The COVID-19 pandemic severely impacts large parts of the world and the further development of this disease cannot be predicted. Patients after heart transplantation represent a particularly vulnerable patient population due to chronic immunosuppression, high rates of comorbidities and frequent contacts with medical professionals. We here present a multicenter study of COVID-19 among heart transplant recipients which represents a first nation-wide survey of this disease in a solid organ transplantation cohort.
Our data demonstrate an increased rate of the severe form of COVID-19 requiring invasive mechanical ventilation (38.1%) as well as a higher mortality (33.3%) compared to international cohorts of general populations [7, 28]. This is in line with findings from a mixed case series of 90 solid organ transplant recipients (46 kidney, 17 lung, 13 liver, 9 heart and 5 dual-organ transplants) by Pereira and colleagues  were a mortality rate of 17.8% (16 of 90 solid organ transplant recipients with COVID-19 deceased) was found, a case series of 36 kidney transplant recipients by Akalin and colleagues  with a mortality rate of 27.8% (10 of 36 kidney transplanted patients with COVID-19 deceased), and a case series of 28 heart transplant recipients in New York by Latif and colleagues  were the mortality rate was 25.0% (7 of 28 heart transplanted patients with COVID-19 deceased).
However, it is remarkable that 13 of 21 patients (61.9%) after heart transplantation had a non-severe course despite continuous immunosuppression and high prevalence of comorbidities in our cohort. The effect of the underlying immunosuppressive drug therapy on the course of COVID-19 infection remains a matter of debate as in vitro data suggest an inhibition of viral replication by immunosuppressive drugs [29,30,31,32,33], while long-term immunosuppression increases susceptibility to infection . The elevated mortality rate in our study as well as in other studies with solid organ recipients rather implies a negative effect of the immunosuppressive drugs on the course of COVID-19 infection [12, 13, 18]. It, therefore, demands further research to better define the role of the immune response and its impact on outcomes in non-transplanted and transplanted (under immunosuppression) COVID-19 patients.
Frequency of COVID-19 in heart transplant recipients
Our data from the first months of the pandemic in Germany rather show a small number of heart transplant recipients with COVID-19 infection, given that between 250 and 350 heart transplantations are performed in Germany annually . This assumption is underpinned by a recently published study of 87 heart transplant patients monitored during January and February in China, without a single COVID-19-positive patient . This observation could be related to a particular awareness in transplanted patients who were commonly trained in infection prevention and hygiene measures already before the COVID-19 pandemic. However, our data relied on reports to the transplant centers and we observed that some of the patients are primarily treated in community hospitals. Thus, our data may be incomplete and may underestimate the prevalence of COVID-19 among heart transplant recipients. Of note, we found only 3 patients from northern and eastern Germany and 18 from southern and western Germany, reflecting the inhomogeneous distribution of SARS-CoV-2 infection in Germany [36, 37].
Clinical presentation of COVID-19 in heart transplant recipients
The clinical presentation of COVID-19 in our cohort did not differ from non-transplant patients or other solid organ transplant recipients, and this was depicted in other reports from immunosuppressed patients likewise [12, 13, 15,16,17,18]. Typical symptoms in this study included dyspnea (85.7%), cough (76.2%), and myalgia/fatigue (76.2%), followed by rhinitis (66.7%) and fever (66.7%). Of note, only one patient (4.8%) had reported anosmia or loss of taste which has been described as an early sign of COVID-19 . A specific treatment for COVID-19 remains unavailable; therefore, the initial clinical management is based on supportive care (antibiotic therapy, oxygen supply and supportive measures including intensive medical care, if needed). Pausing of mycophenolate mofetil as recommended in the “Guidance for Cardiothoracic Transplant and Ventricular Assist Device Centers regarding the SARS CoV-2 pandemic by the International Society of Heart and Lung Transplantation (ISHLT)” and switch from sirolimus to tacrolimus are further options in heart transplant recipients due to the specific pharmacological properties of mycophenolate mofetil and sirolimus  and these strategies were applied in the majority of patients. However, due to the small sample size of our study, effects of differential immunosuppressive and other therapeutic strategies cannot be judged and require further investigations in a larger cohort.
Noteworthy, we observed RV dysfunction, elevated pulmonary artery pressures, and tricuspid valve regurgitation particular in patients with severe course and high mortality. We can only speculate whether this just reflects the invasive mechanical ventilation in these patients or if these observations are a result of potential thromboembolic complications induced by COVID-19 as proposed by others [39, 40].
Several studies have reported a high incidence of thromboembolic complications in patients with COVID-19 [1, 41,42,43]. Patients with COVID-19 and thromboembolic complications tend to be older, have lower lymphocyte counts, and have higher D-dimer levels [41, 43]. Severe course of COVID-19 infection can lead to sepsis and increased release of inflammatory cytokines which can promote coagulation activation and the occurrence of thromboembolic events . As elevated D-dimer levels are a sign of excessive coagulation activation and hyperfibrinolysis, resulting thromboembolic complications may be associated with a poor prognosis in patients with COVID-19 .
In this study, 4 of 21 patients (19.0%) had new thromboembolic events (2 patients with new deep vein thrombosis and 2 patients with new pulmonary embolism). All four patients had a severe course of COVID-19 and were admitted to the intensive care unit. Therefore, in view of our findings and in accordance with other studies, pharmacological anticoagulation should be considered in patients with COVID-19 infection, especially in patients with severe course on the intensive care unit [1, 41,42,43].
Interestingly, COVID-19 was accompanied with an increase of cardiac biomarkers, high-sensitivity cardiac troponin T and NT-proBNP. All patients demonstrated elevated values, but, a significantly higher level of both biomarkers was found in patients with severe course of COVID-19 requiring invasive mechanical ventilation and consequent high mortality. Impaired outcomes in non-transplant patients with elevated cardiac troponins were shown likewise in early reports from China [28, 44, 45]. Multiple pathomechanisms for this observation were discussed, including an imbalance of oxygen demand and supply, direct myocardial injury by viruses or cytokines, or precipitating plaque rupture and a prothrombotic state leading to myocardial infarction . Similarly, elevated NT-proBNP was linked to adverse outcomes, although postulated cut-offs for elevated risk (88.6 pg/ml in the study by Gao et al. ) were far from the values we found in our patient cohort with a mean of 9426.2 ng/l. However, elevated cardiac biomarkers, arrhythmias, thromboembolic events, and RV dysfunction in patients with severe course of COVID-19 in our study, point to the importance of a careful cardiovascular monitoring of patients after heart transplantation when infected with COVID-19.
The present study was conducted as a multicenter survey of all heart transplant centers in Germany (24 centers). However, although all heart transplant centers provided information regarding COVID-19, some patients might have been treated at community hospitals without the knowledge of the related heart transplant centers. Furthermore, we could only include patients who presented at medical facilities, neglecting patients with mild or subclinical course of COVID-19 who were not diagnosed. Moreover, the small number of patients limits the conclusions that can be drawn from our data.