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In severely ill patients undergoing urgent heart transplant (HTX), immunosuppression carries high risks of infection, malignancy, and death. Low-dose immunosuppressive protocols have higher rejection rates. We combined extracorporeal photopheresis (ECP), an established therapy for acute rejection, with reduced-intensity immunosuppression. Twenty-eight high-risk patients (13 with high risk of infection due to infection at the time of transplant, 7 bridging to transplant via extracorporeal membrane oxygenation, 8 with high risk of malignancy) were treated, without induction therapy. Prophylactic ECP for 6 months (24 procedures) was initiated immediately postoperatively. Immunosuppression consisted of low-dose tacrolimus (8–10 ng/ml, months 1–6; 5–8 ng/ml, >6 months) with delayed start; mycophenolate mofetil (MMF); and low maintenance steroid with delayed start (POD 7) and tapering in the first year. One-year survival was 88.5%. Three patients died from infection (POD 12, 51, 351), and one from recurrence of cancer (POD 400). Incidence of severe infection was 17.9% (
Cardiac transplantation remains the best option for patients with end-stage heart failure. In recent decades, the number of patients referred to transplantation has increased significantly. Many patients are at high risk for early postoperative infection, and patients with previous malignant disease are more often seen as potential transplant candidates (
The aim of our pilot study was to evaluate a novel approach consisting of 6-month ECP together with a reduced-intensity immunosuppressive protocol to treat challenging heart transplant recipients at high risk for either early postoperative infection or cancer recurrence.
The primary outcomes of this pilot study were 1-year and overall survival. Secondary outcomes were the safety of ECP, incidence of early postoperative infection (in-hospital and in the first 6 months of ECP therapy), number of rejection episodes according to the International Society of Heart and Lung Transplantation (ISHLT) criteria in the first year, and recurrence of malignancy. Approval for the study was obtained from the institutional review board of the Medical University of Vienna (EK 1107/2020). In accordance with local regulations, all use of patients’ clinical research data required their consent.
Between September 2016 and January 2021, 200 heart transplant procedures were performed at the Medical University of Vienna. Twenty-eight patients (25% female,
Patient demographics and baseline characteristics are listed in
Patient demographics and baseline characteristics I.
Total, |
Infection, |
ECMO, |
Malignancy, |
|
---|---|---|---|---|
Age, years, med (IQR) | 51.9 (42.2–57.6) | 55.7 (52.5–63.4) | 43 (37.2–51.8) | 43.8 (39.5–51.4) |
Gender, female, n (%) | 7 (25) | 2 (15.4) | 1 (14.3) | 4 (50) |
Indication for HTX, n | ||||
Ischemic CMP | 5 | 3 | 2 | 0 |
Dilative CMP | 10 | 5 | 0 | 5 |
Congenital disease | 1 | 1 | 0 | 0 |
Bail out after cardiac surgery | 6 | 1 | 5 | 0 |
Cardiac tumor | 2 | 0 | 0 | 2 |
Other (CAV, HOCM) | 4 | 3 | 0 | 1 |
HKTX, n (%) | 2 (7.1) | 1 (7.7) | 0 | 1 (12.5) |
Previous cardiac surgery, n (%) | 18 (64.3) | 7 (53.8) | 5 (71.4) | 6 (75) |
CAV, cardiac allograft vasculopathy; CMP, cardiomyopathy; HKTX, combined heart-kidney transplant; HTX, heart transplantation; HOCM, hypertrophic obstructive cardiomyopathy; med (IQR), median and interquartile range.
Patient demographics and baseline characteristics II.
Total, |
Infection, |
ECMO, |
Malignancy, |
|
---|---|---|---|---|
High urgency status, n (%) | 24 (85.7) | 12 (92.3) | 7 (100) | 5 (62.5) |
IMPACT score, med (IQR) | 8 (5.8–13) | 7 (6–10) | 14 (12.5–16.5) | 4.0 (2.5–7.8) |
ICU, n (%) | 14 (50) | 6 (46.2) | 7 (100) | 1 (12.5) |
Intubated, n (%) | 3 (10.7) | 0 | 3 (42.9) | 0 |
Infection, n (%) | 20 (71.4) | 13 (100) | 7 (100) | 0 |
ECMO support, n (%) | 7 (25) | 0 | 7 (100) | 0 |
VAD, n (%) | 7 (25) | 5 (38.5) | 0 | 2 (25) |
eGFR, med (IQR) | 84.7 (36.9–104.2) | 93.4 (35–100.9) | 120 (69.8–174.1) | 67.3 (29.6–84.7) |
Creatinine, mg/dl, med (IQR) | 1.1 (0.8–1.8) | 1.2 (0.9–1.9) | 0.6 (0.5–1) | 1.2 (1–2.2) |
RRT, n (%) | 6 (21.4) | 3 (30) | 2 (28.6) | 1 (12.5) |
Bilirubin, (mg/dl), med (IQR) | 0.8 (0.5–1.1) | 0.8 (0.5–1.2) | 1 (0.8–2) | 0.5 (0.4–0.8) |
Diabetes (IDDM), n (%) | 4 (14.3) | 3 (23.1) | 0 | 1 (12.5) |
ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ICU, intensive care unit; IDDM, insulin-dependent diabetes mellitus; IMPACT, index for mortality prediction after cardiac transplantation; med (IQR), median and interquartile range; RRT, renal replacement therapy; VAD, ventricular assist device.
Indication for ECP.
Infection |
Microbiological result | Site of infection at time of HTX | |
---|---|---|---|
1 |
|
Blood culture, postop sternal VAC and ECMO | |
2 |
|
Site of kidney transplant with postop local VAC therapy | |
3 |
|
Blood culture | |
4 |
|
Ascites | |
5 |
|
Blood culture | |
6 | Hepatitis B PCR + | Blood culture; HTX in deep hypothermia with circulatory arrest | |
7 |
|
Recurrent endocarditis, BAL | |
8 |
|
Blood culture | |
9 |
|
Blood culture, driveline, mediastinum | |
10 |
|
Blood culture, mediastinum | |
11 |
|
Blood culture, driveline, mediastinum | |
12 |
|
Fungal sinusitis | |
13 |
|
Blood culture, driveline | |
|
|
|
|
1 | Post cardiotomy | Mech Bentall procedure; LVAD; LVAD explant | 5 |
2 | Myocardial infarction | STEMI with PCI, ischemic ventricular rupture | 14 |
3 | Post cardiotomy | MV-repair and AVR | 25 |
4 | Post cardiotomy | STEMI, CABG | 27 |
5 | Post cardiotomy (endocarditis) | Mitral and aortic valve replacement, CABG (CX) | 17 |
6 | Post cardiotomy | Type A dissection (mech Bentall) | 23 |
7 | Right heart failure | CMP with decompensation | 1 |
|
|
|
|
1 | Myxofibrosarcoma heart | 12 months | no |
2 | Synovial sarcoma heart | 6 months | no |
3 | Osteosarcoma; breast cancer (recurrence) | 30 years; 12 years (8 years) | yes |
4 | PTLD (HTX) | 10 years | yes |
5 | Renal cell carcinoma | 10 years | yes |
6 | ALL; cerebral recurrence | 13 years; 5 years | yes |
7 | Non-Hodgkin’s lymphoma | 42 years | yes |
8 | Adenocarcinoma in donor lung | 0 | yes |
ALL, acute lymphoblastic leukemia; AVR, aortic valve replacement; BAL, bronchoalveolar lavage; CABG, coronary artery bypass graft; CX, circumflex artery; CMP, cardiomyopathy; ECMO, extracorporeal membrane oxygenation; ECP, extracorporeal photopheresis;
Postoperative severe infection was defined as clinically relevant infection in the early postoperative phase. CMV disease was based on international classification (
Graft function was examined by transthoracic echocardiography, which was performed on a routine basis during the first year (weekly in month 1, monthly in months 2–12). Endomyocardial biopsies were performed at weeks 2, 3, and 4, and at months 2, 3, 6, and 12, and in case of clinical signs of rejection. Acute cellular rejection (ACR) as well as antibody-mediated rejection were defined according to the ISHLT nomenclature (
Patients with a history of malignancy underwent close follow-up including CT, MRI, or PET scan where appropriate, on a regular basis.
There was no induction therapy (see
An overview on our immunosuppressive protocol including ECP.
All patients without evidence of infection at the time of HTX received empiric broad-spectrum antibiotics for at least 5 days after transplantation, and all patients with infection at the time of transplantation were treated with targeted antimicrobial therapy adjusted to the antibiogram. Prophylaxis against
ECP therapy was based on the previously published protocol by Barr et al. (
Data including demographic and transplant variables were obtained from the Medical University of Vienna Heart Transplant Database. The statistical analyses were performed using the Statistical Program of Social Sciences 22.0 (SPSS Inc., Chicago, IL United States). Categorical variables are described by absolute and relative frequencies, and continuous variables by median and interquartile range (IQR). The Kaplan-Meier estimate was used for survival analysis. P-values below 0.05 were considered statistically significant.
One-year survival in these high-risk recipients was 88.5% by Kaplan-Meier estimate (25/28 patients). Infectious complications leading to septic multiorgan failure (MOF) were the cause of death in three patients on POD 12, 51, and 351, respectively. One patient with a malignant tumor of the heart as transplant indication died due to recurrence of malignancy 400 days after HTX. Therefore, overall survival in our cohort was 84.0% (
Outcome variables.
Total, |
Infection, |
ECMO, |
Malignancy, |
|
---|---|---|---|---|
1-year survival, n (%) | 25 (88.5) | 10 (75) | 7 (100) | 8 (100) |
Overall survival, n (%) | 24 (84.0) | 10 (75) | 7 (100) | 7 (87.5) |
Follow-up, m, med (IQR) | 23.7 (12.7–33.4) | 23.6 (8.4–32.3) | 30.7 (18.9–38.8) | 24.1 (13.8–43.0) |
ICU stay, d, med (IQR) | 17.5 (10.8–31.8) | 17.5 (10.5–29.5) | 30 (15–32.5) | 17.5 (10.5–29.5) |
In hospital stay, d, med (IQR) | 43 (32–55) | 39.5 (32.5–54.3) | 43.5 (35.5–54.5) | 39.5 (32.5–54.3) |
RRT, n (%) | 13 (46.4) | 8 (61.5) | 2 (28.6) | 3 (37.5) |
Pneumonia, n (%) | 5 (17.9) | 3 (23.1) | 0 | 2 (25) |
Sepsis, n (%) | 2 (7.1) | 2 (15.4) | 0 | 0 |
ACR≥2R in the first year, n (%) | 4 (14.3) | 1 (7.7) | 1 (14.3) | 2 (25) |
AMR | 1 (3.6) | 1 (7.7) | 0 | 0 |
PGD grade 3, n (%) | 2 (7.1) | 2 (15.4) | 0 | 0 |
ACR, acute cellular rejection; AMR, antibody-mediated rejection; d, days; ICU, intensive care unit; med (IQR), median and interquartile range; m, months; PGD, primary graft dysfunction with grading according to the ISHLT, consensus 2014; RRT, renal replacement therapy.
CNI delay was achieved in all patients with a median start time of tacrolimus on POD 3 (IQR 2–4), and the longest CNI delay was 9 days in one patient. Target tacrolimus trough levels were attained for the whole patient cohort (see
Tacrolimus trough levels. The green bar highlights the intended target range of tacrolimus (8–10 ng/ml in months 1–6, and 5–8 ng/ml thereafter).
All patients who survived the first 6 months received ECP according to the protocol. Overall, ECP was tolerated well. In one patient, elevated potassium levels occurred during the third ECP treatment and could not be attributed to ECP. Most likely, intravenous amphotericin A was administered too quickly, causing a shift of potassium (
Severe bacterial (
Three patients showed sensitization prior to transplantation, with calculated panel-reactive antibodies of 23%, 51% and 67%, and were transplanted
Donor-specific antibodies (DSA) were detected in five patients early after transplantation but disappeared or decreased significantly within the first 6 months after HTX. In one of these patients, histological findings revealed antibody-mediated rejection (1H) without increase of DSA in the first two biopsies of one patient. In addition to steroid therapy (500 mg methylprednisolone i.v. for 3 consecutive days), immunoadsorption treatment was started due to reduced biventricular function, which resolved after seven courses. All consecutive biopsies were negative.
During the first year, the incidence of ACR according to ISHLT criteria (≥2R) was 14.3% (
After a median follow-up of 24.1 months (13.8–43.0), all patients are free of cancer without cancer recurrence, except the two patients with malignant cardiac tumor as indication for HTX: one patient died due to disease progression 13.3 months after transplant, and the other is in good clinical condition after post-transplant hepatic metastasectomy and chemotherapy 59.5 months after HTX.
In this hypothesis-generating study including 28 selected high-risk HTX patients, an ECP protocol first described by Barr et al. (
Due to constant improvements in the results of HTX, the number of high-risk patients eligible for transplantation has increased significantly (
In our cohort, risk of early mortality was high, as 50% were already admitted to an intensive care unit before HTX and 25% were supported with temporary mechanical assist devices. This observation is supported by their high median IMPACT score of 8 (IQR 5.8–13).
Furthermore, patients with history of cancer might have a higher risk of developing malignancies after transplantation (
There is a general consensus that higher levels of immunosuppression are associated with a higher risk of infectious complications (
ECP is an established therapy for the treatment of acute and chronic graft-versus-host disease after hematopoietic cell transplantation and rejection of solid organ transplantation and has been used for at least 25–30 years for these indications (
Based on the experience of those two studies, we developed our alternative protocol to test in three high-risk groups (infection, bridge to transplant
One-year survival in our high-risk patient cohort was slightly lower than in the overall patient cohort transplanted in the same time period (88.5% vs 93%). Nevertheless, risk-adjusted patient survival calculated using the IMPACT score was better than expected (88.5% vs 84.6%). Surprisingly, our patients with the highest predicted mortality (ECMO bridging to HTX) had 100% survival, compared with 71% expected survival. Patients with pre-transplant infections did worse than expected (75% vs 86% survival) but two patients died in the immediate postoperative period from fungal infection with strains resistant to empirically administered antifungal therapy. Both had developed grade III primary graft dysfunction (
The incidence of severe infections in our cohort was 17.9% (
An unexpected finding was the low rate of ACR (14.3%) in the first year, all occurring in the first month. ACR episodes were without hemodynamic compromise. ACR was not associated with lower tacrolimus levels. Tacrolimus was delayed until a median of 3 days after transplantation, and the target range was reached at the end of the first week. Median achieved tacrolimus levels were in the upper target range over the first year, and this might have contributed to the low rejection rates. Nevertheless, maintenance steroids were started on day 7, at a lower dosage as recommended by guidelines, and were tapered until the end of the first year (
Most prospective randomized immunosuppressive trials in heart transplantation have reported an acute rejection rate of 15–25% during the first year (
Our eight transplant patients with a high neoplastic risk were heterogeneous: five had a prior history of cancer (three hematologic, one renal cancer, one with osteosarcoma and breast cancer), two had cardiac sarcoma at the time of transplantation, and one received a heart from a donor with lung cancer detected after procurement. Those with a history of cancer were cancer free for at least 5 years pre-transplant. In a retrospective analysis of 111 thoracic transplant patients from northern European centers, time from cancer detection to transplantation had an impact on cancer-free post-transplant outcomes and survival (
This is a hypothesis-generating study describing the outcome of a heterogeneous pilot group. Longer follow-up is needed to evaluate the incidence of cancer recurrence in patients with history of cancer. There is a strong need to compare our approach in a prospective randomized study with control groups for each indication.
To our knowledge, this is the first description of the use of prophylactic ECP as an additional immunomodulatory therapy combined with reduced-intensity immunosuppressive maintenance therapy. There are no published data on a comparable protocol in HTX patients. In our heterogeneous pilot group of high-risk HTX patients, this innovative approach was safe, with low overall risk of rejection, and an effective strategy to address their high risk of infection or malignancy. Based on our data, future studies should be undertaken in a prospective randomized setting.
The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by Institutional review board of the Medical University of Vienna (EK 1107/2020). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
JG, AZ, AA-Z, and NW collected and analyzed the data, performed all statistical procedures and developed the manuscript. All authors managed patients during the study period and critically reviewed the manuscript before publication.
JG, AZ, RK, and NW have been part of Mallinckrodt’s Speaker bureau.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
AMR, antibody-mediated rejection; ACR, acute cellular rejection; CDC, complement-dependent cytotoxicity; CMP, cardiomyopathy; CNI, calcineurin inhibitor; CTCAE, common terminology criteria for adverse events; DSA, donor-specific antibody; ECMO, extracorporeal membrane oxygenation; ECP, extracorporeal photopheresis; HLA, human leucocyte antigen; HOCM, hypertrophic obstructive cardiomyopathy; HTX, heart transplantation; ICU, intensive care unit; INTERMACS, interagency registry for mechanically assisted circulatory support; IMPACT, index for mortality prediction after cardiac transplantation; IQR, interquartile range; ISHLT, international society of heart and lung transplantation; MMF, mycophenolate mofetil; MNC, mononuclear cells; MOF, multiorgan failure; PCR, polymerase chain reaction; POD, postoperative day; PRAs, panel-reactive antibodies; UNOS, united network for organ sharing; VAC, vacuum-assisted closer; VAD, ventricular assist device.