Induction immunosuppression strategies and outcomes post-lung transplant: A single center experience.

PURPOSE: Currently 80% of lung transplant centers use induction immunosuppression. However, there is a lack of standardization of induction protocols within and across lung transplant centers. This study explores the association of two different induction immunosuppression strategies used at our center [single dose rabbit antithymocyte globulin (rATG) vs. alemtuzumab] compared to no induction with immunologic and clinical outcomes after lung transplantation. METHODS: A total of 174 consecutive lung transplant recipients (LTR) between 2016 and 2019 were included in the analysis. Twenty nine LTR (16.7%) received no induction, 22 LTR (12.6%) received alemtuzumab, 123 LTR (70.6%) received a single dose of rATG; 1.5 mg/kg within 24 h of transplant for induction. All LTR had a negative flow cytometry crossmatch on the day of the transplant. All LTR were assessed for de novo HLA donor-specific antibodies (DSA) development and clinical outcomes, including the risk of acute cellular rejection (ACR), antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), and overall survival post-transplant. RESULTS: The median lung allocation score (LAS) was significantly higher in LTR that did not receive Induction immunosuppression (76; range = 35.3-94.3) compared to induction with rATG (41.6; range = 31.6-91) and alemtuzumab (51; range = 33.1-88.2) (p < 0.001). De novo HLA DSA were detected in 50/174 (28.7%) LTR within 12 months post-transplant. They were detected in 13/29 (44.8%) LTR without induction immunosuppression compared to 28/123 (22.8%) and 9/22 (40.9%) LTR with rATG and alemtuzumab induction, respectively (p = 0.02). The percent freedom from ACR rates between LTR who received alemtuzumab induction was significantly higher compared to LTR who received rATG or no induction at 1 (p = 0.02), 2 (p = 0.01) and 3 (p = 0.05) years post-transplant. In addition, the overall 1-year survival rates were significantly higher in LTR who received rATG or alemtuzumab induction compared to LTR without induction immunosuppression (p = 0.02). CONCLUSION: Induction immunosuppression strategies utilizing rATG or Alemtuzumab have unique and contrasting benefits in LTR. Combination of alemtuzumab induction and a lower dose of maintenance immunosuppression may reduce the incidence of ACR in LTR. Single-dose rATG or alemtuzumab induction immunosuppression may also improve the 1 year overall LTR survival compared to no induction.

Chronic lung allograft dysfunction is associated with an increased number of non-HLA antibodies.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the major cause of adverse outcomes in lung transplant recipients. Multiple factors, such as infection, alloimmunity, and autoimmunity, may lead to CLAD. Here, we aim to examine the role of non-human leukocytes antigen (HLA) antibodies in CLAD in a large retrospective cohort. METHODS: We analyzed non-HLA antibodies in the pre- and post-transplant sera of 226 (100 CLAD, 126 stable) lung transplant recipients from 5 centers, and we used a separate cohort to confirm our findings. RESULTS: A panel of 18 non-HLA antibodies was selected for analysis based on their significantly higher positive rates in CLAD vs stable groups. The panel-18 non-HLA antibodies (n > 3) may be positive pre- or post-transplant; the risk for CLAD is higher in the latter. The presence of both non-HLA antibody and HLA donor-specific antibody (DSA) was associated with an augmented risk of CLAD (HR=25.09 [5.52-14.04], p < 0.001), which was higher than that for single-positive patients. In the independent confirmatory cohort of 61 (20 CLAD, 41 stable) lung transplant recipients, the risk for CLAD remained elevated in double-positive patients (HR=10.67 [0.98-115.68], p = 0.052). After adjusting for nonstandard immunosuppression, patients with double-positive DSA/Non-HLA antibodies had an elevated risk for graft loss (HR=2.53 [1.29-4.96], p = 0.007). CONCLUSIONS: Circulating non-HLA antibodies (n > 3) were independently associated with a higher risk for CLAD. Furthermore, when non-HLA antibodies and DSA were detected concomitantly, the risk for CLAD and graft loss was significantly increased. These results show that humoral immunity to HLA and non-HLA antigens may contribute to CLAD development.

Percutaneous Transseptal Extracorporeal Membrane Oxygenation to Rescue a Failing Right Ventricle in an Animal Model.

OBJECTIVE: We tested the feasibility and effectiveness of a percutaneous atrial transseptal extracorporeal membrane oxygenation (ECMO) cannulation strategy in a right ventricular failure (RVF) model. METHODS: We performed 4 nonsurvival porcine experiments. Percutaneous transseptal access was achieved using a steerable introducer. For guidance, we used fluoroscopy, transesophageal echocardiogram (TEE), and intracardiac echocardiography (ICE). A ProtekDuo rapid deployment cannula (LivaNova, London, UK) was advanced across the septum into the left atrium by 2 to 3 cm. Pulmonary hypertension (PH) was induced by partially clamping the pulmonary artery. ECMO flow was cycled from high (2 to 3 L/min) to low (0.2 to 0.3 L/min) over 2 to 3 hours. RESULTS: Transseptal access using TEE and fluoroscopy was successful in 1 animal and unsuccessful in 1 animal. ICE provided optimal visualization for the remaining 2 animals. Mean arterial pressure (MAP) was associated immediately and consistently with high versus low ECMO flow rate (mean difference: 29 ± 3.1 mm Hg, P = 0.004) but was not restored to baseline values. RV pressure values were dynamic. Given time to equilibrate, mean RV pressure was restored to a baseline level. CONCLUSIONS: Percutaneous right atrium to left atrium transseptal cannulation relieved PH-RVF. MAP was restored to a viable level, and mean RV pressure was restored to a baseline level. Transseptal ECMO shows promise as a cannulation strategy to bridge patients with PH-RVF to lung transplant.

Non-invasive detection of cardiac allograft rejection among heart transplant recipients using an electrocardiogram based deep learning model.

Aims: Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG). Methods and results: Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set (n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study (n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity. Conclusion: An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function.

Outcomes of Lung Transplantation in Patients With Combined Pulmonary Fibrosis and Emphysema: A Single-Center Experience.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a distinct clinical entity that can progress to end-stage lung disease. Patients with CPFE may develop pulmonary hypertension and face a predicted 1-year mortality of 60%. Lung transplantation is the only curative therapeutic option for CPFE. This report describes our experience after lung transplantation in patients with CPFE. METHODS: This retrospective, single-center study describes short- and long-term outcomes for adult patients who underwent lung transplant for CPFE. RESULTS: The study included 19 patients with explant pathology-proven diagnosis of CPFE. The patients were transplanted between July 2005 and December 2018. Sixteen recipients (84%) had pulmonary hypertension before transplant. Of the 19 patients, 7 (37%) had primary graft dysfunction at 72 hours post-transplant. 1-, 3-, and 5-year freedom from bronchiolitis obliterans syndrome was 100%, 91% (95% CI, 75%-100%), and 82% (95% CI, 62%-100%), respectively. One-, 3-, and 5-year survival was 94% (95% CI, 84%-100%), 82% (95% CI, 65%-100%), and 74% (95% CI, 54%-100%), respectively. CONCLUSION: Our experience demonstrates the safety and feasibility of lung transplant for patients with CPFE. Significant morbidity and mortality without lung transplant coupled with favorable post-transplant outcomes merit prioritization of CPFE in the Lung Allocation Score algorithm for lung transplant candidacy.

Initial experience and outcomes with a hybrid extracorporeal membrane oxygenation and cardiopulmonary bypass circuit for lung transplantation.

Background: The utilization of extracorporeal life support (ECLS) for intraoperative support during lung transplantation has increased over the past decade. Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has recently emerged as the preferred modality over cardiopulmonary bypass (CPB), many centers continue to use both forms of ECLS during lung transplantation. Our novel hybrid VA-ECMO/CPB circuit allows for seamless transition from VA-ECMO to CPB at a significant cost savings compared to a standalone VA-ECMO circuit. This study describes our initial experience and outcomes in the first 100 bilateral lung transplantations using this novel hybrid VA-ECMO/CPB circuit. Methods: Medical records from September 2017 to May 2021 of the first 100 consecutive patients undergoing bilateral lung transplantation with intraoperative hybrid VA-ECMO support were examined retrospectively. We excluded patients with single lung transplants, retransplantations, preoperative ECLS bridging, and veno-venous (VV) ECMO and those supported with CPB only. Perioperative recipient, anesthetic, perfusion variables, and outcomes were assessed. Results: Of the 100 patients supported with VA-ECMO, 19 were converted intraoperatively to CPB. Right ventricular dysfunction was seen in 37% of patients, and the median mean pulmonary artery pressure was 28 mm Hg. No oxygenator clotting was observed with a median heparin dose of 13,000 units in the VA-ECMO group. Primary graft dysfunction grade 3 at 72 hours was observed in 10.1% of all patients and observed 1-year mortality was 4%. Conclusions: The use of a hybrid VA-ECMO/CPB circuit in our institution allows for rapid conversion to CPB with acceptable outcomes across a diverse recipient group at a significantly reduced cost compared to standalone VA-ECMO circuits.

Feasibility and Safety of Low-Dose Mesenchymal Stem Cell Infusion in Lung Transplant Recipients.

BACKGROUND: We have previously shown bone marrow-derived mesenchymal stem cells (MSCs) may shift immune responses toward anti-inflammatory pathways and stabilize the course of obstructive chronic lung allograft syndrome (o-CLAD) after lung transplantation. In this study, we measured the response of lower dose infusions. METHODS: We infused low-dose MSCs intravenously in 13 patients who had developed moderate-to-severe o-CLAD. Three had previously received an infusion of MSCs from a different donor and were re-dosed at 1 × 106 MSC/kg, while 5 received a first dose at 1 × 106 MSC/kg and five received an even lower dose at 0.5 × 106 MSC/kg. We recorded pulmonary function tests before and after infusion, and patients were followed clinically for 12 months. RESULTS: Infusions were well tolerated, and no significant adverse events were recorded in the first 30 days. There was significant decline (mean ± SD) in forced vital capacity (FVC) (3.49 ± 1.03 vs 3.18 ± 0.94 L, P = .03) and forced expiratory volume in 1 second (FEV1) (2.28 ± 0.86 vs 1.77 ± 0.49 L, P = .04) over the year preceding infusion. FVC (3.18 ± 0.94 vs 3.46 ± 0.99 L, P = .53) and FEV1 was not significantly changed (1.77 ± 0.49 vs 1.88 ± 0.75, P = .72) when comparing values immediately prior to infusion to those obtained 1 year after infusion, indicating a possible stabilizing effect on lung function decline due to o-CLAD. CONCLUSION: Intravenous infusions of bone marrow-derived MSCs are well tolerated in lung transplant recipients with moderate-to-severe CLAD. Low-dose MSCs appear to slow progression of CLAD in some patients.

Colistin neurotoxicity mimicking Guillain-Barré syndrome in a patient with cystic fibrosis: case report and review.

Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy, which is characterized by areflexia and ascending paresthesia which can progress to a respiratory failure. Certain conditions, such as vasculitis and heavy metal and drug toxicity, may have misleadingly similar clinical presentation to GBS. We describe a case of a patient with cystic fibrosis and intravenous colistin-induced neurotoxicity mimicking GBS. The patient had used inhaled colistin on five occasions with no adverse effects, however, developed symptoms on the second day of intravenous treatment. Overlapping findings between immune-mediated polyneuropathy and drug-induced neurotoxicity include limb paresthesia and decreased reflexes. Perioral tingling, however, is a common presentation of colistin-induced neurotoxicity, and therefore, is an important differentiating factor. Early diagnosis prevents further neurologic decline, extensive unnecessary workup and potentially harmful incorrect management.

Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibody detection in lung transplant recipients: A single-center experience.

PURPOSE: Induction immunosuppression has improved the long-term outcomes after lung transplant. This is the first report exploring the association of induction immunosuppression with the development of de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) in lung transplant recipients (LTR). METHODS: Sixty-seven consecutive primary LTR were followed for 3 years posttransplant. A total of 41/67 (61%) LTR-received induction immunosuppression using a single dose of rabbit Antithymocyte Globulin (rATG; 1.5 mg/kg) within 24 h of transplant. All recipients had a negative flow cytometry crossmatch on the day of transplant. Serum samples at 1, 3, 6, and 12 months posttransplant were assessed for the presence of de novo HLA DSA. RESULTS: De novo HLA DSA were detected in 22/67 (32.8%) LTR within 1-year posttransplant. Of these, 9/41 (21.9%) occurred in the induction therapy group and 13/26 (50%) in the noninduction group. Class II DSA were detected in 3/41 (7.3%) LTR who received induction compared to 9/26 (34.6%) LTR without induction immunosuppression (p = .005). Differences in overall survival or freedom from chronic lung allograft dysfunction rates between the two groups were not statistically significant. CONCLUSION: Induction immunosuppression utilizing a modified regimen of single-dose rATG is associated with a significant reduction in de novo DSA production in LTR.

Negative pressure ventilation as a bridge to lung transplant.

Recent years have witnessed evolution of lung allocation strategies to prioritize sicker recipients. In the pre-transplant period, this has translated into increased utilization of invasive extracorporeal or mechanical ventilatory support as a bridge to lung transplantation. The morbidity associated with these strategies warrants consideration to less invasive respiratory support modalities. Herein, we present a case highlighting successful bridge to lung transplantation with a relatively non-invasive negative pressure ventilator.

Refractory chylous effusions in lymphangioleiomyomatosis patient post lung transplant.

Lymphangioleiomyomatosis is a rare systemic disorder of unknown etiology that affects young women almost exclusively. Chylous effusions are known to be associated with lymphangioleiomyomatosis and may be difficult to treat. We present the case of a 37-year-old female who received bilateral lung transplantation for lymphangioleiomyomatosis complicated by refractory chylothorax and chylous ascites, ultimately controlled through repeated, open surgical procedures and percutaneous lymphatic embolization interventions. The combined surgical and interventional radiological approach, while not novel in their own right, suggests that a multi-modal interventional approach may be required in refractory cases.

Successful lung transplantation from a donor with lung and ovarian masses.

Declining a donor when there is a reasonable possibility that the abnormality on chest imaging could be benign carries the risk of losing out on potentially usable lungs in an already parched landscape of donor organ availability. Cautiously aggressive attitudes to acceptance of borderline donors can help bridge the significant discrepancy that exists between the demand and availability of donor organs. Herein, we present a case highlighting successful bilateral lung transplantation from a relatively imperfect donor.

The Use of a Novel Endotracheal Tube and Airway Management System to Prevent Complications in Lung Transplantation.

A key component of the perioperative management of lung transplant recipients is the avoidance of airway and pulmonary complications in the immediate postoperative period. The AnapnoGuard™ AG100s (Hospitech Respiration Ltd, Kfar Saba, Israel), a novel endotracheal tube and ventilation management system, holds the potential to assist the care team in attenuating complications related to excessive cuff pressure, subglottic secretions, and endobronchial intubation. In this report, we describe the successful use of the AnapnoGuard™ AG100s system in the postoperative management of a lung transplant recipient.

Interstitial lung disease in patients with mixed connective tissue disease: pilot study on predictors of lung involvement.

OBJECTIVES: Mixed connective tissue disease (MCTD) is an immune-mediated systemic disorder characterised by serum autoantibodies against U1-ribonucleoprotein and diverse multisystemic clinical manifestations. Approximately 50% of patients with MCTD develop a radiologic pattern of interstitial lung disease (ILD). Our single centre, cross-sectional study sought to identify clinical and serologic associations of ILD in patients with MCTD which may serve as predictors of lung disease and prognosis. METHODS: Patients who met validated criteria for diagnosis of MCTD were included in the study, and were further differentiated into study and control groups based on presence or absence of ILD. RESULTS: Multivariate logistic regression showed an association of two clinical variables: dysphagia with an R2 value of 0.33 (p-value <0.001) and Raynaud's phenomenon with R2 value of 0.28 (p-value <0.001). CONCLUSIONS: An association of dysphagia with the development of ILD in our study is in harmony with the existing literature. There are primarily case reports, suggesting an association of Raynaud's phenomenon with development of ILD in patients with undifferentiated CTD. To our knowledge, this is the first study highlighting the association of Raynaud's phenomenon with development of ILD in patients with MCTD. The mechanistic aspects of the association between Raynaud's phenomenon and ILD remain unexplored. The association of easily elicited historical and clinical features of MCTD with subtle, but worrisome, pulmonary pathology carries the promise of sensitising the unsuspecting clinician about the entity of ILD in MCTD.

Ghrelin in Critical Illness.

Ghrelin, a recently described peptide, has attracted significant attention in recent years, primarily in the context of its endocrine- and appetite-regulating effects. The versatility of this peptide is manifested in a rapidly expanding body of literature highlighting its nonendocrine functions. This review summarizes the available data on the immunomodulatory as well as the non-immune-mediated effects of ghrelin that form the scientific basis of its role in critical illness.

Pulmonary capillary hemangiomatosis associated with connective tissue disease: a report of 4 cases and review of the literature.

Pulmonary hypertension (PHTN) can be seen in patients with connective tissue disease (CTD). The typical pathology associated with CTD is interstitial fibrosis and hypertensive pulmonary arteriopathy. We describe 4 patients with CTD and PHTN unexpectedly found to have pulmonary capillary hemangiomatosis (PCH) at explant after lung transplantation or autopsy. Pulmonary capillary hemangiomatosis is defined as a proliferation of capillaries in alveolar walls and can clinically cause PHTN. We detail the pathologic findings of PCH, describe the differential diagnosis, and present a review of the literature on the possible association of PCH with CTD. Although PCH may present clinically as PHTN, it is critical to differentiate between the typical CTD-associated interstitial fibrosis with hypertensive pulmonary arteriopathy and PCH because the treatment is different. We provide the largest case series to date and highlight the need for pathologists to have a high level of suspicion for PCH in patients with CTD.