Abstract
Background.
The use of extracorporeal membrane oxygenation (ECMO) after transplantation seems to be associated with an increased risk for infectious complications. We assessed the impact of ECMO use on the incidence of infectious diseases in a nationwide cohort of heart transplant recipients.
Methods.
Patients undergoing heart transplantation between 2008 and 2017 and enrolled in the Swiss Transplant Cohort Study were included. We calculated incidence rates of infection at 1-y posttransplant and used Cox regression to identify infection-associated risk factors according to the pathogen group.
Results.
We included 306 heart transplant recipients of whom 42 patients (13.7%) received ECMO in the posttransplant period. Incidence rates at 1 y for overall infection were 259 per 100 patient-years in the ECMO group (176 for bacterial, 52 for viral and 36 for fungal infections) and 126 per 100 patient-years in the non-ECMO group (68 for bacterial, 45 for viral and 14 for fungal infections). In the ECMO group, gram-negative bacterial infections predominated over gram-positive pathogens. Use of ECMO was associated with an increased risk of overall infections (hazard ratio 1.81 [95% CI. 1.02-3.19], P = 0.04) and fungal infections (hazard ratio 3.44 [95% CI, 1.33-8.89], P = 0.01).
Conclusions.
In this nationwide cohort of heart transplant recipients, the use of ECMO was associated with an increased risk for overall and fungal infections. More studies are needed to evaluate whether ECMO is independently associated with infection or a surrogate for a more critical patient condition.
INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is a life-support technique used in patients with reversible refractory respiratory and/or circulatory failure. Since 1970, when it was first introduced as cardiopulmonary support during surgery, the use of ECMO has notably increased worldwide.1 Infections are among the most common complications associated with ECMO and they can be associated with significant mortality.
Patients on ECMO support usually exhibit several predisposing factors for infection, such as preexisting comorbidities, immunosuppressive state associated with the critical illness, and invasiveness of other life-support procedures (eg, invasive mechanical ventilation or renal replacement therapies). In addition, ECMO seems to increase per se the susceptibility to infection likely due to its potentially deleterious immune triggering and inflammatory effects because the exposure of patient’s blood to the nonendothelialized surface of the ECMO circuit may result in the widespread activation of the innate immune system.2
After heart transplantation, ECMO support is required in the case of graft failure due to primary graft dysfunction, acute rejection with hemodynamic compromise or sudden cardiac arrest, to maintain circulation until graft recovery.3 Primary allograft dysfunction requiring ECMO support occurs in up to 15% of heart transplantations4 and is associated with mortality rates as high as 33% at 30 d and 50% at 1 y.5 The impact of ECMO on the risk of other posttransplant complications, such as infections, remains largely unexplored. ECMO seems to be associated with an increased risk for severe infections after heart transplantation, particularly for invasive fungal infections.6 However, data are scarce and mostly come from single-center studies, impeding the development of definitive recommendations for potential prevention strategies.
The aim of this nested cohort study was to describe the epidemiology, incidence, risk factors, and outcomes of infectious complications in heart transplant recipients who have received ECMO support during the early posttransplant period, with a special focus on fungal infections.
MATERIALS AND METHODS
Study Population
The Swiss Transplant Cohort Study (STCS) is a multicenter nationwide cohort, where data of patients receiving a solid organ transplantation are prospectively collected since 2008.7 In this study, we included all pediatric and adult heart transplant recipients of the 3 transplant centers performing heart transplantation in Switzerland (Bern, Lausanne, and Zurich) from May 2008 to June 2017.
Patients without informed consent to participate in the STCS at enrollment or with subsequent consent withdrawal were excluded. The ethics committees at each center approved the STCS. The local Ethics Committee of the Vaud Canton approved the protocol of the present study (protocol no. 2018-00992).
Data Collection and Definitions
In the STCS patient- and organ-specific data, including microbiologically documented infections, are collected in an electronic case report form from medical charts at the time of transplantation, at 6 and 12 mo, and yearly thereafter. Infections are diagnosed and managed at each center according to local guidelines as part of routine clinical practice. Infectious events are collected in the STCS database by infectious diseases specialists at each center. Definitions of bacterial, viral, and fungal infections followed the guidelines developed by the STCS Infectious Diseases Working Group.8 In this study, we considered clinically relevant infections as all proven bacterial, probable and proven fungal, and probable and proven viral infections, as well as viral syndromes.
Antimicrobial prophylaxis practices were not standardized across participating centers. All patients received routine surgical antibacterial prophylaxis for 48 h, as well as oral nystatin prophylaxis for 14 d. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) was administered for 12 mo to life-long (in the case of toxoplasma serology mismatch with donor positive/recipient negative). Antiviral prophylaxis was given for high-risk patients (cytomegalovirus donor positive/recipient negative) in all centers and for intermediate risk (cytomegalovirus seropositive recipients) in 1 center. Antifungal prophylaxis was not routinely prescribed in 2 of the centers, with its use and the choice of antifungal agents left to clinical judgment. In contrast, 1 center administered caspofungin prophylaxis in patients receiving ECMO and/or renal replacement therapy, continuing until the discontinuation of these interventions.6 Immunosuppressive regimes were also center-specific, but most heart transplant recipients initially received an antimetabolite agent (mycophenolate or azathioprine) prednisone, and a calcineurin inhibitors. A late switch to an mTOR inhibitor was done in up to 40% of patients, as previously reported.8
We used the STCS database to identify patients receiving ECMO support for at least 24 h during the first month after heart transplantation and to obtain demographic and clinical data, including induction and maintenance immunosuppressive therapy, use of antimicrobial prophylaxis started within the first month after transplantation, pretransplant support with ECMO and left ventricular assist device (LVAD), and the characteristics of infections. Use of oral nystatin/amphotericin was not included as antifungal prophylaxis. Data not routinely included in the STCS database were collected from medical charts at every transplantation center, including type and duration of ECMO support. The cause of death is systematically adjudicated in the STCS by an independent investigator.
Statistical Considerations
Descriptive statistics were used for baseline characteristics of the included population, according to the use of ECMO. The incidence rates of infectious complications according to the use of ECMO support were calculated at 1-y posttransplant, considering death, graft loss, and dropout as competing risks. The confidence intervals were computed using a Poisson rate model. A bacterial, viral, or fungal infection was considered as a single event even if caused by multiple species at the same time.
A time-dependent cause-specific Cox regression model with multiple imputation was used to identify possible risk factors associated with infections and, specifically, to assess whether the use of ECMO support was an independent risk factor after adjusting for other clinically relevant covariates. Only the first episode of infection was considered to preserve the assumption of independence of observations. Death, dropout, and graft loss were considered competing risks. The use of antimicrobial prophylaxis, as well as pretransplant use of ECMO and LVAD, use of antithymocyte globulins, cold ischemia time, left ventricular heart ejection fraction after transplantation, recipient’s New York Heart Association class, and other variables were incorporated in the model as covariates.
We performed further 2 types of sensitivity analysis: As patients using ECMO posttransplantation had high early mortality and critical conditions, this potentially prevented the effective administration of antimicrobial prophylaxis. Therefore, the first sensitivity landmark analysis looked at the influence of the timing of TMP-SMX on risk of infection. In our time-dependent Cox model, the number of days on ECMO posttransplantation is not considered. Therefore, we performed a second sensitivity landmark analysis where only those patients without graft loss or death during the first month were included, and we investigate the effect of the duration of ECMO therapy on the risk to develop an infection. Variables in the multivariable analyses were chosen based on a combination of clinical relevance and the results of univariable Cox regression (effect size, significance level ≤ 0.10) under consideration of the overall number of events to prevent overfitting. A P value of <0.05 was considered statistically significant. Statistical analysis was performed using R version 4.2.3.
RESULTS
Study Population
Overall, 323 patients underwent heart transplantation during the study period; 306 gave consent (94.7%) and were included, with a median follow-up of 6 y (interquartile range [IQR] 4.00–8.83 y). Median age was 51 y (IQR 37–59 y) with 25 (8%) patients under 18 y of age. Most patients received induction regimen with antithymocyte globulin and a maintenance immunosuppression including mycophenolate, steroids, and cyclosporine. Approximately 40% of patients required LVAD as bridge to transplantation. Concerning antimicrobial prophylaxis started within 30 d after transplantation, 66% of patients received TMP-SMX, 45% antiviral prophylaxis with either (val-)ganciclovir or (val-)aciclovir and 8% antifungal prophylaxis (itraconazole, caspofungin, or nonspecified antifungal agents). Characteristics of the study population according to ECMO use are detailed in Table 1.
TABLE 1.
Baseline characteristics of the study population
| Non-ECMO group (N = 264) | ECMO group (N = 42) | Total (N = 306) | |
|---|---|---|---|
| Recipient sex (female), n (%) | 73 (28) | 9 (21) | 82 (27) |
| Recipient age, y, median (IQR) | 51 (37–58) | 54 (45–63) | 51 (37–59) |
| Donor age, y, median (IQR) | 43 (26–52) | 48 (39–57) | 44 (27–53) |
| Underlying cardiac disease | |||
| Dilated cardiomyopathy, n (%) | 122 (46) | 18 (43) | 140 (46) |
| Ischemic heart disease, n (%) | 80 (30) | 14 (33) | 94 (31) |
| Congenital heart disease, n (%) | 18 (6.8) | 1 (2.4) | 19 (6.2) |
| Other/unknown, n (%) | 44 (16) | 9 (21) | 53 (17) |
| Previous heart transplantation, n (%) | 2 (0.8) | 2 (4.8) | 4 (1.1) |
| Combined heart transplantation, n (%) | 6 (2) | 1 (2) | 7 (2) |
| Heart-lung | 0 | 1 (2) | 1 (0.3) |
| Heart-kidney | 6 (2) | 0 | 6 (2) |
| Pretransplant ECMO, n (%) | 6 (2) | 4/38a (10) | 10/302a (3) |
| Pretransplant LVAD, n (%) | 106 (40) | 17/38a (45) | 123/302a (41) |
| NYHA class, n (%) | |||
| I–II | 69/242 (28) | 9/36 (25)a | 78/278 (32)a |
| III–IV | 173/242 (71) | 27/36 (75)a | 200/278 (72)a |
| Cold ischemia time, h, median (IQR) | 2.7 (2.0–3.2) | 2.9 (2.3–3.6) | 2.8 (2.1–3.2) |
| Left ventricular ejection fraction before transplant, median (range) | 20 (15–29) | 22 (17–30) | 20 (15–30) |
| Induction immunosuppressionb, n (%) | |||
| ATG | 200 (76) | 27 (64) | 226 (74) |
| Basiliximab | 65 (25) | 10 (24) | 75 (26) |
| Other/unknown | 0 | 5 (12) | 5 (2) |
| Maintenance immunosuppressionb,c, n (%) | |||
| Tacrolimus | 97 (37) | 13 (31) | 110 (36) |
| Cyclosporin | 155 (60) | 18 (43) | 173 (57) |
| Mycophenolate | 261 (99) | 25 (69) | 286 (93) |
| Azathioprine | 56 (21) | 7 (17) | 63 (21) |
| Prednisone | 253 (97) | 37 (88) | 290 (96) |
| mTOR inhibitor | 28 (11) | 1 (2) | 29 (9) |
| TMP-SMX prophylaxisd, n (%) | 220 (83) | 19 (45) | 239 (78) |
| Antiviral prophylaxisd, n (%) | 126 (48) | 13 (31) | 139 (45) |
| Antifungal prophylaxisd, n (%) | 11 (4) | 7 (17) | 18 (6) |
| Duration of antifungal prophylaxis, d | |||
| Caspofungin, median (IQR) | 9 (4–12.5) | 8 (2–15.5) | 8 (2.5–13.7) |
| Deaths, n (%) | 17 (6) | 24 (57) | 41 (13) |
Denominator represents the number of patients for whom the data are available.
Patients may have received >1 agent for induction and maintenance immunosuppression.
Refers to initial maintenance immunosuppression regimen following transplantation
Prophylaxis started within 30 d from transplantation.
ATG, antithymocyte globulin; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range; LVAD, left ventricular assist device; NYHA, New York Heart Association; TMP-SMX, trimethoprim-sulfamethoxazole.
Overall, 42 (14%) of 306 patients received ECMO support after transplantation (thereafter referred as ECMO group) for a median duration of 4 d (range 2–7 d). All of them received a venoarterial ECMO support. In the ECMO group, 4 (10%) of 42 patients required ECMO support also before transplantation. In the ECMO group, 7 (17%) of 42 patients received prophylaxis with an antifungal agent (6 with caspofungin, 1 with caspofungin and an azole), 13 (31%) with an antiviral agent, and 19 (45%) with TMP-SMX. In the non-ECMO group, 11 (4%) of 264 patients received antifungal prophylaxis (8 with caspofungin, 3 with nonspecified antifungal agents), 126 (48%) received an antiviral prophylaxis, and 220 (83%) received TMP-SMX prophylaxis.
Epidemiology and Type of Infections
At 1-y posttransplant, at least 1 episode of infection occurred in 29/42 (69%) of patients in the ECMO group (21 [50%] patients had a bacterial, 8 [19%] a viral, and 7 [17%] a fungal infection) and in 163/264 (62%) of patients in the non-ECMO group (108 [41%] patients had a bacterial, 96 [36%] a viral, and 31 [12%] a fungal infection). During the first year after transplantation, we identified a total of 41 (67%) bacterial, 11 (18%) viral, and 9 (15%) fungal infections in the ECMO group, and 201 (57%) bacterial, 114 (32%) viral, and 38 (11%) fungal infections in the non-ECMO group (Table 2).
TABLE 2.
Type of infections according to pathogen during 1 y after heart transplantation
| Non- ECMO (N = 353) | ECMO (N = 61) | |
|---|---|---|
| Bacterial infection, n (%) | 201 (57) | 41 (67) |
| Enterobacterales | 80 (40) | 14 (34) |
| Coagulase-negative staphylococci | 30 (15) | 5 (12) |
| Pseudomonas aeruginosa | 17 (8.5) | 5 (12) |
| Enterococcus spp. | 15 (7.5) | 4 (10) |
| Clostridium spp. | 13 (6.5) | 4 (10) |
| Staphylococcus aureus | 9 (4.5) | 2 (5) |
| Streptococci | 3 (1.5) | 2 (5) |
| Other | 34 (17) | 4 (10) |
| Viral infection, n (%) | 114 (32) | 11 (18) |
| HSV/VZV | 49 (43) | 5 (45.5) |
| Respiratory viruses | 26 (23) | 2 (18) |
| CMV | 25 (22) | 2 (18) |
| Other | 14 (12) | 1 (9) |
| Fungal infections, n (%) | 38 (11) | 9 (15) |
| Candida spp. | 14 (37) | 3 (33) |
| Aspergillus fumigatus | 11 (29) | 3 (33) |
| Non-fumigatus Aspergillus | 3 (8) | 0 |
| Mucorales | 1 (3) | 1 (11) |
| Pneumocystis jirovecii | 4 (10.5) | 0 |
| Other/unknown | 5 (13) | 2 (22) |
CMV, cytomegalovirus; ECMO, extracorporeal membrane oxygenation; HSV/VZV, herpes simplex virus/varicella-zoster virus.
Infections occurred at a median of 23 d from transplantation (IQR 8–103 d) in the ECMO group (58% during the first month) and at a median time of 64 d (IQR 13–164 d) in the non-ECMO group (37% during the first month). Figure 1 shows the timeline of infections according to the ECMO use and type of pathogen. Infections during the first 48 h after transplantation occurred in 7% of patients.
FIGURE 1.
Timeline of infection according to pathogen at 1 y after transplantation.
The overall incidence rate for all infections at 1 y was 259 per 100 person-years (95% CI, 192-342) in the ECMO group and 126 per 100 person-years (95% CI, 113-141) in the non-ECMO group. Specifically, the incidence rates per 100 person-years for bacterial infections were 176 (95% CI, 122-246) in the ECMO group versus 68 (95% CI, 58-79) in the non-ECMO group, for viral infections were 52 (95% CI, 25-95) in the ECMO group versus 45 (95% CI, 37-55) in the non-ECMO group, and for fungal infections were 36 (95% CI, 16-75) in the ECMO group versus 14 (95% CI, 10-20) in the non-ECMO group.
In both groups, most bacterial infections were caused by Enterobacterales followed by coagulase-negative staphylococci and Pseudomonas aeruginosa and most viral infections by herpes viruses. In the ECMO group, respiratory tract infections were the most common (11 of 41, 27%, 36% of them caused by Enterobacterales, 18% by P. aeruginosa, 18% by Stenotrophomonas spp.) followed by surgical site infections (8 of 41, 19.5%; 50% of them caused by staphylococci, 25% by P. aeruginosa), and catheter-related infections (5 of 41, 12%; 2 of them caused by Enterobacterales, 1 by Enterococci, 1 by Staphylococci, 1 by Clostridium spp.). In the non-ECMO group, the most frequent site of infection was respiratory tract (41 of 201, 20%; 49% of them caused by Enterobacterales and 12% by P. aeruginosa), followed by urinary tract (35 of 201, 17%; 85% of them caused by Enterobacterales and 15% by P. aeruginosa) and surgical site (32 of 201, 16%; 36% of them caused by Staphylococci and 29% by Enterococci).
The respective frequency of invasive aspergillosis and candidiasis were similar in both groups (Table 2). In the ECMO group, there were 2 cases of invasive pulmonary aspergillosis and 1 case of disseminated aspergillosis that occurred during the immediate posttransplant period (on days 5, 11, and 15, respectively) during intensive care unit hospitalization. Aspergillus fumigatus was identified in culture or biopsy in all 3 cases (in 1 case with a Zygomycosis co-infection). Concerning risk factors for aspergillosis, all these patients underwent surgical reoperation; 2 had renal failure, one of whom required hemodialysis and 1 patient experienced acute graft rejection. Voriconazole was used as monotherapy in 2 cases, whereas in 1 case, it was combined with caspofungin. In the non-ECMO group, 8 patients developed invasive pulmonary aspergillosis and 2 patients disseminated aspergillosis (unavailable data for 4 patients) occurring during the first month after transplantation in 6 of 10 cases. Aspergillus spp. was identified in culture or biopsy and serum galactomannan antigen testing was negative in 5 of 7 cases. Of 10 patients, 7 had renal failure (with 2 requiring hemodialysis), 6 underwent reoperation, and 4 experienced an acute rejection.
One center reported a higher incidence of fungal infections, although no outbreak was observed during the study period.
In the non-ECMO group, 4 patients developed Pneumocystis jirovecii pneumonia; none of them received specific prophylaxis (TMP-SMX, atovaquone, or pentamidine) at the time of diagnosis.
In the ECMO group, 75% (43 of 57) of infections occurred after ECMO removal, whereas 25% (14 of 57) occurred during ECMO support. Although the prevalence of bacterial infections was similar before and after ECMO removal (64% and 72%, respectively), fungal infections were more common before ECMO removal (28.6% versus 9.3%).
Risk Factors for Infection
The analysis of risk factor for overall and fungal infections within the first-year posttransplant is shown in Table 3. The use of ECMO support posttransplant was significantly associated with an increased risk of overall infections (hazard ratio [HR] 1.81 [95% CI, 1.02-3.19], P = 0.04) and fungal infections (HR 3.44 [95% CI, 1.33-8.89], P = 0.01). The duration of ECMO therapy also influenced the risk of infection, with an increased risk of 31% per each day of additional ECMO use (odds ratio [OR] per 1-d increment 1.31 [95% CI 1.00-1.82], P = 0.05) (Table S1, SDC, https://links.lww.com/TXD/A805).
TABLE 3.
Cox regression assessing risk factor for overall and fungal infections in heart transplant recipients
| Hazard ratio (95% CI) | P | ||
|---|---|---|---|
| Overall infection | |||
| ECMO posttransplantation | 1.82 (1.02-3.19) | 0.04 | |
| Sex (male) | 1.29 (0.91-1.84) | 0.15 | |
| Recipient age (y) [per 1-y increment] | 1.00 (0.99-1.02) | 0.50 | |
| Donor age (y) [per 1-y increment] | 1.00 (0.98-1.01) | 0.91 | |
| LVAD pretransplantation | 1.36 (0.99-1.83) | 0.06 | |
| ECMO pretransplantation | 2.10 (0.97-4.53) | 0.06 | |
| Antifungal prophylaxis | 1.16 (0.68-1.94) | 0.58 | |
| TMP-SMX prophylaxis | 0.45 (0.30-0.65) | <0.01 | |
| Induction with ATG | 1.10 (0.78-1.57) | 0.57 | |
| Cold ischemia time | 1.07 (0.92-1.23) | 0.37 | |
| NYHA class III/IV before transplantation | 1.11 (0.78-1.58) | 0.55 | |
| Left ventricular ejection fraction before transplantation | 1.01 (0.99-1.02) | 0.34 | |
| Fungal infection | |||
| ECMO posttransplantation | 3.44 (1.33-8.89) | 0.011 | |
| Sex (male) | 1.12 (0.48-2.60) | 0.79 | |
| Recipient age (y) [per 1-y increment] | 1.04 (1.01-1.07) | 0.003 | |
| Antifungal prophylaxis | 0.81 (0.24-2.69) | 0.73 | |
ATG, antithymocyte globulin; ECMO, extracorporeal membrane oxygenation; LVAD, left ventricular assist device; NYHA, New York Heart Association; TMP-SMX, trimethoprim/sulfamethoxazole.
We identify that the use of TMP-SMX was associated with a lower risk of infection (HR 0.44 [95% CI, 0.33-0.66], P < 0.01). Because patients in the ECMO group were less likely to receive TMP-SMX prophylaxis because of early high mortality and more critical conditions, this could represent a prescription bias toward a higher use of TMP-SMX in the other group. A sensitivity analyses showed that the use of TMP-SMX during the first month, but not during the first 6 mo posttransplant, remained associated with a lower risk of infection (Table S2 and S3, SDC, https://links.lww.com/TXD/A805).
In the ECMO group, incidence of fungal infection was 0 (0%) of 7 in patients receiving antifungal prophylaxis, and 7 (20%) of 35 in patients not receiving antifungal prophylaxis. However, in the Cox regression, antifungal prophylaxis was not associated with a significant lower risk of fungal infections (HR 0.81 [95% CI, 0.24-2.69], P = 0.76).
Mortality
Mortality after 1 y was 57% (24 of 42) in the ECMO group and 6.4% (17 of 264) in the non-ECMO group (P < 0.001). Median time to death was 8.5 d in the ECMO group (IQR 2.75–17 d) versus 119 d in the non-ECMO group (IQR 1.5–166 d). The most frequent cause of death in the ECMO group was allograft failure (10 of 24, 42%) followed by hemodynamic shock (8 of 24, 33%), and hemorrhagic shock (4 of 24, 17%). In the non-ECMO group, causes of death were allograft failure (5 of 17, 29%) followed by hemorrhagic shock (3 of 17, 18%) and respiratory failure (2 of 17, 12%). One patient in each group died from infectious complications (1 of 24, 4.2% in the ECMO group and 1 of 17, 5.9% in the non-ECMO group).
Among patients in the ECMO group who survived 30 d posttransplantation, 1-y mortality was significantly higher in those with fungal infections compared with those without (2 of 3 [66.7%] versus 2 of 18 [11.1%], P = 0.02).
DISCUSSION
This nationwide study showed that infections were a frequent and early complication among heart transplant recipients requiring ECMO support after transplantation. Over a 9-y period, the incidence rate of overall infections in this population was twice as high as that observed in patients without ECMO support. Bacterial and fungal infections were significantly more frequent in the ECMO group. The risk of infection increased with the duration of ECMO therapy. Because of the observational nature, the main limitation of our study is the difficulty in differentiating whether ECMO support is a risk of infection per se or only a marker of a more critical clinical condition. However, our study is one of the largest series specifically describing the epidemiology of infections in heart transplant recipients receiving ECMO support.
Most of the data regarding ECMO-associated infections come from cohorts of predominantly immunocompetent patients. In these studies, the prevalence of nosocomial infections ranged widely from 9% to 64%.9-12 This large variability was explained by differences in the study population, with lower rates in the neonatal and pediatric group compared with the adult group, as well as in the definition of infections, patient management, and infection control strategies.13 Among heart transplant recipients, the incidence of infection has been estimated to be between 60% and 80%, with higher rates of infection in the early posttransplant period.8,14-17 In line with our results, in a cohort of 113 heart transplant recipients, of whom 52% were under ECMO within 24 h after transplantation, up to 81% of patients developed at least 1 infection (mostly bacterial and fungal) within 180 d from transplantation.16
The etiology of bacterial infections during ECMO support varies according to the study. While in a multicenter large registry of patients with ECMO support, most bacterial infections were caused by coagulase-negative staphylococci, followed by P. aeruginosa, Enterobacterales and Staphylococcus aureus,9 in our cohort, Enterobacterales were responsible for up to 34% of bacterial infections. As reported in other cohorts of heart transplant recipients, the most common infections in our population with or without ECMO support were pneumoniae.16,18
Incidence of invasive fungal infection in heart transplant recipients varies from 2.2% to 7.1%,19-23 with more than a half of episodes occurring within the first 90 d after heart transplantation.21 In the study of Pons et al, including a high proportion of patients on ECMO support after transplantation, 14% of heart recipients developed a fungal infection.16 In addition, some case reports have documented cases of invasive aspergillosis associated with the use of ECMO in otherwise immunocompetent patients.24-26
In a retrospective study at Lausanne University Hospital, the use of ECMO was identified as a risk factor for fungal infection among adult heart transplant recipients. The administration of targeted antifungal prophylaxis with caspofungin among recipients with at least 1 of the risk factors for fungal infection previously identified (ECMO, renal replacement therapy, or Aspergillus spp. colonization) was associated with a lower number of fungal infection and lower 30-d mortality.6 However, because of insufficient data, current guidelines do not recommend antifungal prophylaxis in patients with ECMO support.27,28 Despite the limitation of the low number of events and the retrospective nature of our data, because of the high mortality associated with invasive fungal infection, antifungal preventive strategies need to be evaluated specifically in patients receiving ECMO support.
In our study, the use of TMP-SMX was associated with a lower risk of overall infections. However, only 45% of patients in the ECMO group received TMP-SMX, probably because they died before prophylaxis could be introduced. Our findings showing that TMP-SMX was only associated with a lower incidence of infection during the first 30 d posttransplant, but not thereafter (when most patients should have received prophylaxis), argues against a significant protective role of the use of TMP-SMX in our cohort with respect to overall infection.
The present study has several limitations. First, we were not able to prove whether ECMO is a risk factor for infection or only a marker of severity, despite applying a time-dependent Cox regression taking death as a competing risk. This is because of the impossibility to find a control group with a similar critical condition but not receiving ECMO support, so that we were not able to construct a meaningful propensity score-adjusted model to compare these groups. Moreover, some variables that may be associated with an increased risk of infections, such as renal replacement therapy, presence and duration of mechanical ventilation, related complications, acute liver failure, and duration of ICU hospitalization, are missing. Furthermore, plasma concentrations of antimicrobials, potentially influenced by ECMO support, were not measured in our study, thereby preventing an assessment of their impact on infection outcomes. Because this is a national cohort, data on epidemiology may not be extrapolated to other countries.
In conclusion, in this nationwide cohort of heart transplant recipients, the use of ECMO support after transplantation is associated with higher risk of infection, especially fungal infections. These findings underscore the need for an increased awareness among clinicians and a low threshold of suspicion of infection. More studies are necessary to investigate the potential benefit of antifungal prophylaxis in this population.
ACKNOWLEDGMENTS
The authors thank all patients who participate in the STCS, the study nurses, the central and local data managers, and all of the investigators involved in the STCS.
Supplementary Material
APPENDIX
Members of the STCS are Patrizia Amico, Adrian Bachofner, Vanessa Banz, Sonja Beckmann, Guido Beldi, Christoph Berger, Ekaterine Berishvili, Annalisa Berzigotti, Isabelle Binet, Pierre-Yves Bochud, Sanda Branca, Anne Cairoli, Emmanuelle Catana, Yves Chalandon, Sabina De Geest, Sophie De Seigneux, Joëlle Lynn Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Andreas Flammer, Jaromil Frossard, Déla Golshayan, Nicolas Goossens, Fadi Haidar, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Linard Hoessly, Günther Hofbauer, Uyen Huynh-Do, Nina Khanna, Michael Koller, Andreas Kremer, Thorsten Krueger, Christian Kuhn, Bettina Laesser, Frédéric Lamoth, Roger Lehmann, Alexander Leichtle, Oriol Manuel, Hans-Peter Marti, Michele Martinelli, Valérie McLin, Katell Mellac, Aurélia Merçay, Karin Mettler, Nicolas Müller, Ulrike Müller-Arndt, Mirjam Nägeli, Graziano Oldani, Manuel Pascual, Rosmarie Pazeller, Klara Posfay-Barbe, David Reineke, Juliane Rick, Simona Rossi, Fabian Rössler, Silvia Rothlin, Thomas Schachtner, Stefan Schaub, Dominik Schneidawind, Macé Schuurmans, Simon Schwab, Thierry Sengstag, Federico Simonetta, Jürg Steiger, Guido Stirnimann, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Jean Villard, Julien Vionnet, Caroline Wehmeier, Madeleine Wick, Markus Wilhelm, Patrick Yerly
Footnotes
A full list of members is included under the Appendix.
This study has been conducted in the framework of the STCS, supported by the Swiss National Science Foundation (grant no. 33CS30_177522), Unimedsuisse, and the Swiss Transplant Centers.
The authors declare no conflicts of interest.
L.v.d.B., M.F.-R., and O.M. conceived and designed this study. L.v.d.B. collected additional variables not included in the Swiss Transplant Cohort Study (STCS) database. L.D.H. performed statistical analysis. L.v.d.B., L.D.H., and O.M. wrote the first draft of the article. All the authors contributed to data interpretation, participated in revision of the article and approved his final version.
Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantationdirect.com).
Contributor Information
Mario Fernández-Ruiz, Email: mario_fdezruiz@yahoo.es.
Linard D. Hoessly, Email: linarddavid.hoessly@usb.ch.
Roger Hullin, Email: roger.hullin@chuv.ch.
Matthias Kirsch, Email: matthias.kirsch@chuv.ch.
Antoine Schneider, Email: antoine.schneider@chuv.ch.
Nicolas J. Mueller, Email: nicolas.mueller@usz.ch.
Markus J. Wilhelm, Email: markus.wilhelm@usz.ch.
Andreas J. Flammer, Email: Andreas.Flammer@usz.ch.
Michele Martinelli, Email: michele.martinelli@insel.ch.
Andreas Bloch, Email: andreas.bloch@luks.ch.
David Reineke, Email: david.reineke@insel.ch.
Dionysios Neofytos, Email: dionysios.neofytos@hcuge.ch.
Frédéric Lamoth, Email: frederic.lamoth@chuv.ch.
Cédric Hirzel, Email: cedric.hirzel@insel.ch.
Laura N. Walti, Email: laura.walti@insel.ch.
Oriol Manuel, Email: Oriol.Manuel@chuv.ch.
Collaborators: Patrizia Amico, Adrian Bachofner, Vanessa Banz, Sonja Beckmann, Guido Beldi, Christoph Berger, Ekaterine Berishvili, Annalisa Berzigotti, Isabelle Binet, Pierre-Yves Bochud, Sanda Branca, Anne Cairoli, Emmanuelle Catana, Yves Chalandon, Sabina De Geest, Sophie De Seigneux, Joëlle Lynn Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Andreas Flammer, Jaromil Frossard, Déla Golshayan, Nicolas Goossens, Fadi Haidar, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Linard Hoessly, Günther Hofbauer, Uyen Huynh-Do, Nina Khanna, Michael Koller, Andreas Kremer, Thorsten Krueger, Christian Kuhn, Bettina Laesser, Frédéric Lamoth, Roger Lehmann, Alexander Leichtle, Oriol Manuel, Hans-Peter Marti, Michele Martinelli, Valérie McLin, Katell Mellac, Aurélia Merçay, Karin Mettler, Nicolas Müller, Ulrike Müller-Arndt, Mirjam Nägeli, Graziano Oldani, Manuel Pascual, Rosmarie Pazeller, Klara Posfay-Barbe, David Reineke, Juliane Rick, Simona Rossi, Fabian Rössler, Silvia Rothlin, Thomas Schachtner, Stefan Schaub, Dominik Schneidawind, Macé Schuurmans, Simon Schwab, Thierry Sengstag, Federico Simonetta, Jürg Steiger, Guido Stirnimann, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Jean Villard, Julien Vionnet, Caroline Wehmeier, Madeleine Wick, Markus Wilhelm, and Patrick Yerly
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