A total of 21 heart transplant recipients diagnosed with COVID-19 could be identified across all heart transplant centers in Germany in a period between March and June 2020. Three patients were treated at community-based hospitals, whereas 18 patients were treated at transplant centers. Three patients (14.3%) received heart transplantation within prior 12 months and three other patients (14.3%) had heart transplant within the last 24 months, whereas the majority of patients were long-term transplanted (mean time from transplantation to COVID-19: 2858.3 ± 2516.4 days). Mean patient age was 58.6 ± 12.3 years and 17 of 21 (81.0%) were male. Comorbidities included cardiac allograft vasculopathy in 4 patients (19.0%), arterial hypertension in 15 (71.4%), dyslipidemia in 15 (71.4%), diabetes mellitus in 7 patients (33.3%), dialysis in 6 patients (28.6%) and chronic-obstructive lung disease/asthma in 4 patients (19.0%). Principal diagnosis for heart transplantation included 5 patients with ischemic cardiomyopathy (23.8%), 13 patients with dilated cardiomyopathy (61.9%), 1 patient with hypertrophic cardiomyopathy (4.8%), 1 patient with arrhythmogenic cardiomyopathy (4.8%) and 1 patient with congenital heart disease (4.8%). Most patients received an immunosuppressive drug regimen consisting of mycophenolate mofetil (85.7%) and steroids (71.4%) in addition to a calcineurin inhibitor (ten patients with tacrolimus [47.6%] and five patients with cyclosporine A [23.8%]). About 40% of patients received mTOR (mammalian target of rapamycin) inhibitors (eight patients with everolimus [38.1%] and one patient with sirolimus [4.8%]). Concomitant medication comprised aspirin or clopidogrel in 14 patients (66.7%), beta blockers in 6 patients (28.6%), calcium channel blockers in 9 patients (42.9%), ivabradine in 4 patients (19.0%), angiotensin converting enzyme inhibitors (ACE-I)/angiotensin II receptor blockers (ARB) in 8 patients (38.1%), and statins in 18 patients (85.7%). Baseline characteristics are provided in Table 1.

The most common reported symptoms of COVID-19 were dyspnea (85.7%), cough (76.2%), and myalgia/fatigue (76.2%), followed by rhinitis (66.7%) and fever (66.7%). A minority of patients presented with diarrhea (28.6) or reported pain (23.8%). Only one patient had reported anosmia or loss of taste (4.8%).

No patient showed an impairment of left ventricular ejection fraction, but six patients (28.6%) developed a reduced right ventricular (RV) function in the further course in addition to an elevated systolic pulmonary artery pressure (28.6%) and a moderate-to-severe tricuspid regurgitation (19.0%). Sixteen patients (76.2%) had an abnormal chest CT with atypical pneumonia including bilateral infiltrates. Four patients developed ECG abnormalities during their hospital stay (two patients had new-onset atrial fibrillation and two patients had a non-sustained ventricular tachycardia) and four patients had new thromboembolic events (two patients with new deep vein thrombosis and two patients with new pulmonary embolism). No patient in this study had atrial fibrillation before the COVID-19 infection and no patient had an anticoagulant before the COVID-19 infection. The two patients with new-onset atrial fibrillation and the four patients with new thromboembolic events received full-dose unfractionated heparin. Patients with non-severe course of COVID-19 infection predominantly received a prophylactic anticoagulation, while patients with severe course received a full anticoagulation with unfractionated heparin or direct thrombin inhibitor.

At the beginning of the pandemic, there were no established protocols for the treatment of heart transplant recipients with COVID-19. Hence, the decision for antibiotic and antifungal treatment was based on the experience of the local transplant team. Blood cultures were routinely taken at the time of admission but were mostly negative or showed unspecific findings (staphylococcus epidermidis or enterococcus faecium). All patients received antibiotic therapy (12 patients with piperacillin/tazobactam [57.1%] and 9 patients with meropenem [42.9%]). Additionally, azithromycin (19.0%) and caspofungin (19.0%) were administered. For treatment of COVID-19, three (14.3%) patients received an experimental therapy with hydroxychloroquine. No patient received remdesivir.

In terms of the immunosuppressive drug therapy, drug trough levels of calcineurin inhibitors and mTOR inhibitors were slightly reduced depending on the period after heart transplantation. Drug doses were closely monitored and adapted accordingly. As the respective aims for the drug trough levels varied between centers, no further analysis was performed. Mycophenolate mofetil was suspended in half of patients (52.4%) and one patient on sirolimus was switched to tacrolimus (4.8%). Patients with severe course additionally received a pulse steroid therapy with a steroid dose of up to 200 mg to prevent pathological immune responses and to omit adrenal insufficiency.

Six patients were on dialysis before (28.6%) and five additional patients (23.8%) required dialysis in the further course. Eight patients (38.1%) required invasive mechanical ventilation of whom seven deceased (87.5%). Extracorporeal life support (ECLS) was applied in three patients (14.3%) who after all passed away and intended in another patient who beforehand deceased as a result of septic shock. Clinical presentation and treatment are given in Table 2.

Laboratory values showed an increased mean high-sensitivity cardiac troponin T of 137.5 ± 113.3 pg/ml and an N-terminal prohormone of brain natriuretic peptide (NT-proBNP) of 9426.2 ± 12,835.1 ng/l. High-sensitivity troponin I instead of troponin T was measured in three out of 21 patients, however, as the assays are difficult to compare [26], we did not include these data. Blood count revealed leucocytosis (12.0 ± 6.1/nl) with a high neutrophil count (83.4 ± 3.8%) and a low lymphocyte count (9.2 ± 5.4%). In addition, analysis of markers of inflammation showed a pronounced elevation of mean C-reactive protein (132.7 ± 109.0 mg/l), procalcitonin (5.9 ± 8.2 ng/ml), lactate dehydrogenase (635.6 ± 317.1 U/l), ferritin (2619.4 ± 2451.4 µg/l), and D-dimer (4.4 ± 3.2 mg/l). Laboratory findings are displayed in Table 3.

Eight patients had a severe course (38.1%) and 13 patients had a non-severe course (61.9%). As per our definition, all patients with severe course required invasive mechanical ventilation, 62.5% had a reduced right ventricular (RV) function, 50.0% had new-onset arrhythmias (two patients with new-onset atrial fibrillation and two patients with new-onset ventricular tachycardia), and 50% had new thromboembolic events (two patients with new deep vein thrombosis and two patients with new pulmonary embolism). One of the latter patients with ventricular tachycardia was treated with hydroxychloroquine, which has been linked to pro-arrhythmogenic effects [27]. Only one patient with non-severe course had a reduced right ventricular function (7.7%). No one in this group displayed arrhythmias or had thromboembolic complications. Regarding kidney function, three patients with non-severe course (23.1%) and three patients with severe course (37.5%, p = 0.631) were on dialysis before COVID-19 infection. During COVID-19 infection, two additional patients with non-severe course (15.4%) and three patients with severe course (37.5%, p = 0.325) required dialysis in the further course. There were no statistically significant differences concerning creatinine (p = 0.148) or glomerular filtration rate between groups (p = 0.080).

Comparison of markers of infection showed a significantly lower lymphocyte count (p = 0.013), and higher values for platelet count (p = 0.017), procalcitonin (p = 0.002), lactate dehydrogenase (p < 0.001), and D-dimer (p = 0.011) in patients with severe course. Furthermore, patients with severe course had significantly higher levels of high-sensitivity cardiac troponin T (p = 0.017) and NT-proBNP (p < 0.001). Data from comparison between patients with severe and non-severe course are given in detail in Table 4.

Taken all patients together, the severe form of COVID-19 occurred in 38.1% of heart transplant recipients with an underlying mortality of 87.5% in those patients. The overall mortality in this study was at 33.3% (7 out of 21 patients). All but 2 patients were hospitalized (90.5%) and 15 patients (71.4%) were at least temporarily treated on intensive care or intermediate care wards. At 30-day follow-up after COVID-19 diagnosis, 10 of 13 patients (76.9%) were discharged and 3 of 13 patients (23.1%) were still hospitalized in the non-severe disease group. In the severe course group, one patient already deceased one day after admission to hospital in septic shock, while further five patients passed away within 30 days. One patient in this group deceased 32 days after admission to the hospital after a prolonged intensive care unit stay. The last remaining patient in the severe course group is 60 days after hospital admission still on the intensive care unit requiring invasive mechanical ventilation at the time of preparing the manuscript.

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 [34]. 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 [35]. 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].

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, 15‐18]. 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 [38]. 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 [17] 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, 41‐43]. 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 [41]. 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 [41].

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, 41‐43].

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 [46]. 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. [47]) 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.