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.

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.

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.

Impact of Tacrolimus vs. Cyclosporine on CLAD Incidence and Allograft Survival in the ISHLT Registry.

PURPOSE: The ScanCLAD study reported a lower incidence of CLAD with the use of once-daily tacrolimus vs. twice-daily cyclosporine. Using the ISHLT Thoracic Organ Transplant (TTX) Registry data, we evaluated the hypothesis that tacrolimus is superior to cyclosporine in real world clinical practice. METHODS: This study is a retrospective cohort study of adult lung transplant recipients in the ISHLT Registry from January 1, 2000 through June 30, 2018 with known CLAD status. The primary exposure variable was patients' maintenance calcineurin inhibitor (CNI) regimen captured at post-transplant discharge. The primary outcome variables were time to CLAD development (with death/retransplantation analyzed as a competing risk) and allograft survival (i.e., time to death/retransplant). RESULTS: Of the 57,403 adult lung transplant recipients in the registry, 22,222 had both CNI and CLAD data available. Of these, 19,698 (88.6%) received tacrolimus immediate release (IR), 2,477 (11.2%) received cyclosporine, and 47 (0.2%) received tacrolimus extended release (XR) for maintenance CNI. Receiving cyclosporine for maintenance immunosuppression (vs. tacrolimus IR) was associated with an increased risk of developing CLAD (HR 1.16, 95% CI 1.08-1.23, p<0.001) and with an increased overall risk for death/retransplant (HR 1.16, 95% CI 1.09-1.23, p<0.001). Receiving tacrolimus XR vs. tacrolimus IR was not associated with differences in long-term post-transplant outcomes, although these analyses were limited by a small sample size. CONCLUSIONS: Patients receiving cyclosporine vs. tacrolimus IR for maintenance calcineurin inhibition had an increased risk of CLAD and decreased overall allograft survival in the ISHLT TTX registry.

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.