Hepatitis B transmission/reactivation associated with Hepatitis B core antibody and Hepatitis C nucleic acid testing positive organs: A report from the Organ Procurement and Transplantation Network Disease Transmission Advisory Committee.

BACKGROUND: Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation. AIM: To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy. METHODS: The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted. RESULTS: From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis. CONCLUSION: HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population.

Safety and utility of indwelling pleural catheters in lung transplant recipients.

INTRODUCTION: The safety and efficacy of indwelling pleural catheters (IPCs) in lung allograft recipients is under-reported. METHODS: We performed a multicenter, retrospective analysis between 1/1/2010 and 6/1/2022 of consecutive IPCs placed in lung transplant recipients. Outcomes included incidence of infectious and non-infectious complications and rate of auto-pleurodesis. RESULTS: Seventy-one IPCs placed in 61 lung transplant patients at eight centers were included. The most common indication for IPC placement was recurrent post-operative effusion. IPCs were placed at a median of 59 days (IQR 40-203) post-transplant and remained for 43 days (IQR 25-88). There was a total of eight (11%) complications. Infection occurred in five patients (7%); four had empyema and one had a catheter tract infection. IPCs did not cause death or critical illness in our cohort. Auto-pleurodesis leading to the removal of the IPC occurred in 63 (89%) instances. None of the patients in this cohort required subsequent surgical decortication. CONCLUSIONS: The use of IPCs in lung transplant patients was associated with an infectious complication rate comparable to other populations previously studied. A high rate of auto-pleurodesis was observed. This work suggests that IPCs may be considered for the management of recurrent pleural effusions in lung allograft recipients.

Transplant of organs from donors with positive SARS-CoV-2 nucleic acid testing: A report from the organ procurement and transplantation network ad hoc disease transmission advisory committee.

BACKGROUND: Decisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test-positive (NAT+) donors must balance risk of donor-derived transmission events (DDTE) with the scarcity of available organs. METHODS: Organ Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS-CoV-2 NAT+ and NAT- donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee. RESULTS: From May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT- donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT- donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30-day mortality, and 30-day graft loss were similar for all organ types. No SARS-CoV-2 DDTE occurred in this interval. CONCLUSIONS: Transplantation of SARS-CoV-2 NAT+ donor organs appears safe for short-term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes.

Monoclonal antibody treatment for COVID-19 in solid organ transplant recipients.

Solid organ transplant (SOT) recipients are at high risk for severe coronavirus disease 2019 (COVID-19). Studies suggest that early intervention with monoclonal antibody (MAB) treatment directed against the SARS-CoV-2 spike protein may reduce the risk of emergency department visits or hospitalization for COVID-19, especially in high-risk patients. Herein, we describe our single-center experience of 93 SOT (50 kidney, 17 liver, 11 lung, nine heart, and six dual-organ) recipients with mild to moderate COVID-19 who were treated with bamlanivimab or casirivimab-imdevimab per emergency use authorization guidelines. Median age of recipients was 55 [(Interquartile range) 44-63] years, and 41% were diabetic. Median time from transplant to MAB was 64 (IQR 24-122) months and median time from the onset of COVID-19 symptoms to the infusion was 6 (IQR 4-7) days. All patients had a minimum 30 days of study follow-up. The 30-day hospitalization rate for COVID-19-directed therapy was 8.7%. Infusion-related adverse events were rare and generally mild. Biopsy-proven organ rejection occurred in two patients, and there were no graft losses or deaths. A comparator group of 72 SOT recipients diagnosed with COVID-19 who were eligible but did not receive MAB treatment had a higher 30-day hospitalization rate for COVID-19-directed therapy (15.3%), although this difference was not statistically significant, after adjustment for age (Odds Ratio 0.49 [95% Confidence Interval 0.18-1.32], p = 0.16). Our experience suggests that MAB treatment, with respect to the available MAB formulations and circulating viral variants present during our study period, may provide favorable outcomes for mild to moderate COVID-19 in SOT recipients.

Clinical course of SARS-CoV-2 infection and recovery in lung transplant recipients.

BACKGROUND: Reports on outcomes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung transplant recipients remain limited. METHODS: We performed a single-center, observational study of outcomes in lung transplant recipients diagnosed with SARS-CoV-2 between 5/1/2020 and 3/15/2022 that were followed for a median of 123 days. We analyzed changes in spirometry, acute lung allograft dysfunction (ALAD) incidence, hospitalization, mechanical ventilation needs, secondary infection, and survival. RESULTS: In our cohort of 336 patients, 103 developed coronavirus disease (COVID) (27 pre-Delta, 20 Delta, and 56 Omicron-era). Twenty-five patients (24%) required hospitalization and 10 patients ultimately died (10%). Among 85 survivors who completed ambulatory spirometry, COVID-19 did not alter change in forced expiratory volume in 1 s (FEV1 ) or forced vital capacity (FVC) over time compared to the preceding 6 months. The pre-COVID FEV1 change was -0.05 ml/day (IQR -0.50 to 0.60) compared to -0.20 ml/day (IQR -1.40 to 0.70) post-COVID (p = .16). The pre-COVID change in FVC was 0.20 ml/day (IQR -0.60 to 0.70) compared to 0.05 ml/day (IQR -1.00 to 1.10) post-COVID (p = .76). Although the cohort overall had stable lung function, 33 patients (39%) developed ALAD or accelerated chronic lung allograft dysfunction (FEV1 decline >10% from pre-COVID baseline). Nine patients (35%) with ALAD recovered lung function. Within 3 months of acute COVID infection, 18 patients (17%) developed secondary infections, the majority being bacterial pneumonia. Finally, vaccination with at least two doses of mRNA vaccine was not associated with improved outcomes. CONCLUSIONS: This study describes the natural history of SARS-CoV-2 infection in a large cohort of lung transplant recipients. Although one third of patients develop ALAD requiring augmented immunosuppression, infection with SARS-CoV-2 is not associated with worsening lung function.

Impact of anticoagulation intensity on blood transfusion for venoarterial extracorporeal membrane oxygenation during lung transplantation.

Venoarterial extracorporeal membrane oxygenation is increasingly used for mechanical circulatory support during lung transplant. Optimal intensity of intraoperative anticoagulation would be expected to mitigate thromboembolism without increasing bleeding and blood product transfusions. Yet, the optimal intensity of intraoperative anticoagulation is unknown. We performed a retrospective cohort study of 163 patients who received a bilateral lung transplant at a single center. We categorized the intensity of anticoagulation into 4 groups (very low to high) based on the bolus dose of unfractionated heparin given during lung transplant and compared the rates of intraoperative blood transfusions and the occurrence of thromboembolism between groups. When compared to the very low-intensity group, each higher intensity group was associated with higher red blood cell, fresh frozen plasma, and platelet transfusions. The occurrence of thromboembolism was similar across groups. These preliminary data suggest that lower intensity anticoagulation may reduce the rate of intraoperative blood transfusions, although further study is needed.

Listing Dilemmas: Age, Frailty, Weight, Preexisting Cancers, and Systemic Diseases.

Selection of lung transplant candidates is an evolving field that pushes the boundaries of what is considered the norm. Given the continually changing demographics of the typical lung transplant recipient as well as the growing list of risk factors that predispose patients to poor posttransplant outcomes, we explore the dilemmas in lung transplant candidate selections pertaining to older age, frailty, low and high body mass index, preexisting cancers, and systemic autoimmune rheumatic diseases.

Extracorporeal Membrane Oxygenation Selection by Multidisciplinary Consensus: The ECMO Council.

Coronavirus disease 2019 (COVID-19) has increased the demand for extracorporeal membrane oxygenation (ECMO) and introduced distinct challenges to patient selection for ECMO. Standardized processes for patient selection amidst resource limitations are lacking, and data on ECMO consults are underreported. We retrospectively reviewed consecutive adult ECMO consults for acute respiratory failure received at a single academic medical center from April 1, 2020, to February 28, 2021, and evaluated the implementation of a multidisciplinary selection committee (ECMO Council) and standardized framework for patient selection for ECMO. During the 334-day period, there were 202 total ECMO consults; 174 (86.1%) included a diagnosis of COVID-19. Among all consults, 157 (77.7%) were declined and 41 (20.3%) resulted in the initiation of ECMO. Frequent reasons for decline included the presence of multiple relative contraindications (n = 33), age greater than 60 years (n = 32), and resource limitations (n = 27). The ECMO Council deliberated on every case in which an absolute contraindication was not present (n = 96) via an electronic teleconference platform. Utilizing multidisciplinary consensus together with a standardized process for patient selection in ECMO is feasible during a pandemic and may be reliably exercised over time. Whether such an approach is feasible at other centers remains unknown.

Relative Change in Donor-Derived Cell-free DNA is Superior to Absolute Values for Diagnosis of Acute Lung Allograft Dysfunction.

Donor-derived cell-free DNA (dd-cfDNA%) is a biomarker of early acute lung allograft dysfunction (ALAD), with a value of ≥1.0% indicating injury. Whether dd-cfDNA% is a useful biomarker in patients >2 y posttransplant is unknown. Our group previously demonstrated that median dd-cfDNA% in lung recipients ≥2 y posttransplant without ALAD was 0.45%. In that cohort, biologic variability of dd-cfDNA% was estimated by a reference change value (RCV) of 73%, suggesting that change exceeding 73% may be pathologic. In this study, we aimed to determine whether dd-cfDNA% variability or absolute thresholds are optimal for detecting ALAD. Methods: We prospectively measured plasma dd-cfDNA% every 3 to 4 mo in patients ≥2 y post-lung transplant. ALAD was defined as infection, acute cellular rejection, possible antibody-mediated rejection, or change in forced expiratory volume in 1 s >10%, and was adjudicated retrospectively. We analyzed area under the curve for RCV and absolute dd-cfDNA% and reported performance of RCV ≥73% versus absolute value >1% for discriminating ALAD. Results: Seventy-one patients had ≥2 baseline measurements of dd-cfDNA%; 30 developed ALAD. RCV of dd-cfDNA% at ALAD had a greater area under the receiver operator characteristic curve than absolute dd-cfDNA% values (0.87 versus 0.69, P = 0.018). Test characteristics of RCV >73% for ALAD diagnosis were sensitivity 87%, specificity 78%, positive predictive value 74%, and negative predictive value 89%. In contrast, dd-cfDNA% ≥1% had sensitivity 50%, specificity 78%, positive predictive value 63%, and negative predictive value 68%. Conclusions: Relative change in dd-cfDNA% has improved test characteristics for diagnosing ALAD compared with absolute values.

Assessment of dd-cfDNA Levels in Clinically Stable Lung Allograft Recipients Beyond the Initial 2 y Posttransplant.

Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker for the diagnosis of acute allograft injury within the first 1 to 2 y after lung transplant, but its utility for diagnosing chronic lung allograft dysfunction (CLAD) has not yet been studied. Understanding baseline dd-cfDNA kinetics beyond the initial 2 y posttransplant is a necessary first step in determining the utility of dd-cfDNA as a CLAD biomarker. We seek to establish baseline dd-cfDNA% levels in clinically stable lung allograft recipients who are >2 y posttransplant. Methods: We performed a prospective, single-center, observational study to identify plasma dd-cfDNA levels in clinically stable lung allograft recipients >2 y posttransplant. Results: Fifty-one subjects were enrolled and ≥3 baseline dd-cfDNA measurements were acquired during a median of 252 d. The median baseline percent dd-cfDNA level in our cohort was 0.45% (interquartile range [IQR], 0.26-0.69). There were statistically significant differences in dd-cfDNA based on posttransplant duration (≤5 y posttransplant median 0.41% [IQR, 0.21-0.64] versus >5 y posttransplant median 0.50% [IQR, 0.33-0.76]; P < 0.02). However, the clinical significance of this small change in dd-cfDNA is uncertain because this magnitude of change is within the biologic test variation of 73%. Conclusions: This study is the first to define levels of dd-cfDNA in clinically stable patients who are >2 y post-lung transplant. These findings lay the groundwork for the study of dd-cfDNA as a possible biomarker for CLAD.

1-year outcomes for lung transplantation recipients with non-alcoholic fatty liver disease.

Advanced hepatic fibrosis and cirrhosis are absolute contraindications to lung transplantation. [ 1] However, whether fatty liver disease with mild-moderate fibrosis contributes to increased adverse outcomes post-lung transplantation remains unknown. We present a retrospective analysis of patients transplanted at Brigham and Women's Hospital between 2015 and 2017 to identify whether patients with mild-moderate non-alcoholic fatty liver disease (NAFLD) experience increased short-term complications compared to patients with normal liver architecture. Patients with advanced (F3-F4) fibrosis and/or cirrhosis were considered non-suitable transplant candidates, a priori. This study was powered for a difference in index hospital-free days within the first 30 days of 25% (α=0.05, ß=0.8). Secondary outcomes included index intensive care unit (ICU)-free days within the first 10 days post-transplant, perioperative blood product transfusion, incidence of index hospitalisation arrhythmias and delirium, need for insulin on discharge post-transplant, tacrolimus dose required to maintain a trough of 8-12 ng·mL-1 at index hospital discharge, and 1-year post-transplant incidence of insulin-dependent diabetes, acute kidney injury, acute cellular rejection, unplanned hospital readmissions and infection. 150 patients underwent lung transplantation between 2015 and 2017 and were included in the analysis; of these patients 40 (27%) had evidence of NAFLD. Median index hospital-free days for patients with NAFLD were non-inferior to those without (16 days, IQR 10.5-19.5 versus 12 days, IQR 0-18.0, p=0.03). Regarding secondary outcomes, both index hospitalisation and 1-year outcomes were non-inferior between patients with NAFLD and those with normal liver architecture. This study demonstrates that mild-moderate severity NAFLD may not be a contraindication to lung transplantation.

Alemtuzumab as a Therapy for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients With Short Telomeres.

Alemtuzumab, a monoclonal antibody targeting CD52 that causes lymphocyte apoptosis, is a form of advanced immunosuppression that is currently used as a therapy for refractory acute cellular rejection and chronic lung allograft dysfunction in lung transplant recipients (1-3). Side effects of alemtuzumab include bone marrow suppression, infection, and malignancy. Whether alemtuzumab can be safely used in allograft recipients that have an increased propensity for bone marrow suppression due to telomeropathies is unknown. In a retrospective case series, we report outcomes associated with alemtuzumab in three lung allograft recipients with short telomere lengths, comparing endpoints such as leukopenia, transfusion needs, infection, hospitalization and survival to those of 17 patients without known telomeropathies that received alemtuzumab. We show that the use of alemtuzumab in lung transplant recipients with short telomeres is safe, though is associated with an increased incidence of neutropenia, thrombocytopenia and anemia requiring packed red blood cell transfusions. Alemtuzumab appears to be an acceptable advanced immunosuppressive therapy in patients with telomeropathies, though given the design and scope of this study, the actual clinical effect needs further evaluation in larger trials.

Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival.

Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease. This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival. Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1-3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03-1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01-1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05-15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27-7.01, p=0.70). Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease.

Hyaluronan and LYVE-1 and allograft function in lung transplantation recipients.

Hyaluronan (HA) is associated with innate immune response activation and may be a marker of allograft dysfunction in lung transplant recipients. This was a prospective, single center study comparing levels of bronchioalveolar lavage (BAL) and serum HA and the HA immobilizer LYVE-1 in lung transplant recipients with and without acute cellular rejection (ACR). Chronic lung allograft dysfunction (CLAD)-free survival was also evaluated based on HA and LYVE-1 levels. 78 recipients were enrolled with a total of 115 diagnostic biopsies and 1.5 years of median follow-up. Serum HA was correlated with BAL HA (r = 0.25, p = 0.01) and with serum LYVE-1 (r = 0.32, p = 0.002). There was significant variation in HA and LYVE-1 over time, regardless of ACR status. Levels of serum HA (median 74.7 vs 82.7, p = 0.69), BAL HA (median 149.4 vs 134.5, p = 0.39), and LYVE-1 (mean 190.2 vs 183.8, p = 0.72) were not associated with ACR. CLAD-free survival was not different in recipients with any episode of elevated serum HA (HR = 1.5, 95% CI = 0.3-7.7, p = 0.61) or BAL HA (HR = 0.94, 95% CI = 0.2-3.6, p = 0.93). These results did not differ when stratified by bilateral transplant status. In this small cohort, serum HA, BAL HA, and LYVE-1 levels are not associated with ACR or CLAD-free survival in lung transplant recipients.