Ten-Year Follow-up Cohort of the Everolimus versus Azathioprine Multi-National Prospective Study Focusing on Intravascular Ultrasound Findings.

BACKGROUND: Long-term clinical outcomes of early intravascular ultrasound (IVUS) findings in a prospective cohort of heart transplantation (HTx) patients have not been evaluated. METHODS: This study included patients from 20 centers across Europe, North and South America among the original cohort of RAD B253 study. Among these patients, 91 had paired IVUS images at baseline and 1-year post-transplant, including 25 in the everolimus 1.5 mg group, 33 in the everolimus 3.0 mg group, and 33 in the azathioprine group. The primary outcome was a composite of cardiovascular death, re-transplantation, myocardial infarction (MI), coronary revascularization, and cardiac allograft vasculopathy (CAV) within a 10-year follow-up period. The secondary outcome was all-cause death, cardiovascular death, re-transplantation, MI, coronary revascularization, and CAV. Donor disease was defined as baseline maximal intimal thickness (MIT) > 0.66 mm and rapid progression was defined as a change in MIT > 0.59 mm at one-year. RESULTS: Donor disease (46 patients) was associated with a higher incidence of primary outcome (HR 4.444, 95% CI 1.946-10.146, p<0.001). Rapid progression (44 patients) was associated with a significantly higher incidence of primary outcome (HR 2.942, 95% CI 1.383-6.260, p=0.005). Higher risk features on IVUS (positive both donor disease and rapid progression) was independently associated with poor clinical outcomes (HR 4.800, 95% CI 1.816-12.684, p=0.002). CONCLUSIONS: An increase in baseline MIT > 0.66 mm and a change in first-year MIT > 0.59 mm measured by IVUS post HTx was associated with poor outcomes up to 10 years. Early IVUS findings can be considered as surrogate endpoints for evaluating long-term outcomes in HTx clinical trials.

Perioperative Risk Factors of Acute Kidney Injury After Heart Transplantation and One-Year Clinical Outcomes: A Retrospective Cohort Study.

OBJECTIVES: This study aimed to identify perioperative risk factors of acute kidney injury after heart transplantation and to evaluate 1-year clinical outcomes. DESIGN: A retrospective single-center cohort study. SETTING: At a university hospital. PARTICIPANTS: All patients who underwent heart transplantation from January 2015 to December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors recorded acute kidney injury after heart transplantation. One-year mortality and renal function also were recorded. Risk factors of acute kidney injury were evaluated using a multivariate logistic regression model. Long-term survival was compared between patients developing acute kidney injury and those who did not, using a log-rank test. Among 209 patients included in this study, 134 patients (64% [95% CI (58; 71)]) developed posttransplantation acute kidney injury. Factors independently associated with acute kidney injury were high body mass index (odds ratio [OR]: 1.18 [1.02-1.38] per kg/m2; p = 0.030), prolonged duration of cold ischemic period (OR: 1.11 [1.01-1.24] per 10 minutes; p = 0.039), and high dose of intraoperative dobutamine support (OR: 1.24 [1.06-1.46] per µg/kg/min; p = 0.008). At 1 year, patients who developed postoperative acute kidney injury had higher mortality rates (20% v 8%, p = 0.015). Among 172 survivors at 1 year, 82 survivors (48%) had worsened their renal function compared with preheart transplantation. CONCLUSIONS: This study highlighted the high incidence of acute kidney injury after heart transplantation and its impact on patient outcomes. Risk factors such as body mass index, prolonged cold ischemic period duration, and level of inotropic support with dobutamine were identified, providing insights for preventive strategies.

Legionnaires Disease in Solid Organ Transplant Recipients: A Decade-Long Nationwide Study in France.

BACKGROUND: Legionnaires disease (LD) is a rare, life-threatening opportunistic bacterial infection that poses a significant risk to patients with impaired cell-mediated immunity such as solid organ transplant recipients. However, the epidemiologic features, clinical presentation, and outcomes of LD in this population are poorly described. RESEARCH QUESTION: What are the clinical manifestations, radiologic presentation, risk factors for severity, treatment, and outcome of LD in solid organ transplant recipients? STUDY DESIGN AND METHODS: In this 10-year multicenter retrospective cohort study in France, where LD notification is mandatory, patients were identified by hospital discharge databases. Diagnosis of LD relied on positive culture findings from any respiratory sample, positive urinary antigen test (UAT) results, positive specific serologic findings, or a combination thereof. Severe LD was defined as admission to the ICU. RESULTS: One hundred one patients from 51 transplantation centers were eligible; 64 patients (63.4%) were kidney transplant recipients. Median time between transplantation and LD was 5.6 years (interquartile range, 1.5-12 years). UAT results were positive in 92% of patients (89/97). Among 31 patients with positive culture findings in respiratory samples, Legionella pneumophila serogroup 1 was identified in 90%. Chest CT imaging showed alveolar consolidation in 98% of patients (54 of 57), ground-glass opacity in 63% of patients (36 of 57), macronodules in 21% of patients (12 of 57), and cavitation in 8.8% of patients (5 of 57). Fifty-seven patients (56%) were hospitalized in the ICU. In multivariate analysis, severe LD was associated with negative UAT findings at presentation (P = .047), lymphopenia (P = .014), respiratory symptoms (P = .010), and pleural effusion (P = .039). The 30-day and 12-month mortality rates were 8% (8 of 101) and 20% (19 of 97), respectively. In multivariate analysis, diabetes mellitus was the only factor associated with 12-month mortality (hazard ratio, 3.2; 95% OR, 1.19-8.64; P = .022). INTERPRETATION: LD is a late and severe complication occurring in solid organ transplant recipients that may present as pulmonary nodules on which diabetes impacts its long-term prognosis.

Long-term outcomes after heart transplantation in adult patients with univentricular versus biventricular congenital heart disease.

OBJECTIVES: Heart transplantation (HT) is the only life-extending therapy in adults with congenital heart disease (CHD) and end-stage heart failure. HT is considered at high risk in complex CHD given the anatomical complexity and past medical history. Little is known about long-term outcomes after HT in these patients. We aimed to evaluate early and long-term outcomes after HT in adult patients with univentricular versus biventricular CHD. METHODS: This multicentre retrospective cohort study included all adult CHD patients who underwent HT between 1988 and 2021 in 3 tertiary centres. Factors associated with early (<30 days) and conditional long-term survival were assessed in the entire cohort. RESULTS: Over a mean follow-up of 10.1 ± 7.8 years, 149 patients were included, of whom 55 (36.9%) had univentricular CHD. Sixty-four patients died during follow-up including 47 deaths before discharge from hospital. In multivariable analysis, univentricular physiology and female recipient gender were independently associated with a higher risk of early mortality (odds ratio 2.99; 95% confidence interval [1.33-6.74] and odds ratio 2.76; 95% confidence interval [1.23-6.20], respectively). For patients who survived the early period, conditional long-term survival was excellent for both groups and was not different between 2 groups (P = 0.764). CONCLUSIONS: Adult CHD patients have a high incidence of overall mortality due to a high rate of early mortality. Univentricular physiology was associated with a significant increased risk of early death compared to biventricular physiology. However, late mortality was excellent and no longer different between the 2 physiologies.

Sudden cardiac death after heart transplantation: a population-based study.

AIMS: The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population. METHODS AND RESULTS: Consecutive HTx recipients (n = 1246, 2 centres) transplanted between 2004 and 2016 were included. We prospectively assessed clinical, biological, pathologic, and functional parameters. SCD was centrally adjudicated. We compared the SCD incidence beyond the first year post-transplant in this cohort with that observed in the general population of the same geographic area (registry carried out by the same group of investigators; n = 19 706 SCD). We performed a competing risk multivariate Cox model to identify variables associated with SCD. The annual incidence of SCD was 12.5 per 1,000 person-years [95% confidence interval (CI), 9.7-15.9] in the HTx recipients cohort compared with 0.54 per 1,000 person-years (95% CI, 0.53-0.55) in the general population (P < 0.001). The risk of SCD was markedly elevated among the youngest HTx recipients with standardized mortality ratios for SCD up to 837 for recipients ≤30 years. Beyond the first year, SCD was the leading cause of death. Five variables were independently associated with SCD: older donor age (P = 0.003), younger recipient age (P = 0.001) and ethnicity (P = 0.034), pre-existing donor-specific antibodies (P = 0.009), and last left ventricular ejection fraction (P = 0.048). CONCLUSION: HTx recipients, particularly the youngest, were at very high risk of SCD compared with the general population. The consideration of specific risk factors may help identify high-risk subgroups.

Practical application of the French two-score heart allocation scheme: Insights from a high-volume heart transplantation centre.

BACKGROUND: In 2018, a cardiac allocation scheme based on an individual score considering the risk of death both on the waitlist and after heart transplantation was implemented in France. AIMS: To analyse the practical application of the pre- and post-transplant risk score in a French high-volume heart transplantation centre. METHODS: All consecutive adult patients listed for a first non-combined heart transplantation between 02 January 2018 and 30 June 2022 at our centre were included. Baseline characteristics of candidates and recipients were retrieved from the national CRISTAL registry. Both scores were calculated at listing and at transplant. RESULTS: Overall, 364 patients were included. During follow-up, 257 patients (70.6%) were transplanted, and 57 (15.6%) died or were removed from the waitlist. Post-transplant 3-month survival was 84.8%. Total bilirubin and natriuretic peptides had the most important weight in the pretransplant risk score. This score had a major impact on waitlist outcomes: quartile 1 was characterized by low access to heart transplantation (58.2%) and risk of death on the waitlist (9.9%) compared with quartile 4 (heart transplantation rate 74.1%, mortality on the waiting list>20%). According to the post-transplant risk score, a minimal number of candidates were considered ineligible for heart transplantation (<1%), but 12.4% were contraindicated to at least one donor category. The number of contraindicated donor categories had a significant impact on waitlist outcomes. Although adequately calibrated, the post-transplant score had a limited discrimination (area under the curve 0.65, 95% confidence interval 0.59-0.71). CONCLUSION: Our results highlight the major impact of pre- and post-transplantation risk scores on waitlist outcomes following the allocation scheme update.

Association between vasoactive-inotropic score, morbidity and mortality after heart transplantation.

OBJECTIVES: The aim of this study was to evaluate the association between vasoactive-inotropic score (VIS), calculated in the 24 h after heart transplantation, and post-transplant mortality and morbidity. METHODS: This was an observational single-centre retrospective study. Patients admitted to surgical intensive care unit after transplantation, between January 2015 and December 2018, were reviewed consecutively. VISmax was calculated as dopamine+ dobutamine+ 100 × epinephrine + 100 × norepinephrine + 50 × levosimendan + 10 × milrinone (all in µg/kg/min) + 10 000 × vasopressin (units/kg/min), using the maximum dosing rates of vasoactive and inotropic medications in the 24 h after intensive care unit admission. The primary outcome was mortality at 1 year post-transplant. The secondary outcomes included length of stay, duration of mechanical ventilation and inotropic support and the occurrence of septic shock, ventilator-associated pneumonia, bloodstream infection or renal replacement therapy. RESULTS: A total of 151 patients underwent heart transplantation and admitted to intensive care unit. The median VISmax was 39.2 (interquartile range = 19.4-83.0). VISmax was independently associated with 1-year post-transplant mortality, as well as recipient age [hazard ratio (HR) = 1.004, P-value = 0.013], recipient gender (female to male: hazard ratio = 2.23, P-value = 0.047) and combined transplantation (hazard ratio = 2.85, P-value = 0.048). There was a significant association between VISmax and duration of mechanical ventilation (P-value < 0.001), length of stay (P-value = 0.002), duration of infused inotropes (P-value < 0.001), occurrence of bloodstream infections, septic shocks, ventilation-acquired pneumonia and renal replacement therapy. CONCLUSIONS: VISmax calculated during the first 24 h after postoperative intensive care unit admission in transplanted patients is independently associated with 1-year mortality. In addition, length of stay, duration of mechanical ventilation and infused inotropes increased with increasing VISmax.

Implication of the new definition of pulmonary hypertension in patients evaluated for heart transplantation.

BACKGROUND: The 2018 World Symposium on Pulmonary Hypertension (WSPH) changed the definition of pulmonary hypertension (PH) with a new threshold of mean pulmonary artery pressure (mPAP) above 20 mmHg. OBJECTIVE: To evaluate the profile and prognosis of patients with chronic heart failure (HF) considered for heart transplantation with the new definition of PH. METHODS: Patients with chronic HF considered for heart transplantation were classified as mPAP≤20mmHg, mPAP 20-25 mmHg, and mPAP≥25mmHg. Using a multivariate Cox model, we compared the mortality of patients with mPAP20-25mmHg, and mPAP≥25mmHg versus those with mPAP≤20mmHg. RESULTS: Of 693 patients with chronic HF considered for heart transplantation, 12.7%, 77.5% and 9.8% were classified as mPAP20-25mmHg, mPAP≥ 25mmHg and mPAP≤20mmHg. Patients of mPAP ≥ 25mmHg and mPAP 20-25 mmHg categories were older than mPAP ≤ 20 mmHg (56 versus 55 and 52 year-old, p = 0.02) with more frequent co-morbidities. Within 2.8 years, the mPAP20-25mmHg category displayed a higher risk of mortality compared with those of the mPAP≤20mmHg category (aHR 2.75, 95% CI 1.27-5.97, p = 0.01). Overall, the new PH definition using a threshold of mPAP >20 mmHg was associated with a higher risk of death (adj HR 2.71, 95% CI 1.26-5.80) than the previous definition (mPAP >25 mmHg, aHR: 1.35 95% CI 1.00-1.83, p = 0.05). CONCLUSIONS: One out of 8 patients with severe HF are reclassified as having PH following the 2018 WSPH. Patients with mPAP20-25 evaluated for heart transplantation displayed significant co-morbidities and high mortality rates.

Severity of SARS-CoV-2 Omicron variant infection in heart transplant recipients.

SARS-CoV-2 Omicron variant was first detected in France mid-November 2021 in wastewater treatment plants while cases started to increase at the beginning of December. The maximum incidence occurred in mid-January 2022. The Omicron wave spread rapidly throughout France in general population with lower case-fatality rate compared with previous waves. Little is known about infection with Omicron variant in heart transplant (HT) recipients. In this study, we examined incidence and mortality rate of COVID-19 in the general population and among 1,263 HT recipients during the period from June, 2021 to February, 2022, described characteristics of HT recipients infected with SARS-CoV-2 during Omicron (December 1st, 2021-February 7, 2022) and Delta (June 1st- November 30, 2021) periods, and compared hospital course of HT recipients with Omicron and Delta variant infection. Our findings contrast with the reported lower severity for Omicron variant infection compared with Delta variant infection in immunocompetent individuals.

Impact of the 2018 French two-score allocation scheme on the profile of heart transplantation candidates and recipients: Insights from a high-volume centre.

BACKGROUND: In 2018, a new cardiac allograft allocation scheme, based on an individual scoring system, considering the risk of death both on the waiting list and after heart transplantation, was implemented in France. AIM: To assess the impact of this new scheme on the profile of transplantation candidates and recipients. METHODS: In this single-centre retrospective study, we included consecutive patients listed and/or transplanted between 01 January 2012 and 30 September 2021 at La Pitié-Salpêtrière Hospital. Baseline characteristics of patients were retrieved from the national CRISTAL registry and were compared according to the type of allocation scheme (before or after 2018). RESULTS: A total of 1098 newly listed transplantation candidates and 855 transplant recipients were included. One-year mortality rates after listing and after transplantation were 12.4% and 20%, respectively. At listing, the proportion of candidates on inotropes significantly declined following the scheme update (26.3 versus 20.9%; P=0.038), reflecting a change in medical practice. At transplantation, recipients had worse kidney function (estimated glomerular filtration rate<60mL/min/1.73 m2: old scheme, 29.7%; new scheme, 46.4%; P<0.001) and were more likely to be on extracorporeal membrane oxygenation support (33.5% versus 28.1%; P=0.080) under the new scheme, reflecting the prioritization of more severe patients. Outcomes after transplantation were not significantly influenced by the allocation system. CONCLUSIONS: The implementation of the 2018 French allocation scheme had a limited impact on the profile of transplantation candidates, but selected more severe patients for transplantation without significant impact on outcomes after transplantation.

Clinical course of arrhythmogenic right ventricular cardiomyopathy with end-stage heart failure and outcome after heart transplantation.

BACKGROUND: Few data exist on the characteristics and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy and advanced heart failure who undergo heart transplantation. AIM: To explore the pretransplant course and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy after heart transplantation. METHODS: This observational retrospective monocentric study included all consecutive patients with arrhythmogenic right ventricular cardiomyopathy who underwent heart transplantation during a 13-year period (2006-2019) at Pitié-Salpêtrière University Hospital (Paris). RESULTS: A total of 23 patients with arrhythmogenic right ventricular cardiomyopathy underwent heart transplantation between 2006 and 2019. The median time from diagnosis to heart transplantation was 9 years, and the median age at transplantation was 50 years. At diagnosis, half of the patients had left ventricular dysfunction, 59% had extensive T-wave inversion and 43% had a history of sustained ventricular tachycardia. Only five patients were involved in intensive sport activity. Indications for heart transplantation were end-stage biventricular dysfunction in 13 patients, end-stage right ventricular heart failure in seven and electrical storm in three. Only three patients had pulmonary hypertension, and half of the patients had atrial arrhythmias. The survival rate 1 year after heart transplantation was 74% (95% confidence interval 53-88%). Eight patients experienced primary graft dysfunction needing extracorporeal membrane oxygenation. CONCLUSIONS: Patients with arrhythmogenic right ventricular cardiomyopathy who eventually needed heart transplantation mostly exhibited extended disease with biventricular dysfunction at diagnosis. Intensive sport activity did not seem to be a major determinant. Advanced heart failure usually occurred late in the course of the disease. Primary graft dysfunction after heart transplantation was frequent, and should be anticipated. Additional data are needed to identify the optimal timing for heart transplantation and predictors of end-stage heart failure in patients with arrhythmogenic right ventricular cardiomyopathy.

Clinical Prediction Model for Antibody-Mediated Rejection: A Strategy to Minimize Surveillance Endomyocardial Biopsies After Heart Transplantation.

BACKGROUND: In heart transplantation, antibody-mediated rejection (AMR) is a major contributor to patient morbidity and mortality. Multiple routine endomyocardial biopsies (EMB) remain the gold standard to detect AMR, but this invasive procedure suffers from many limitations. We aimed to develop and validate an AMR risk model to improve individual risk stratification of AMR. METHODS: Heart recipients from 2 referral transplant centers, Cedars-Sinai (US) and Pitié-Salpêtrière (France), were included from 2012 to 2019. Database included detailed clinical, immunologic, imaging, and histological parameters. The US cohort was randomly distributed in a derivation (2/3) and in a test set (1/3). The primary end point was biopsy-proven AMR. A mixed effect logistic regression model with a random intercept was applied to identify variables independently associated with AMR. Simulation analyzes were performed. RESULTS: The US and French cohorts comprised a total of 1341 patients, representing 12 864 EMB. Overall, 490 AMR episodes were diagnosed (3.8% of EMB). Among the 26 potential determinants of AMR, 5 variables showed independent association: time post-transplant (P<0.001), pretransplant sensitizing event (P=0.001), circulating donor-specific anti-human leukocyte antigen antibody (P=0.001), graft dysfunction (P=0.004), and prior history of definite AMR (P<0.001). In the US test set, the calibration and the discrimination of the model were accurate (area under the curve, 0.79 [95% CI, 0.78-0.81]). Those results were confirmed in the external validation cohort (area under the curve, 0.78 [95% CI, 0.77-0.79]) and reinforced by various sensitivity analyses. The model also showed good performance to predict overall cause of rejection. Simulation models revealed that the AMR risk model could safely reduce the number of EMB. CONCLUSIONS: Our results support the use of the AMR risk model as a clinical decision tool to minimize the number of routine EMB after heart transplantation.

Suppression of tumorigenicity-2 (ST2) is a promising biomarker in heart transplantation.

BACKGROUND: To evaluate the association between donors' and recipients' serum levels of soluble ST2 (sST2) and recipients' outcome after heart transplantation (HT). METHODS: Blood samples were collected in 50 heart donors before organ procurement and in 50 recipients before HT (D0), a week after HT (D7) and at every first year's endomyocardial biopsy (EMB); sST2 levels were evaluated by ELISA. RESULTS: Donors who sustained a cardiac arrest, had significantly higher sST2 levels. Recipients on national high emergency waiting list had significantly higher preoperative sST2 levels compared to recipients who did not. Recipients with postoperative sepsis or continuous renal replacement therapy had significantly higher sST2 levels at D7. Recipients who needed a postoperative ECMO for allograft dysfunction had significantly higher sST2 levels in their corresponding donors. Recipients who died during the hospitalization after the transplantation had significantly higher sST2 levels at D7 compared to recipients who did not. No difference was observed in sST2 levels in recipients who had mild allograft rejection and recipient who did not. CONCLUSIONS: Higher sST2 levels in donors are associated to allograft dysfunction requiring ECMO in recipients; higher postoperative sST2 levels in recipients are associated with in-hospital mortality.

Poor Antibody Response After Two Doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine in Transplant Recipients.

A low anti-spike antibody response of 28.6% was observed 28 days after BNT162b2 vaccine second dose among 133 solid organ transplant recipients without previous coronavirus disease 2019 (COVID-19). No serious adverse events were recorded. Four severe COVID-19 cases were reported between or after the 2 doses. Our data suggest to change the vaccine strategy.

Impact of Sex in the Efficacy of Perioperative Desensitization Procedures in Heart Transplantation: A Retrospective Cohort Study.

Background: Sensitized patients, i.e. recipients with preformed donor-specific HLA antibodies (pfDSA), are at high-risk of developing antibody-mediated rejections (AMR) and dying after heart transplantation (HTx). Perioperative desensitization procedures are associated with better outcomes but can cause sensitization, which may influence their efficacy. Methods: In sensitized patients (pfDSA>1000 mean immunofluorescence (MFI) units), we assessed the effect of perioperative desensitization by comparing treated patients to a historical control cohort. Multivariable survival analyses were performed on the time to main outcome, a composite of death and biopsy-proven AMR with 5-year follow-up. Results: The study included 68 patients: 31 control and 37 treated patients. There was no difference in preoperative variables between the two groups, including cumulative pfDSA [4026 (1788;8725) vs 4560 (3162;13392) MFI units, p=0.28]. The cause of sensitization was pregnancy in 24/68, 35.3%, transfusion in 61/68, 89.7%, and previous HTx in 4/68, 5.9% patients. Multivariable analysis yielded significant protective association between desensitization and events (adjusted (adj.) hazard ratio (HR)=0.44 (95% confidence interval (95CI)=0.25-0.79), p=0.006) and deleterious association between cumulative pfDSA and events [per 1000-MFI increase, adj.HR=1.028 (1.002-1.053), p=0.031]. There was a sex-difference in the efficacy of desensitization: in men (n=35), the benefit was significant [unadj.HR=0.33 (95CI=0.14-0.78); p=0.01], but not in women (n=33) [unadj.HR=0.52 (0.23-1.17), p=0.11]. In terms of the number of patients treated, in men, 2.1 of patients that were treated prevented 1 event, while in women, 3.1 required treatment to prevent 1 event. Conclusion: Perioperative desensitization was associated with fewer AMR and deaths after HTx, and efficacy was more pronounced in men than women.

Clinical manifestations and outcomes of coronavirus disease-19 in heart transplant recipients: a multicentre case series with a systematic review and meta-analysis.

Available data on clinical presentation and mortality of coronavirus disease-2019 (COVID-19) in heart transplant (HT) recipients remain limited. We report a case series of laboratory-confirmed COVID-19 in 39 HT recipients from 3 French heart transplant centres (mean age 54.4 ± 14.8 years; 66.7% males). Hospital admission was required for 35 (89.7%) cases including 14/39 (35.9%) cases being admitted in intensive care unit. Immunosuppressive medications were reduced or discontinued in 74.4% of the patients. After a median follow-up of 54 (19-80) days, death and death or need for mechanical ventilation occurred in 25.6% and 33.3% of patients, respectively. Elevated C-reactive protein and lung involvement ≥50% on chest computed tomography (CT) at admission were associated with an increased risk of death or need for mechanical ventilation. Mortality rate from March to June in the entire 3-centre HT recipient cohort was 56% higher in 2020 compared to the time-matched 2019 cohort (2% vs. 1.28%, P = 0.15). In a meta-analysis including 4 studies, pre-existing diabetes mellitus (OR 3.60, 95% CI 1.43-9.06, I2  = 0%, P = 0.006) and chronic kidney disease stage III or higher (OR 3.79, 95% CI 1.39-10.31, I2  = 0%, P = 0.009) were associated with increased mortality. These findings highlight the aggressive clinical course of COVID-19 in HT recipients.

Association between cytomegalovirus infection and allograft rejection in a large contemporary cohort of heart transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection remains a common complication after heart transplantation (HTx). The association between CMV infection and allograft rejection is debated in the era of efficient prophylactic antiviral therapies. METHODS: This single-center cohort study utilized a highly phenotyped database of HTx recipients (2012-2016). The primary endpoint was the analysis of the association between CMV infection (CMV load ≥ 500 IU/mL whole blood) and the risk of allograft rejection (cellular rejection ≥ 1R1B, antibody-mediated rejection ≥ pAMR1). Secondary endpoints included the analysis of a higher CMV load threshold (≥10 000 IU/mL) and different risk periods after PCR positivity. A mixed-effect logistic regression model with a random intercept was applied. Results were adjusted for important risk factors of rejection. RESULTS: Overall, 384 patients were included and 6388 CMV loads and 3,494 endomyocardial biopsies were analyzed. CMV infections ≥ 500 IU/mL were diagnosed on 1223 (19.2%) blood samples from 284 (72.1%) patients and allograft rejections on 246 biopsies (7%) from 149 patients (38.8%). We did not find any association between CMV infection ≥ 500 IU/mL and rejection (univariable: OR 0.94, 95% CI [0.61, 1.45], P = .78, multivariable: OR 0.86, 95% CI [0.55, 1.33], P = .85). These results were consistent when analyzing a higher CMV load threshold and different periods of risk, reinforced by internal validation procedures and a posteriori calculation of the power (primary endpoint: power = 0.82, 95% CI [0.79-0.84]) and reproducible across different clinical scenarios. CONCLUSIONS: CMV infection was not associated with an increased risk of rejection in a contemporary cohort of HTx recipients.

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.