Lung Transplantation for Coronavirus Disease-2019 Patients and Coronavirus Disease-2019 in Lung Transplant Recipients.

Lung transplant is a life-saving treatment for carefully selected patients with respiratory failure related to the infection with coronavirus disease-2019. Despite a complex pretransplant medical course, the posttransplant outcomes are excellent when performed by experienced centers.

Humoral and T-cell response 12 months after the first BNT162b2 vaccination in solid organ transplant recipients and controls: Kinetics, associated factors, and role of SARS-CoV-2 infection.

Introduction: We investigated humoral and T-cell responses within 12 months after first BNT162b2 vaccine in solid organ transplant (SOT) recipients and controls who had received at least three vaccine doses. Furthermore, we compared the immune response in participants with and without previous SARS-CoV-2 infection. Methods: We included adult liver, lung, and kidney transplant recipients, and controls were selected from a parallel cohort of healthcare workers. Results: At 12th-month, the IgG geometric mean concentrations (GMCs) (P<0.001), IgA GMCs (P=0.003), and median IFN-γ (P<0.001) were lower in SOT recipients than in controls. However, in SOT recipients and controls with previous infection, the neutralizing index was 99%, and the IgG, and IgA responses were comparable. After adjustment, female-sex (aOR: 3.6, P<0.009), kidney (aOR: 7.0, P= 0.008) or lung transplantation (aOR: 7.5, P= 0.014), and use of mycophenolate (aOR: 5.2, P=0.03) were associated with low IgG non response. Age (OR:1.4, P=0.038), time from transplantation to first vaccine (OR: 0.45, P<0.035), and previous SARS-CoV-2 infection (OR: 0.14, P<0.001), were associated with low IgA non response. Diabetes (OR:2.4, P=0.044) was associated with T-cell non response. Conclusion: In conclusion, humoral and T-cell responses were inferior in SOT recipients without previous SARS-CoV-2 infection but comparable to controls in SOT recipients with previous infection.

Lung Transplantation for COVID-19 Pulmonary Sequelae.

BACKGROUND: The role of lung transplantation for coronavirus disease 2019 (COVID-19)-related lung failure is evolving as the pandemic persists. METHODS: From January 2021 to April 2022, 20 patients (median age 62 y; range 31-77) underwent lung transplantation for COVID-related lung failure at our institution. We reviewed their clinical and intraoperative characteristics and early outcomes including postoperative complications. RESULTS: Eleven patients (55%) had chronic lung disease when they contracted COVID-19. All 20 patients required hospitalization for antivirus treatment. Median lung allocation score was 74.7 (33.1-94.0). Thirteen patients (65%) underwent single-lung transplants, and 7 patients (35%) underwent double-lung transplants. Concomitant coronary artery bypass graft surgery was performed in 2 (10%) patients because of severe coronary artery disease. Postoperatively, venovenous extracorporeal membrane oxygenation was needed in 3 patients (15%) because of severe primary graft dysfunction; all were eventually weaned. Ten patients (50%) experienced deep venous thrombosis, and 1 eventually developed a major pulmonary embolus. The median intensive care unit stay and hospital stays were 6.5 d (3-44) and 18 d (7-77), respectively. During a median follow-up of 201 d (47-418), we experienced 1 late mortality due to COVID-19-related myocarditis. Among the 13 patients with single-lung transplant, 5 demonstrated improvement in their native lungs. CONCLUSIONS: Lung transplantation yielded favorable early outcomes in a heterogeneous patient cohort that included older patients, obese patients, and patients with coronary artery disease or preexisting chronic lung disease. Our data also shed light on the transforming role of lung transplantation for the pulmonary sequelae of a complex multisystem COVID-19 disorder.

Immunogenicity and Safety of the BNT162b2 COVID-19 Vaccine in Patients with Cystic Fibrosis with or without Lung Transplantation.

Cystic fibrosis (CF) is characterized by a progressive decline in lung function, which may be further impaired by viral infections. CF is therefore considered a comorbidity of coronavirus disease 2019 (COVID-19), and SARS-CoV-2 vaccine prioritization has been proposed for patients with (pw)CF. Poor outcomes have been reported in lung transplant recipients (LTR) after SARS-CoV-2 infections. LTR have also displayed poor immunization against SARS-CoV-2 after mRNA-based BNT162b2 vaccination, especially in those undergoing immunosuppressive treatment, mostly those receiving mycophenolate mofetil (MMF) therapy. We aimed to determine here the immunogenicity and safety of the BNT162b2 vaccine in our cohort of 260 pwCF, including 18 LTR. Serum levels of neutralizing anti-SARS-CoV-2 IgG and IgA antibodies were quantified after the administration of two doses. PwCF displayed a vaccine-induced IgG and IgA antiviral response comparable with that seen in the general population. We also observed that the immunogenicity of the BNT162b2 vaccine was significantly impaired in the LTR subcohort, especially in patients undergoing MMF therapy. The BNT162b2 vaccine also caused minor adverse events as in the general population, mostly after administration of the second dose. Overall, our results justify the use of the BNT162b2 vaccine in pwCF and highlight the importance of a longitudinal assessment of the anti-SARS-CoV-2 IgG and IgA neutralizing antibody response to COVID-19 vaccination.

Donor Lung Evaluation and Lung Transplantation in the COVID-19 Era.

OBJECTIVES: The COVID-19 pandemic, which emerged in late 2019, adversely affected all solid-organ transplant processes. Here we share the donor presentations evaluated in a lung transplant center during the COVID-19 pandemic,the measures taken at every stage of transplant management, and the outcomes of our transplants. MATERIALS AND METHODS: Data from 15 lung donors selected by the national coordination center presented to our lung transplant center as of March 11, 2020, when the first COVID-19 case was reported in Turkey, and data of 5 lung transplant cases in this period were retrospectively analyzed. All donors were examined in detail for COVID-19 disease. Procurement processes for accepted donors,transplant surgeries of recipients, and postoperative follow-up and care processes of recipients were carried out with the least number of personnel, but all with appropriate personal protective equipment. RESULTS: There were 15 donor organs procured by our center during a 9-month period coincident with the COVID-19 pandemic. The number of donor presentations to our center between the same dates in the previous year was 78. Five of the 15 donors were accepted, and of those accepted, 4 were male and 1 was female. There was no statistically significant difference between the accepted and rejected donors in terms of the ratio of Pao2 to fraction of inspired oxygen, age, duration of endotracheal intubation (days), and smoking (pack-years). All SARS-CoV-2 reverse transcription-polymerase chain reaction tests performed on bronchoalveolar lavage samples and nasopharyngeal, conjunctival, and rectal samples collected from the recipients during the follow-up period were negative. No pathological finding suggestive of COVID-19 infection was noted in the radiological evaluations. CONCLUSIONS: Lung transplant can be successfully managed during the COVID-19 pandemic period, despite the high risk of infection.The major obstacle to the continuity of lung transplantin this period was the limited number of donors.

COVID-19 in Lung Transplant Recipients.

BACKGROUND: A concern about the susceptibility of immunocompromised patients to the worldwide pandemic of coronavirus disease 2019 (COVID-19) has been raised. We aimed at describing COVID-19 infections in the French cohort of lung transplant (LT) patients. METHODS: Multicenter nationwide cohort study of all LT recipients with COVID-19 diagnosed from March 1 to May 19, 2020. Recipient main characteristics and their management were retrieved. Hospitalization characteristics, occurrence of complications and survival were analyzed. RESULTS: Thirty-five LT patients with a COVID-19 infection were included. Median age was 50.4 (40.6-62.9) years, 16 (45.7%) were female, and 80% were double-LT recipients. Infection was community-acquired in 25 (71.4%). Thirty-one (88.6%) required hospitalization, including 13 (41.9%) in the intensive care unit. The main symptoms of COVID-19 were fever, cough, and diarrhea, present in 71.4%, 54.3%, and 31.4% of cases, respectively. Extension of pneumonia on chest CT was moderate to severe in 51.4% of cases. Among the 13 critically ill patients, 7 (53.9%) received invasive mechanical ventilation. Thrombotic events occurred in 4 patients. Overall survival rate was 85.7% after a median follow-up of 50 days (41.0-56.5). Four of 5 nonsurvivors had had bronchial complications or intensification of immunosuppression in the previous weeks. On univariate analysis, overweight was significantly associated with risk of death (odds ratio, 16.0; 95% confidence interval, 1.5-170.6; P = 0.02). CONCLUSIONS: For the 35 LT recipients with COVID-19, the presentation was severe, requiring hospitalization in most cases, with a survival rate of 85.7%.

Initiation of extracorporeal photopheresis in lung transplant patients with mild to moderate refractory BOS: A single-center real-life experience.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the main limitation to long-term survival following lung transplantation. Several studies generated promising results regarding the efficacy of extracorporeal photopheresis (ECP) in BOS management. We aimed to compare FEV1 evolution in ECP-treated versus non-ECP treated patients among BOS recipients. METHODS: Overall, 25 BOS patients were included after receiving optimized treatment. Data were collected retrospectively. Twelve patients with moderate and refractory BOS received ECP treatment. RESULTS: Among non-ECP treated control patients (n = 13), six experienced persistent decline without undergoing ECP for various reasons. ECP stabilized pre-ECP lung function during the subsequent 6 to 24 months (repeated measures one-way Anova, p = 0.002), without any significant impact observed by either FEV1 decline speed prior to ECP or time between BOS diagnosis and ECP onset. ECP-treated patients displayed a similar risk of an additional permanent 20% or higher drop in FEV1 after BOS onset compared to controls, but a lower risk compared to control decliners (p = 0.05). ECP quickly stabilized FEV1 decline in refractory BOS patients compared to non-treated decliners. CONCLUSIONS: We confirmed that this therapeutic option against refractory BOS can be managed in a medium-size LTx center, with a satisfactory efficacy and an acceptable tolerance.

Critical Care of the Lung Transplant Patient.

Lung transplantation is a therapeutic option for end-stage lung disease that improves survival and quality of life. Prelung transplant admission to the intensive care unit (ICU) for bridge to transplant with mechanical ventilation and extracorporeal membrane oxygenation (ECMO) is common. Primary graft dysfunction is an important immediate complication of lung transplantation with short- and long-term morbidity and mortality. Later transplant-related causes of respiratory failure necessitating ICU admission include acute cellular rejection, atypical infections, and chronic lung allograft dysfunction. Lung transplantation for COVID-19-related ARDS is increasingly common..

A pilot randomized controlled trial of de novo belatacept-based immunosuppression following anti-thymocyte globulin induction in lung transplantation.

The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.

Gamma-glutamyltransferase is a strong predictor of secondary sclerosing cholangitis after lung transplantation for COVID-19 ARDS.

BACKGROUND: Lung transplantation (LTx) can be considered for selected patients suffering from COVID-19 acute respiratory distress syndrome (ARDS). Secondary sclerosing cholangitis in critically ill (SSC-CIP) patients has been described as a late complication in COVID-19 ARDS survivors, however, rates of SSC-CIP after LTx and factors predicting this detrimental sequela are unknown. METHODS: This retrospective analysis included all LTx performed for post-COVID ARDS at 8 European LTx centers between May 2020 and January 2022. Clinical risk factors for SSC-CIP were analyzed over time. Prediction of SSC-CIP was assessed by ROC-analysis. RESULTS: A total of 40 patients were included in the analysis. Fifteen patients (37.5%) developed SSC-CIP. GGT at the time of listing was significantly higher in patients who developed SSC-CIP (median 661 (IQR 324-871) vs 186 (109-346); p = 0.001). Moreover, higher peak values for GGT (585 vs 128.4; p < 0.001) and ALP (325 vs 160.2; p = 0.015) were found in the 'SSC' group during the waiting period. Both, GGT at the time of listing and peak GGT during the waiting time, could predict SSC-CIP with an AUC of 0.797 (95% CI: 0.647-0.947) and 0.851 (95% CI: 0.707-0.995). Survival of 'SSC' patients was severely impaired compared to 'no SSC' patients (1-year: 46.7% vs 90.2%, log-rank p = 0.004). CONCLUSIONS: SSC-CIP is a severe late complication after LTx for COVID-19 ARDS leading to significant morbidity and mortality. GGT appears to be a sensitive parameter able to predict SSC-CIP even at the time of listing.

Heterotopic lung transplant: a feasible approach to compensate for organ shortages.

Lung transplants are still limited by the shortage of suitable donor lungs, especially during the coronavirus disease 2019 pandemic. A heterotopic lung transplant (HLTx), as a flexible surgical procedure, can maximize the potential of donor lungs in an emergency, but its widespread use is hindered by difficulties in anastomosis and paucity of outcome data. We performed a retrospective review of 4 patients, each of whom received an HLTxs over 1 year, including 1 left-to-right single HLTx, 2 right-to-left single HLTxs and 1 lobar HLTx (right upper lobe-to-left). The median recipient age was 58.5 years (46-68); 3 patients were male. The postoperative hospital stay was 33 days (30-42). One recipient lived for 10 years and died of bronchiolitis obliterans syndrome; the others were alive with no major morbidity at 12 to 31 months after the operation with a 1-year survival of 100%. The follow-up chest images showed that transplanted lungs could be inflated well and adapted morphologically to fill the thoracic cavity in the short and long term. This study demonstrates that an HLTx is a feasible alternative to a conventional lung transplant in emergency cases and could be considered in selected patients at advanced medical centres.

Lung Transplant as a Treatment for Patients with End-Stage Respiratory Failure Due to COVID-19.

BACKGROUND: COVID-19 may lead to development of irreversible acute respiratory distress syndrome. Some patients sustain severe respiratory failure after infection subsides. They may require lung transplant as a last resort treatment. The aim of the study is to assess the effect and feasibility of lung transplant as a treatment for patients with severe irreversible respiratory failure due to COVID-19. METHODS: This retrospective study pertains to analysis of 119 patients in critical condition who were referred to Lung Transplant Ward (Zabrze, Poland). between July 2020 and June 2021 after developing respiratory failure requiring extracorporeal membrane oxygenation, invasive ventilation, or both, as well as a few patients on high-flow oxygen therapy. Inclusion criteria for referral were confirmed lack of viral disease and exhaustion of other therapeutic options. RESULTS: Of the referred patients, 21.84% were disqualified from such treatment owing to existing contraindications. Among the suitable patients, 75.8% died without transplant. Among all patients who were qualified for lung transplant, only 9 patients became double lung transplant recipients. Intraoperative mortality for this procedure was 33%. Four patients were discharged after the procedure and are currently self-reliant with full respiratory capacity. CONCLUSIONS: Patients with severe irreversible respiratory failure after COVID-19 present significantly high mortality without lung transplant. This procedure may present satisfactory results but must be performed in a timely fashion owing to critical condition and scarcity of lung donors, only aggravated around the time of peak infection waves.

Clinico-Radiological-Pathologic Profile and Outcomes of Lung Transplant in Post-COVID-19 Phenotype: A Single Center Experience.

BACKGROUND: Lung transplantation (LTx) has come as hope for select patients with post-COVID acute respiratory distress syndrome (ARDS). It has a different phenotype with unique challenges. We aimed to bring out our experience with and outcomes of LTx for post-COVID ARDS. METHODS: This study is retrospective case series from a single center in India. All the patients with post-COVID end stage lung disease (ESLD) who underwent bilateral LTx between 1st May 2020 and 30th August 2021 were included. LTx was performed following no improvement with optimal medical management with adequate time provided for recovery. Information relating to demographics, comorbidities, pretransplant status, perioperative parameters, gross and histopathological findings of explanted lungs, posttransplant morbidity, and mortality were analyzed. RESULTS: This study included 23 patients. The median age of the patients in this study was 42 years and 20 participants were men (87%). The mean duration of intensive care unit stay was 15.83 ± 6.61 days. Mortality was observed among 8 participants (34.78%). Mean survival time was 34.54 weeks. Among the 8 patients who expired, the cause of death was sepsis for 6 patients (75.0%), neurologic cerebrovascular accident for 1 patient (12.5%), and cytomegalovirus for 1 patient (12.5%). All the deaths were reported in primary graft dysfunction grade 2 & 3 category. No rejections were observed on first and third month surveillance biopsies. CONCLUSIONS: LTx is the definitive option for survival in select patients with severe post-COVID-19-associated ESLD. This study brings out various challenges involved in such phenotypes and also observations in postoperative recovery.

Post-COVID-19 Lung Transplantation Italian Pivotal Protocol: Some Ethical Considerations.

SARS­CoV­2 mostly affects the respiratory system with clinical patterns ranging from the common cold to fatal pneumonia. During the first wave of the COVID-19 pandemic, owing to the high number of patients who were infected with SARS­CoV­2 and subsequently recovered, it has been shown that some patients with post-COVID-19 terminal respiratory failure need lung transplantation for survival. There is increasing evidence coming from worldwide observations that this procedure can be performed successfully in post-COVID-19 patients. However, owing to the scarcity of organs, there is a need to define the safety and efficacy of lung transplant for post-COVID-19 patients as compared to patients waiting for a lung transplant for other pre-existing conditions, in order to ensure that sound ethical criteria are applied in organ allocation. The Milan's Policlinic Lung Transplant Surgery Unit, with the revision of the National Second Opinion for Infectious Diseases and the contribution of the Italian Lung Transplant Centres and the Italian National Transplant Centre, set up a pivotal observational protocol for the lung transplant of patients infected and successively turned negative for SARS­CoV­2, albeit with lung consequences such as acute respiratory distress syndrome or some chronic interstitial lung disease. The protocol was revised and approved by the Italian National Institute of Health Ethics Committee. Description of the protocol and some ethical considerations are reported in this article.

Sars-CoV-2 Infection After Lung Transplantation: Is There Professional Liability?

Abstract: For the first time in the literature, a case of Sars-Cov-2 infection after lung Transplantation has been described. This case, particularly rare, brought attention on the in-depth screening for Sars-CoV-2 on lung donor. In addition to infectious problems, it is important to focus attention on medico-legal issues related to this case. In fact, from the point of view of professional responsibility, in theory, there could be criteria for identifying professional responsibility. The author analyzes the possible presence of medical liability in this specific case.

Interferon-stimulated and metallothionein-expressing macrophages are associated with acute and chronic allograft dysfunction after lung transplantation.

BACKGROUND: Lung transplant recipients experience episodes of immune-mediated acute lung allograft dysfunction (ALAD). ALAD episodes are a risk factor for chronic lung allograft dysfunction (CLAD), the major cause of death after lung transplantation. Our objective was to determine key cellular elements in dysfunctional lung allografts, with a focus on macrophages. METHODS: We have applied single-cell RNA sequencing (scRNAseq) to bronchoalveolar lavage cells from stable and ALAD patients and to cells from explanted CLAD lung tissue. RESULTS: We identified 2 alveolar macrophage (AM) subsets uniquely represented in ALAD. Using pathway analysis and differentially expressed genes, we annotated these as pro-inflammatory interferon-stimulated gene (ISG) and metallothionein-mediated inflammatory (MT) AMs. Functional analysis of an independent set of AMs in vitro revealed that ALAD AMs exhibited a higher expression of CXCL10, a marker of ISG AMs, and increased secretion of pro-inflammatory cytokines compared to AMs from stable patients. Using publicly available bronchoalveolar lavage scRNAseq datasets, we found that ISG and MT AMs are associated with more severe inflammation in COVID-19 patients. Analysis of cells from 4 explanted CLAD lungs revealed similar macrophage populations. Donor and recipient cells were identified using expressed single nucleotide variations. We demonstrated contributions of donor and recipient cells to all AM subsets early post-transplant, with loss of donor-derived cells over time. CONCLUSIONS: Our data reveal extensive heterogeneity among lung macrophages after lung transplantation and indicates that specific sub-populations may be associated with allograft dysfunction, raising the possibility that these cells may represent important therapeutic targets.