First, the number of cases of LDLLT enrolled in this study was small, because the number of donations from living donors was limited in Japan. Second, DNA analysis of brain-dead donors is not legally approved in Japan, and these researchers could not compare the plasma dd-cf-DNA levels between patients who underwent LDLLT and those who underwent cadaveric LT. Third, because of the similar DNA patterns between the blood-relative donors and the recipients of LDLLT, detection of the target SNPs using a total of 35 SNPs resulted in the exclusion of 2 recipients of LDLLT from this study. Finally, because AR is diagnosed clinically without histological confirmation after LDLLT, and treated by steroid pulse therapy, other possible steroid-responsive pulmonary disorders could not be completely excluded. However, consistent with a previous report, all patients clinically diagnosed as showing AR showed elevated plasma levels of dd-cf-DNA in this study, and monitoring of the plasma dd-cf-DNA levels could provide pertinent information for the diagnosis of AR even after LDLLT.

Sayah et al (2020) noted that telehealth platforms with remote phlebotomy and biomarker implementation represent a novel paradigm for surveillance after LT. In a pilot study, these investigators examined dd-cfDNA in plasma using a clinical-grade "next-generation sequencing (NGS)" assay. dd-cfDNA levels were determined in biorepository venous plasma samples obtained during the lung allograft rejection gene expression observation study, implementing a clinical-grade NGS assay. A total of 69 unique LT patients encompassing 9 LT centers, with associated clinical-histopathologic diagnoses, were examined -- allograft infection (n = 26), normal histopathology without infection (n = 30), and acute cellular rejection (ACR; n = 13). dd-cfDNA in ACR patients were significantly elevated (1.52 %; inter-quartile range [IQR], 0.520 to 2.2550) compared with the normal stable patients (0.485 %; IQR, 0.220 to 0.790) (p = 0.026). During allograft infection, dd-cfDNA values were not different (0.595; IQR, 0.270 to 1.170) from normal (p = 0.282) and ACR (p = 0.100). Area under the curve-receiver operator characteristics curve (AUC-ROC) analysis for allograft ACR was 0.717 (95 % confidence interval [CI]: 0.547 to 0.887; p = 0.025). At a 0.87 % threshold dd-cfDNA-sensitivity = 73.1 %, specificity = 52.9 %, positive predictive value (PPV) = 34.1 %, and negative predictive value (NPV) = 85.5 %. The authors concluded that biomarker surveillance utilizing dd-cfDNA holds promise for the non-invasive detection of acute lung transplant rejection and quiescence and should provide additional support to clinical surveillance after LT. These researchers speculated that dd-cfDNA monitoring may be valuable during longitudinal assessment and future prospective, multi-center trials for the spectrum of LT rejection and allograft dysfunction.

The authors stated that drawbacks of this study included the prospectively collected, however, archival use of the samples. Nevertheless, these investigators attempted to eliminate bias while utilizing an international, multicenter-collected biorepository with determined clinical-pathologic diagnoses from unique transplant recipients; thus, encompassing the breadth of transplant experiences. Another drawback, the ACR cohort consisted predominantly of ISHLT grades A2/B0 (mild) and A1/B2r (minimal) rejection; nevertheless, dd-cfDNA levels were significantly elevated as reported previously with "shotgun" sequencing techniques. This finding was particularly intriguing, in that dd-cfDNA levels may complement the histopathologic diagnosis. Prior studies have demonstrated that even grade A17 or an isolated lymphocytic bronchiolitis (grade B), portend risk for subsequent development of obstructive-phenotype CLAD. Similarly, elevation in dd-cfDNA after kidney transplantation in association with biopsy and the ambiguous Banff criteria diagnoses of borderline or minimal TCMR1A rejection, portend risk for renal function decrement, recurrent ACR, and AMR. Thus, further evaluation of treatment algorithms in the context of dd-cfDNA assessment as a biomarker of allograft injury, should be considered for prospective clinical trials. In addition, the plasma samples were intentionally selected to encompass the earlier post-transplant period (2 weeks to 1 year), thereby eliminating the confounding development of chronic lung allograft dysfunction (CLAD) from the analysis. These investigators speculated that assessment of dd-cfDNA in the context of obstructive and restrictive phenotypes of CLAD10 may provide additional insights into pathophysiology and treatment algorithms. Finally, the "lung allograft rejection gene expression observational (LARGO)" study preceded the elucidation of antibody-mediated allograft rejection (AMR) in LT, therefore, further assessment of dd-cfDNA in this spectrum of rejection, would be warranted as increased dd-cfDNA has been previously reported with AMR after kidney, heart, and LT.

Khush et al (2021) noted that surveillance after LT is critical to the detection of acute cellular rejection (ACR) and prevention of CLAD. These researchers measured dd-cfDNA implementing a clinical-grade, next-generation targeted sequencing assay in 107 plasma samples from 38 unique lung transplantation recipients with diagnostic cohorts classified as: (i) biopsy-confirmed or treated ACR, (ii) AMR, (iii) obstructive CLAD, (iv) allograft infection (INFXN), and (v) stable healthy allografts (STABLE). The key findings were as follows: (i) dd-cfDNA level was elevated in ACR (median of 0.91 %; IQR: 0.39 to 2.07 %), CLAD (2.06 %; IQR: 0.57 to 3.67 %) and an aggregated cohort of rejection encompassing allograft injury (1.06 %; IQR: 0.38 to 2.51 %), compared with the STABLE cohort (0.38 %; IQR: 0.23 to 0.87 %) (p = 0.02); (ii) dd-cfDNA level with AMR was elevated (1.34 %; IQR: 0.34 to 2.40 %) compared to STABLE, although it did not reach statistical significance (p = 0.07) due to limitations in sample size; (iii) there was no difference in dd-cfDNA for allograft INFXN (0.39 %; IQR: 0.18 to 0.67 %) versus STABLE, which may relate to differences in "tissue injury" with the spectrum of bronchial colonization versus invasive infection; (iv) there was no difference for dd-cfDNA in unilateral versus bilateral LT; (v) "optimal threshold" for dd-cfDNA for aggregated rejection events representing allograft injury was determined as 0.85 %, with sensitivity = 55.6 %, specificity = 75.8 %, PPV = 43.3 % and NPV = 83.6 %. The authors concluded that measurement of plasma dd-cfDNA may be a clinically useful tool for the assessment of lung allograft health and surveillance for "tissue injury" with a spectrum of rejection. Moreover, these researchers stated that further prospective studies incorporating dd-cfDNA as a non-invasive tool for detection of rejection and assessment of lung allograft health may prove valuable.

The author stated that drawbacks of this study included the use of archived biorepository plasma samples; however, these were associated with appropriate clinical-pathological data to allow assignment to the different cohort categories. Admittedly further clarification of the INFXN cohort with additional radiographic and clinical data would have allowed for a more detailed analysis. These investigators speculated that limitations in sample size likely accounted for a lack of statistical significance for the observed elevation in dd-cfDNA with AMR. Nevertheless, there was an evident trend (1.34 %; IQR: 0.34 to 2.40) for this cohort that should be further assessed in the context of a prospective, multi-center study. Furthermore, a preliminary estimate of a threshold dd-cfDNA level for aggregated allograft rejection was determined from this data; however, this threshold will require further prospective validation. During the analysis, these researchers included ISHLT Grade A1 ("minimal") ACR episodes, despite less certainty regarding clinical significance of these episodes. Intriguing was the observation that despite only minimal peri-vascular lymphocytic infiltration, the elevated dd-cfDNA levels with Grade A1 ACR were not statistically different from the values with Grades A2 to A4, which suggested a similar extent of tissue injury occurred during the Grade A1 rejection events. Indeed, Hopkins et al (2004) had previously reported an increased predisposition to bronchiolitis obliterans syndrome (BOS) (68 % versus 43 %) in lung transplantation recipients with multiple episodes of Grade A1 ACR compared to those who experienced less than or equal to 1 episode. Furthermore, approximately 25 % of Grade A1 episodes progressed to high-grade ACR within the subsequent 3-month period; thus, histopathological diagnosis alone may lack adequate sensitivity for determining the biological effect of ACR on allograft injury that may require specific therapeutic interventions. These researchers speculated that the histopathological diagnosis of ACR may be further complemented by dd-cfDNA assessment of allograft injury. Another potential limitation to this study was that these researchers did not stratify episodes of Grade A1 to A4 ACR for the presence or absence of associated lymphocytic bronchiolitis (Grade B 0 to 2R), and they specifically excluded specimens with an isolated lymphocytic bronchiolitis from the healthy NORMAL cohort to avoid the potential confounding variable. As previously reported by Ross et al (1997), isolated lymphocytic bronchiolitis was likely to be the incipient histopathological lesion in the continuum of obstructive CLAD. Therefore, assessment of dd-cfDNA in isolated lymphocytic bronchiolitis will be a critical area of further investigation, to determine associated allograft tissue injury and thereby evaluate subtle patterns of ACR that may require treatment as a pre-emptive strategy to mitigate development of CLAD or BOS.

Jang et al (2021) stated that AR, which includes AMR and ACR, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance trans-bronchial biopsies to detect and treat AR before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high inter-observer variability. In a cohort, multi-center study, these investigators examined the performance of percent ddcfDNA (%ddcfDNA) to detect AR. They monitored 148 lung transplant subjects over a median of 19.6 months. These researchers collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data were collected to adjudicate for AR. The primary analysis consisted of computing the AUC-ROC of %ddcfDNA to detect AR. Secondary analysis determined %ddcfDNA rule-out thresholds for AR. ddcfDNA levels were high after transplant surgery and decayed logarithmically. With AR, ddcfDNA levels rose 6-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA AUC_ROC for AR, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of less than 0.5 % and less than 1.0 % showed a NPV of 96 % and 90 % for AR, respectively. Histopathology detected 1/3 of episodes with ddcfDNA levels greater than or equal to 1.0 %, even though greater than 90 % of these events were co-incident to clinical complications missed by histopathology. The authors concluded that the findings of this study demonstrated that %ddcfDNA reliably detected AR and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury.

Trindade et al (2022) stated that donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker for the diagnosis of acute allograft injury within the first 1 to 2 years following LTX; however, its use for diagnosing CLAD has not yet been investigated. Understanding baseline dd-cfDNA kinetics beyond the initial 2 years post-transplant is a necessary 1st step in determining the use of dd-cfDNA as a CLAD biomarker. In a prospective, observational, single-center study, these researchers attempted to establish baseline dd-cfDNA% levels in clinically stable lung allograft recipients who are more than 2-year post-transplant. They identified plasma dd-cfDNA levels in clinically stable lung allograft recipients more than 2-year post-transplant. A total of 51 subjects were enrolled and 3 or more baseline dd-cfDNA measurements were attained during a median of 252 days. The median baseline dd-cfDNA% level in this cohort was 0.45 % (interquartile range [IQR], 0.26 to 0.69). There were statistically significant differences in dd-cfDNA based on post-transplant duration (5 years or less post-transplant: median of 0.41 % [IQR, 0.21 to 0.64] versus more than 5 years post-transplant: median of 0.50 % [IQR, 0.33 to 0.76]; p < 0.02). However, the clinical significance of this small change in dd-cfDNA was uncertain because this magnitude of change was within the biologic test variation of 73 %. The authors concluded that this study was the 1st to define levels of dd-cfDNA in clinically stable patients who were 2-year post-LTX. These researchers stated that these findings laid the groundwork for the study of dd-cfDNA as a possible biomarker for CLAD.

The authors stated that the main drawbacks of this study were its single-center design and the lack of additional objective measurements of potential subclinical graft injury. These investigators included samples from 3 patients with previous acute lung allograft dysfunction (ALAD) with a documented resolution of symptoms and recovery of changes in lung function. These patients may not only contribute to the variability of dd-cfDNA beyond 2 y following LTX, but also reflect a real-world patient population suggesting that dd-cfDNA levels at distant times after LTX may have clinical utility. Lastly, these findings were based on the use of the AlloSure test kit and may not apply to other platforms for assaying dd-cfDNA, especially regarding biologic variation. However, dd-cfDNA% thresholds that define acute lung allograft injury have been comparable across different propriety platforms.

Keller et al (2022a) stated that previous studies showed that dd-cfDNA in LTX recipients may serve as a marker of allograft injury for detecting allograft rejection and infection. Clinical interpretation of dd-cfDNA requires understanding its biological variation in stable LTX patients to identify abnormal results suggesting underlying allograft dysfunction. These researchers attempted to establish the biological variation and reference change values (RCV) of dd-cfDNA in stable LTX recipients using an analytically validated assay with an established analytic coefficient of variation (CVA). The AlloSure assay was used to measure plasma dd-cfDNA in a cohort of LTX patients at 4 centers that used dd-cfDNA to monitor for allograft dysfunction in preference to surveillance trans-bronchial biopsy. Patients with stable allograft function and 3 or more dd-cfDNA samples were included. Intra-individual coefficient of variation (CVI), inter-individual CV (CVG), index of individuality (II) and the RCV were calculated. A total of 35 patients with a combined 124 dd-cfDNA samples were included in the final analysis. The median dd-cfDNA was 0.31 % (IQR of 0.18 % to 0.68 %), the 97.5th percentile and 95th percentile were 1.3 % and 1.0 %, respectively. In 30 stable patients with an average of 3.7 tests, the CVI was 25 %, CVG 53 %, II 0.47, and RCV 70 %. The authors concluded that the findings of this study established the biological variability of dd-cfDNA as well as reference cut-offs for the identification of abnormal values in stable LTX recipients. These findings enhanced the understanding of the clinical interpretation of dd-cfDNA and provided insight into the degree of change in observed values that constitutes a difference beyond normal biological variation; thus, providing the essential foundation for the identification of underlying allograft pathology. These researchers stated that with further validation, these thresholds may be incorporated into surveillance monitoring algorithms to identify potentially abnormal results indicating allograft dysfunction.

The authors stated that this study had several drawbacks. First, it was possible that some patients were incorrectly assigned as stable. Previous studies reported that elevated dd-cfDNA levels may precede clinical or histological signs of allograft injury by several months; thus, there was a possibility that some "stable" patients indeed had underlying allograft pathology that was not identified on biopsy or pulmonary function testing and remained asymptomatic over the course of the study period. Second, the dd-cfDNA assay measures the fraction of dd-cfDNA to total cfDNA; therefore, marked changes in recipient cfDNA levels, such as in the setting of other systemic pathology, may alter the levels of dd-cfDNA. Third, this study did not assess recipient cfDNA. dd-cfDNA is computed as a fraction of donor to donor-plus-recipient cfDNA. Accurate assessment of dd-cfDNA requires a stable recipient cfDNA, which may not be the case in these patients with frequent infections and other end-organ injury. Fourth, the sample size of this study was small (35 patients) and may limit the ability to make definitive conclusions based on this analysis. However, while the sample size of this study may appear limited, these researchers could not identify any other study with a sample size greater than 30 that estimated the biological variability of a comparable clinical biomarker. These investigators stated that further studies using a larger sample size would be valuable to validate the findings of this study and examine the contribution of recipient cfDNA.

Keller et al (2022b) noted that as a marker of underlying lung allograft injury, dd-cfDNA may be used to identify episodes of acute allograft injury in LTX recipients. In a retrospective, multi-center study, these investigators examined the use of dd-cfDNA to monitor subjects at risk of acute rejection or infection in routine clinical practice. They collected data from LTX recipients within 3 years of transplant at 4 centers between March 24, 2020 and September 1, 2020. During this period, as part of routine care during the COVID-19 pandemic, these centers implemented a home-based surveillance program using plasma dd-cfDNA in preference to surveillance bronchoscopy; dd-cfDNA was used to detect ALAD -- a composite endpoint of acute rejection and infection. dd-cfDNA levels in patients with ALAD were compared to stable patients. The performance characteristics of dd-cfDNA 1.0 % or higher to detect ALAD were estimated. A total of 175 patients underwent 380 dd-cfDNA measurements, of which 290 were for routine surveillance purposes. dd-cfDNA was higher in patients with ALAD than stable patients (median IQR of 1.7 % (0.63 % to 3.1 %) versus 0.35 % (0.22 % to 0.79 %), p < 0.001). As an indication of underlying ALAD during surveillance testing, the estimated sensitivity of dd-cfDNA 1 % or higher was 73.9 %, specificity of 87.7 %, PPV of 43.4 % and NPV of 96.5 %. The authors concluded that dd-cfDNA identified ALAD in asymptomatic lung transplant patients that may not have been identified by using a clinically indicated biopsy strategy alone. dd-cfDNA of less than 1.0 % may be useful in ruling out acute rejection and infection, supporting its use as a potential non-invasive marker for surveillance monitoring.

Furthermore, UpToDate reviews on "Lung transplantation: Procedure and postoperative management" (Hartwig and Klapper, 2022) and "Lung transplantation: An overview" (Hachem, 2022) do not mention donor-derived cell-free DNA testing as a management tool.

Anti-Fibrotic Treatment on Post-Operative Complications in Patients with Interstitial Lung Diseases Undergoing Lung Transplantation

Zhu et al (2022) examined if continuation of anti-fibrotic treatment before LT would influence post-transplant outcomes in patients with idiopathic pulmonary fibrosis (IPF) with regard to mortality, bronchial anastomotic dehiscence, reoperation for bleeding and wound complications, primary graft dysfunction or longer-term survival and allograft rejection. A total of 261 studies were identified using the reported search strategy, of which 7 represented the best evidence to answer the clinical question; 6 of the 7 included studies reported equivalent post-transplant survival among IPF patients on antifibrotic treatment before LT compared with controls; 5 out of 6 studies reported no increase in the risk of major bleeding, wound or bronchial anastomotic complications. One 2-center trial found a higher incidence of early bronchial anastomotic dehiscence; however, this difference was not statistically significant after longer term follow-up. In a study that only included IPF patients who underwent single LT, a lower incidence of grade-3 primary graft dysfunction was reported in the anti-fibrotic treatment group compared with controls. Overall, only small (n of less than 40 in the anti-fibrotic group), non-risk-adjusted, retrospective observational studies have been published. The authors concluded that available evidence suggested that, in IPF patients, continuation of anti-fibrotic therapy before LT was likely safe, and the rates of peri-operative bleeding, wound or bronchial anastomotic complications, as well as 30-day and 1-year survival, were similar to patients not on anti-fibrotic therapy before LT. These researchers noted that studies that had examined the outcomes of LT among IPF patients treated with anti-fibrotic therapy before LT compared with on anti-fibrotic therapy had so far been limited to retrospective, observational, small, non-risk-adjusted studies with relatively short-term follow-up. They stated that whether the continuation of anti-fibrotic therapy before LT may have beneficial effects such as reducing the incidence of primary graft dysfunction or allograft rejection warrants further investigation.

Cuesta et al (2022) stated that anti-fibrotic drugs are the standard treatments for patients with IPF. In a retrospective, case-controlled, multi-center study, these investigators examined the safety of anti-fibrotic treatment in IPF patients undergoing LT. Patients with a diagnosis of IPF who received a lung transplant between January 2015 and June 2019 at 4 Spanish hospitals specialized in LT were recruited. Cases were defined as patients receiving anti-fibrotic treatments at time of transplantation. Each case was matched with a control who did not receive anti-fibrotic treatment. A total of 164 patients were included in the study cohort (103 cases and 61 controls). There were no statistically significant differences between the cases and controls in any of the items studied related to transplantation except the time until the appearance of chest wall dehiscence: although there were no differences in the incidence of wall dehiscence in either group (12.3 % versus 13.7 %; p = 0.318), the patients on anti-fibrotic drugs experienced it earlier (21 days [IQR = 12.5 to 41.5] versus 63 days [IQR = 46.75 to 152.25]; p = 0.012). There were no differences in overall post-transplant survival between the 2 groups (p = 0.698) or in conditional survival at 30 days, 90 days, 3 years or 5 years. However, 1 year survival was significantly greater among controls (80.6 % versus 93.3 %; p = 0.028). The authors concluded that there was evidence that chest wall dehiscences appeared earlier post-transplant in patients using anti-fibrotics, even though this factor did not significantly impact survival.

Taweesedt et al (2023) noted that anti-fibrotic treatment has been approved for reducing disease progression in fibrotic interstitial lung disease (ILD). As a result of increased bleeding risk, some experts suggested cessation of anti-fibrotic before LT. However, extensive knowledge regarding the impact of anti-fibrotic treatment on post-operative complications remains unclear. These investigators carried out a comprehensive search of several databases from their inception through to September 30, 2021. Original studies were included in the final analysis if they compared post-operative complications, including surgical wound dehiscence, anastomosis complication, bleeding complications, and primary graft dysfunction, between those with and without anti-fibrotic treatment undergoing LT. Of 563 retrieved studies, 6 studies were included in the final analysis. A total of 543 ILD patients completing LT were included, with 161 patients continuing anti-fibrotic treatment up to the time of LT and 382 without prior treatment. Anti-fibrotic treatment was not significantly associated with surgical wound dehiscence (RR 1.05; 95 % CI: 0.31 to 3.60; I2 = 0 %), anastomotic complications (RR 0.88; 95 % CI: 0.37 to 2.12; I2 = 31 %), bleeding complications (RR 0.76; 95 % CI: 0.33 to 1.76; I2 = 0 %), or primary graft dysfunction (RR 0.87; 95 % CI: 0.59 to 1.29; I2 = 0 %). Finally, continuing anti-fibrotic treatment before LT was not significantly associated with decreased 1-year mortality (RR 0.80; 95 % CI: 0.41 to 1.58; I2 = 0 %). The authors concluded that the findings of this study suggested a similar risk of post-operative complications in ILD patients undergoing LT who received anti-fibrotic treatment compared to those not on anti-fibrotic therapy. These investigators stated that these findings suggested that anti-fibrotic treatment may be continued until the time of LT with minimal post-operative effect.

The authors stated that in the current clinical practice guideline from the ISHLT, anti-fibrotic treatment may be continued in patients with ILD on the transplant wait-list until the time of LT. These researchers stated that further studies with prospective designs and larger numbers of subjects are needed to better examine the risks and benefits of peri-operative anti-fibrotic utilization in those with advanced stage pulmonary fibrosis awaiting LT, in order to establish substantial evidence for practice guidelines.

Furthermore, an UpToDate review on "Treatment of idiopathic pulmonary fibrosis" (King, 2023) stated that "While antifibrotic agents slow disease progression, a therapeutic response is obtained in only a portion of patients, and survival is poor even for those who respond. A number of potential therapies are in various stages of development. Participation in clinical trials is an important way to improve the therapeutic options available for IPF".

Appendix

The BODE Index (Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise) is a multidimensional capacity index for COPD. The index uses the four factors for predicting the risk of death from the disease: FEV1, body mass index, dyspnea score and 6 minute walk test.

Table The BODE Index
Variable	Points on BODE Index
Variable	0	1	2	3
FEV1 (% predicted)	≥ 65	50 - 64	36 - 49	≤3 5
6-Minute Walk Test (meters)	≥ 350	250 - 349	150 - 249	≤ 149
MMRC Dyspnea Scale	0 - 1	2	3	4
Body Mass Index	> 21	≤ 21

An online tool for calculating the BODE Index is available at the following website: BODE Index for COPD Survival Prediction.

References

The above policy is based on the following references:

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Last Review 09/07/2023

Effective: 03/12/2002

Next Review: 06/27/2024
Review History
Definitions

Lung Transplantation

Table Of Contents

Policy

Scope of Policy

Medical Necessity

Qualifying Conditions for Lung Transplantation (not an all-inclusive list)

Disease-Specific Selection Criteria

General Selection Criteria

Experimental and Investigational

Related Policies

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

CPT codes not covered for indications listed in the CPB:

HCPCS codes covered if selections criteria are met:

HCPCS codes not covered for indications listed in the CPB:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes contraindicated for this CPB (not all-inclusive):

There is no specific code for the TransMedics Organ Care System: