Lung transplantation for lung cancer: A systematic review of the literature.

BACKGROUND: Lung transplant (LTx) is an accepted treatment for end-stage pulmonary failure. A small proportion of explanted lungs harbor incidentally identified nonsmall cell lung cancers (NSCLC). We review the literature on studies assessing LTx patients found to have NSCLC lung cancer in their explanted lungs, and perform a pooled analysis of outcomes. METHODS: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched. We included studies assessing outcomes of patients with incidentally identified NSCLC following LTx, or following LTx for diffuse lepidic adenocarcinoma as a primary indication. RESULTS: A total of 1404 articles were reviewed. 17 eligible studies were identified: 14 studies on incidental NSCLC (N = 169), 4 on diffuse lepidic adenocarcinoma (N = 70). Overall survival (OS) for patients with incidentally identified lung cancer at 1-year, 3-year, and 5-year was 60.8% (95%CI 43.7%-77.9%, I2 =81.8%), 25.5% (95%CI 1.6%-49.5%, I2 =93.6%), and 23.0% (95%CI 2.0%-44.0%, I2 =92.0%) respectively. When restricted to those with earlier stage disease, those with stage I or II NSCLC had better 1-year, 3-year, and 5-year OS at 72.7% (95%CI 57.2%-88.2%, I2 =67.3%), 41.6% (95%CI 14.0%-69.1%, I2 =89.1%), and 34.5% (95%CI 8.1%-61.0%, I2 =89.8%), respectively. A sensitivity analysis limited to stage I showed 1-year, 3-year, and 5-year survival of 73.0% (95%CI 56.3%-89.7%), 40.4% (95%CI 110.3%-70.6%), and 35.4% (95%CI 6.2%-64.5%), respectively. The 4 studies on diffuse lepidic adenocarcinoma were too heterogeneous for pooled analysis. CONCLUSIONS: We present a review and pooled analysis examining survival following LTx with incidentally identified NSCLC. Patients with earlier stage incidentally explanted NSCLC had better survival outcomes. OS in the stage I population approximates that of LTx without incidental NSCLC.

The intersection of race and ethnicity, gender, and primary diagnosis on lung transplantation outcomes.

BACKGROUND: Reducing racial disparities in lung transplant outcomes is a current priority of providers, policymakers, and lung transplant centers. It is unknown how the combined effect of race and ethnicity, gender, and diagnosis group is associated with differences in 1-year mortality and 5-year survival. METHODS: This is a longitudinal cohort study using Standard Transplant Analysis Research files from the United Network for organ sharing. A total of 25,444 patients undergoing first time lung transplantation between 2006 and 2019 in the United States. The primary exposures were lung transplant recipient race and ethnicity, gender, and primary diagnosis group at listing. Multivariable regression models and cox-proportional hazards models were used to determine adjusted 1-year mortality and 5-year survival. RESULTS: Overall, 25,444 lung transplant patients were included in the cohort including 15,160 (59.6%) men, 21,345 (83.9%) White, 2,318 (9.1%), Black and Hispanic/Latino (7.0%). Overall, men had a significant higher 1-year mortality than women (11.87%; 95% CI 11.07-12.67 vs 12.82%; 95% CI 12.20%-13.44%). Black women had the highest mortality of all race and gender combinations (14.51%; 95% CI 12.15%-16.87%). Black patients with pulmonary vascular disease had the highest 1-year mortality (19.77%; 95% CI 12.46%-27.08%) while Hispanic/Latino patients with obstructive lung disease had the lowest (7.42%; 95% CI 2.8%-12.05%). 5-year adjusted survival was highest among Hispanic/Latino patients (62.32%) compared to Black (57.59%) and White patients (57.82%). CONCLUSIONS: There are significant differences in 1-year and 5-year mortality between and within racial and ethnic groups depending on gender and primary diagnosis. This demonstrates the impact of social and clinical factors on lung transplant outcomes.

The mitigating effect of exogenous carbon monoxide on chronic allograft rejection and fibrosis post-lung transplantation.

BACKGROUND: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti-fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS: Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/J→DBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS: Murine lung allografts treated with CO (250 ppm × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and ß-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesenchymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and -independent mechanisms in mediating the effect of CO. CONCLUSION: These results suggest a potential role for CO in alleviating allograft fibrosis and mitigating chronic rejection pathology post-lung transplant.

One-Year Mortality Is Not a Reliable Indicator of Lung Transplant Center Performance.

BACKGROUND: In the United States, the Organ Procurement and Transplant Network (OPTN) uses 1-year mortality as the primary measure of transplant center quality. We sought to evaluate the reliability of mortality outcomes in lung transplantation and to compare statistical methods of program performance evaluation. METHODS: We used the Standard Transplant Analysis and Research files from the United Network for Organ Sharing to identify lung transplant recipients from 2013 to 2018 in the United States. We stratified hospitals on the basis of 30-day, 1-year, and 5-year survival by risk adjustment, reliability adjustment with empirical Bayes technique, and hierarchical bayesian mixed effects models currently used by the OPTN. We measured variation in mortality rates and identification of performance outliers between techniques. RESULTS: We identified 12,769 recipients in 69 centers. Reliability adjustment reduced variation in hospital outcomes and had a large impact on hospital mortality rankings. For example, with 1-year mortality, 28% (5 hospitals) of the "best" hospitals (top 25%) and 18% (3 hospitals) of the "worst" hospitals (bottom 25%) were reclassified after reliability adjustment. The overall reliability of 1-year mortality was low at 0.42. Compared with the bayesian method used by the OPTN, reliability adjustment identified fewer outliers. The 5-year survival reached a higher reliability plateau with a lower volume of cases required. CONCLUSIONS: The reliability of 1-year mortality in lung transplantation is low, whereas 5-year survival estimates may be more reliable at lower case volumes. Reliability adjustment yielded more conservative measures of center performance and fewer outliers compared with current bayesian methods.

Use of Argatroban in Donor Lung Procurement: A Case Report.

BACKGROUND Heparin-induced thrombocytopenia (HIT) is an immunological response to heparin exposure that predisposes patients to hypercoagulable reactions with subsequent heparin administration. Traditionally, heparin is the standard anticoagulant used during organ procurement to prevent clot formation in grafts. This creates a problem in donors or recipients that develop HIT as they are at risk of developing life-threatening coagulopathy. This raises the question of how to use alternative anticoagulation therapies, such as argatroban, that provide rapid-onset prophylaxis by reversibly inhibiting thrombin. Additionally, there are few studies that have assessed how recipients of multiorgan donors treated with argatroban do post-operatively. CASE REPORT In this report, we discuss the procurement protocol and hospital course of a lung transplant recipient who received a graft treated with argatroban due to a HIT-positive liver recipient. The post-operative course for our patient was uneventful, with improved lung function and no complications attributable to argatroban use. Further, none of the 4 other recipients who received organs from the same donor experienced graft dysfunctions secondary to coagulopathy, including the HIT-positive liver recipient. CONCLUSIONS The ultimate success of grafts without thromboembolic complications suggests the use of argatroban in multiorgan procurement in the setting of a HIT-positive recipient is safe and effective. This case report highlights an alternative to the traditional process of organ procurement with heparin, in which patients at risk of coagulopathies secondary to HIT are able to receive organs when traditional protocols would otherwise be prohibitive.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements.

Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.

Radiographic Graft Surveillance in Lung Transplantation: Prognostic Role of Parametric Response Mapping.

Rationale: Chronic lung allograft dysfunction (CLAD) results in significant morbidity after lung transplantation. Potential CLAD occurs when lung function declines to 80-90% of baseline. Better noninvasive tools to prognosticate at potential CLAD are needed. Objectives: To determine whether parametric response mapping (PRM), a computed tomography (CT) voxel-wise methodology applied to high-resolution CT scans, can identify patients at risk of progression to CLAD or death. Methods: Radiographic features and PRM-based CT metrics quantifying functional small airway disease (PRMfSAD) and parenchymal disease (PRMPD) were studied at potential CLAD (n = 61). High PRMfSAD and high PRMPD were defined as ⩾30%. Restricted mean modeling was performed to compare CLAD-free survival among groups. Measurements and Main Results: PRM metrics identified the following three unique signatures: high PRMfSAD (11.5%), high PRMPD (41%), and neither (PRMNormal; 47.5%). Patients with high PRMfSAD or PRMPD had shorter CLAD-free median survival times (0.46 yr and 0.50 yr) compared with patients with predominantly PRMNormal (2.03 yr; P = 0.004 and P = 0.007 compared with PRMfSAD and PRMPD groups, respectively). In multivariate modeling adjusting for single- versus double-lung transplant, age at transplant, body mass index at potential CLAD, and time from transplant to CT scan, PRMfSAD ⩾30% or PRMPD ⩾30% continue to be statistically significant predictors of shorter CLAD-free survival. Air trapping by radiologist interpretation was common (66%), was similar across PRM groups, and was not predictive of CLAD-free survival. Ground-glass opacities by radiologist read occurred in 16% of cases and were associated with decreased CLAD-free survival (P < 0.001). Conclusions: PRM analysis offers valuable prognostic information at potential CLAD, identifying patients most at risk of developing CLAD or death.

The Lung Allocation Score and Its Relevance.

Lung transplantation in the United States, under oversight by the Organ Procurement Transplantation Network (OPTN) in the 1990s, operated under a system of allocation based on location within geographic donor service areas, wait time of potential recipients, and ABO compatibility. On May 4, 2005, the lung allocation score (LAS) was implemented by the OPTN Thoracic Organ Transplantation Committee to prioritize patients on the wait list based on a balance of wait list mortality and posttransplant survival, thus eliminating time on the wait list as a factor of prioritization. Patients were categorized into four main disease categories labeled group A (obstructive lung disease), B (pulmonary hypertension), C (cystic fibrosis), and D (restrictive lung disease/interstitial lung disease) with variables within each group impacting the calculation of the LAS. Implementation of the LAS led to a decrease in the number of wait list deaths without an increase in 1-year posttransplant survival. LAS adjustments through the addition, modification or elimination of covariates to improve the estimates of patient severity of illness, have since been made in addition to establishing criteria for LAS value exceptions for pulmonary hypertension patients. Despite the success of the LAS, concerns about the prioritization, and transplantation of older, sicker individuals have made some aspects of the LAS controversial. Future changes in US lung allocation are anticipated with the current development of a continuous distribution model that incorporates the LAS, geographic distribution, and unaccounted aspects of organ allocation into an integrated score.

Donor to recipient transmission of SARS-CoV-2 by lung transplantation despite negative donor upper respiratory tract testing.

We describe a case of proven transmission of SARS-CoV-2 from lung donor to recipient. The donor had no clinical history or findings suggestive of infection with SARS-CoV-2 and tested negative by reverse transcriptase polymerase chain reaction (RT-PCR) on a nasopharyngeal (NP) swab obtained within 48 h of procurement. Lower respiratory tract testing was not performed. The recipient developed fever, hypotension, and pulmonary infiltrates on posttransplant day (PTD) 3, and RT-PCR testing for SARS-CoV-2 on an NP swab specimen was non-reactive, but positive on bronchoalveolar lavage (BAL) fluid. One thoracic surgeon present during the transplantation procedure developed COVID-19. Sequence analysis of isolates from donor BAL fluid (obtained at procurement), the recipient, and the infected thoracic surgeon proved donor origin of recipient and health-care worker (HCW) infection. No other organs were procured from this donor. Transplant centers and organ procurement organizations should perform SARS-CoV-2 testing of lower respiratory tract specimens from potential lung donors, and consider enhanced personal protective equipment for HCWs involved in lung procurement and transplantation.

Ribavirin and cellular ribavirin-triphosphate concentrations in blood and bronchoalveolar lavage fluid in two lung transplant patients with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient 1, iRTP BAL concentrations decreased by 45% over 3 days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/106 cells). In patient 2, iRTP BAL concentrations were 103 pmol/106 cells after 5 days of oral followed by 5 days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.

Fibroproliferation in chronic lung allograft dysfunction: Association of mesenchymal cells in bronchoalveolar lavage with phenotypes and survival.

BACKGROUND: Chronic lung allograft dysfunction (CLAD), the primary cause of poor outcome after lung transplantation, arises from fibrotic remodeling of the allograft and presents as diverse clinical phenotypes with variable courses. Here, we investigate whether bronchoalveolar lavage (BAL) mesenchymal cell activity at CLAD onset can inform regarding disease phenotype, progression, and survival. METHODS: Mesenchymal cell colony-forming units (CFUs) were measured in BAL obtained at CLAD onset (n = 77) and CLAD-free time post-transplant matched controls (n = 77). CFU counts were compared using Wilcoxon's rank-sum test. Cox proportional hazards and restricted means models were utilized to investigate post-CLAD survival. RESULTS: Higher mesenchymal CFU counts were noted in BAL at the time of CLAD onset than in CLAD-free controls. Patients with restrictive allograft syndrome had higher BAL mesenchymal CFU count at CLAD onset than patients with bronchiolitis obliterans syndrome (p = 0.011). Patients with high mesenchymal CFU counts (≥10) at CLAD onset had worse outcomes than those with low (<10) CFU counts, with shorter average survival (2.64 years vs 4.25 years; p = 0.027) and shorter progression-free survival, defined as time to developing either CLAD Stage 3 or death (0.97 years vs 2.70 years; p < 0.001). High CFU count remained predictive of decreased overall survival and progression-free survival after accounting for the CLAD phenotype and other clinical factors in multivariable analysis. CONCLUSIONS: Fulminant fibroproliferation with higher mesenchymal CFU counts in BAL is noted in restrictive allograft syndrome and is independently associated with poor survival after CLAD onset.

Invasive Microascus trigonosporus Species Complex Pulmonary Infection in a Lung Transplant Recipient.

Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient's fungal burden. Despite this apparent improvement, the patient's pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death.

Pre-transplant presence of antibodies to MICA and HLA class I or II are associated with an earlier onset of bronchiolitis obliterans syndrome in lung transplant recipients.

Previous reports using cell-based methods (CDC-AHG) suggest that the presence of pre-transplant HLA Class I and II antibodies are associated with worse survival following lung transplantation. Similarly, antibodies to major histocompatibility complex Class I chain-related gene A (MICA) have been associated with increased graft failure following kidney transplantation. Using highly sensitive solid phase assays, we sought to determine whether the pre-transplant presence of antibodies to MICA or HLA Class I or II predicted short or long-term lung allograft function. Pre-transplant sera screened for antibodies to MICA by Labscreen Single Antigen format and HLA by Luminex (n = 192) revealed antibody presence in 31 (16.1%) and 70 (36.4%) patients, respectively. HLA antibody presence correlated with increased bronchiolitis Obliterans syndrome (BOS)-1 development at 3 years [32.9% (23/70) vs. 18.9% (23/122), p = 0.03] while MICA antibodies correlated with BOS-2 development [32.3% (10/31) vs. 14.9% (24/161), p = 0.02]. The presence of HLA or MICA antibodies correlated with BOS-1 development [32.5% (26/81) vs.18.0% (20/111), p = 0.02] and BOS-2 [24.7% (20/81) vs. 12.6% (14/111), p = 0.02] at 3 years. We found no correlation between antibody presence and episodes of acute cellular rejection or overall survival. We conclude that the presence of pre-transplant HLA or MICA antibodies is associated with earlier BOS onset following lung transplantation.

Medical complications of lung transplantation.

As short- and long-term survival rates for lung transplantation continue to improve, and as more lung transplantations are occurring with each year, a multitude of medical complications are encountered by the clinician. This article reviews the long-term non-pulmonary noninfectious medical complications that arise beyond the postoperative period in patients who have undergone lung transplantation. This article reviews the development of renal failure, diabetes, cardiovascular complications of hypertension and atherosclerosis, osteoporosis and avascular necrosis, hematologic complications, thromboembolic disease, gastrointestinial complications, neurologic complications, and malignancy, including post-transplant lymphoproliferative disorder.

Native lung volume reduction surgery relieves functional graft compression after single-lung transplantation for chronic obstructive pulmonary disease.

OBJECTIVE: Single-lung transplantation is an accepted treatment for end-stage lung disease caused by chronic obstructive pulmonary disease. A complication unique to single-lung transplantation for chronic obstructive pulmonary disease is graft dysfunction due to compression caused by native lung hyperinflation. We hypothesized that patients with functional compromise from native lung hyperinflation would benefit from native lung volume reduction surgery. METHODS: The charts of all patients undergoing single-lung transplantation for chronic obstructive pulmonary disease were reviewed for lung volume reduction surgery of their native lung. Data regarding length of stay, surgical morbidity and mortality, overall survival, type of lung volume reduction surgery, and pulmonary function were recorded to evaluate the effect of lung volume reduction surgery. RESULTS: Between February 1992 and May 2007, 206 single-lung transplantations were performed for chronic obstructive pulmonary disease. Ten (5%) patients had clinically significant graft compression from native lung hyperinflation. After excluding other causes for functional decline, these patients underwent a modified lung volume reduction surgery between 12 and 142 months after single-lung transplantation (mean, 50 months). Lung volume reduction surgery consisted of anatomic resection. Two (20%) of 10 patients died during their hospitalization. Of the remaining 8 patients, 7 (87.5%) have demonstrated functional improvement on the basis of forced expiratory volume in 1 second improving from 12% to 200% (mean improvement, 57%). Within 6 months of lung volume reduction surgery, mean 6-minute walk values improved significantly (866 to 1055 feet), whereas desaturation with exertion decreased significantly. CONCLUSIONS: Lung volume reduction surgery by means of formal lobectomy in patients with native lung hyperinflation undergoing single-lung transplantation and significant graft compression appears feasible. Additionally, improvements in forced expiratory volume in 1 second can be accomplished in nearly all properly selected patients. Lung volume reduction surgery should be considered in patients with decreasing graft function caused by graft compression from native lung hyperinflation.

Oxidants selectively reverse TGF-beta suppression of proinflammatory mediator production.

Although TGF-beta inhibits the production of proinflammatory mediators in vitro and in vivo, its anti-inflammatory activities may be ineffective in early or severe acute inflammatory circumstances. In this study, we suggest a role for oxidative stress on TGF-beta signaling, leading to prevention of its normal anti-inflammatory effects but leaving its Smad-driven effects on cellular differentiation or matrix production unaffected. Stimulation of the RAW 264.7 macrophage cells, human or mouse alveolar macrophages with LPS led to NF-kappaB-driven production of proinflammatory mediators, which were inhibited by TGF-beta. This inhibition was prevented in the presence of hydrogen peroxide. We found that hydrogen peroxide acted by inducing p38 MAPK activation, which then prevented the ERK activation and MAPK phosphatase-1 up-regulation normally induced by TGF-beta. This was mediated through Src tyrosine kinases and protein phosphatase-1/2A. By contrast, hydrogen peroxide had no effects on TGF-beta-induced Smad2 phosphorylation and SBE-luc reporter gene transcription.