Clinical course and challenging management of early COVID-19 infection after heart transplantation: case report of two patients

In the current context of coronavirus disease 2019 (COVID-19), the management of patients with end-stage heart failure on the transplant waiting list, and of heart transplant recipients (HTR) is challenging. To date, only a few case reports or small case series of COVID-19 in HTR have been described in China, Spain, Germany, and the United States, with mainly HTR who were remote from transplant and on chronic immunosuppressive drugs [1‐8]. The limited data published so far have shown that the clinical presentation of COVID-19 in those patients did not differ from non-transplant patients or other solid organ transplant recipients [1, 2, 5, 6, 8]. However, the case fatality rate in some case series varied from 23% to up to 33% [6, 8, 9]. Newly HTR constitute a particularly vulnerable cohort for severe COVID-19 infection due to high levels of immunosuppression and frequent comorbidities. Unfortunately, the clinical characteristics and the management of COVID-19 in this subgroup of patients remain largely unknown. Herein, we report on two HTR who developed and ultimately died from severe COVID-19 a few days after their urgent transplant procedure (TP). Both were completely asymptomatic at their admission in our center with no respiratory complaints. These cases highlight the clinical course of these two patients and the difficulties encountered in their management.

The global pandemic of COVID-19 has severely challenged the health care systems that face the battle to limit the spread of the SARS-CoV-2 while providing the treatment and care that will save lives. In most countries, cardiac surgery activity has been restricted to urgent or emergent cases, including heart transplantation. The safety of continuing this procedure during the current COVID-19 outbreak is, however, unknown. The literature on this topic is still scant. HTR appears to be at particular high risk for both acquisition of COVID-19 infection and progression to severe disease due to high rates of comorbidities, immunosuppression, and multiple healthcare contacts [12].

Li et al. were the first to report the clinical course of two HTR with COVID-19. However, TP was performed 32 and 194 months before the infection, respectively [1]. The two patients presented with variable levels of severity, one mild, the other more severe and requiring prolonged hospitalization. Both patients survived the infection. Fernando-Ruiz et al. reported the occurrence of COVID-19 among 4 HTR in a single center in Spain. The median interval from transplantation was 12.6 years (range, 8.7–17.9 years). One patient died 10 days after admission for respiratory failure, one patient was still in the ICU, and two patients survived and were discharged home [3]. Since these initial reports, other papers describing the clinical course of COVID-19 in HTR have been published from Germany and the United States. They also featured HTR who were remote from transplant and were mostly receiving relatively low-dose maintenance immunosuppression [2, 4, 5, 7‐9]. Recently, Latif et al. described a single-center case series of 28 HTR with a confirmed diagnosis of COVID-19 in the United States. The median time from HT was 8.6 years, and the case fatality rate was 25% [6]. Singhvi et al. also described a single -center case series of 22 HTR in the disease epicenter in New York. The median time from HT was 4.6 years, and the overall mortality was 22.7%, reaching 26.3% in hospitalized patients [9]. Finally, Rivinius et al. reported 21 HTR with COVID-19 in a recent nation-wide survey of all HT centers in Germany during the first months of the pandemic. The overall mortality in their study was 33.3% [8].

To our knowledge, our report is the first to highlight the clinical course of two HTR for whom viral carriage was confirmed by RT-PCR performed on NPS during the perioperative period. Both patients developed severe COVID-19 infection and ultimately died. The two patients had significant lymphopenia and elevation of inflammatory biomarkers such as CRP. However, the interpretation of the laboratory findings is complicated by confounding factors such as the recent transplant surgery, and the initiation of high doses of immunosuppressive drugs (MM). Laboratory findings are displayed in Fig. 4, Additional files 1 and 2, and Table 1. Histopathological analysis of the myocardial biopsy specimens of both patients did not demonstrate cellular or humoral rejection. However, analysis by electron microscopy revealed viral-like particles within myocardial endothelial cells but not in cardiomyocytes. SARS-CoV-2 gains entry to human cells by binding to the angiotensin-converting enzyme 2 receptor which is expressed in cardiac myocytes. In a case report of a 69-year-old patient with COVID-19 and cardiogenic shock, endomyocardial biopsy revealed viral like particles within interstitial cytopathic macrophages but not in cardiomyocytes or endothelial cells [13]. The coronary microvasculature and endothelium may be at risk for viral entry due to SARS-Cov-2 receptor expression on these cells. Indeed, Vargaz et al. found evidence of direct viral invasion of endothelial cells in several organs of patients with COVID-19 infection using electron microscopic images [14]. Both endotheliitis and cytokine release may play a major role in the pathophysiology of COVID-19 infection and may explain the association between cardiovascular disease and increased morbidity of this illness. In our patients, histological signs of endotheliitis or viral antigen immunoreactivity were not detected in the biopsy specimens suggesting a direct cytolytic effect of the virus unlikely but rather a pathophysiology mechanism based on cytokine release or immune response. This may result in systemic alteration of the microcirculatory function in different vascular beds, causing vasoconstriction, organ ischaemia, inflammation and a pro-coagulant state [14]. It is also likely that the underlying frailty of both patients, related to the heart failure condition, may have contributed to their unfavorable outcome.

Defining the precise mechanism of the viral transmission process in our report is challenging. At the time of both procedures, exposure investigations and contact tracing were not performed preoperatively. Recipient 1 was an unknown asymptomatic carrier before the surgery. It appeared later on that he lived in an area of high incidence for COVID-19 infection. Recipient 2 had been hospitalized for 9 days at the time of organ offer. Her preoperative SARS-CoV-2 screening test performed 2 days before the TP was negative, but she further tested positive on POD2. Transmission could theoretically have occurred through inhalation of the first recipient’s viral particles aerosolized in the OR. However, given the number of typical air changes per hour and the associated reduction in airborne contaminants, the possibility of OR transmission is relatively low [15]. Another possibility is contamination in the early preoperative period. The second recipient was never in contact with the first patient’s surgeon during her stay before transplantation. Among the health care workers (HCWs) with exposure to both patients from their hospital admission to their death, only the surgeon of the first procedure tested positive soon after the intervention. However, at that time, testing was only performed among HCWs who exhibited symptoms suggestive of SARS-Cov-2 infection; therefore, asymptomatic HCWs in close contact with both patients were not tested. After both HTR tested positive for SARS-CoV-2, inquiries were carried out among their close relatives and no cases of COVID-19 were reported. Consequently, the origin of viral transmission was never explained for recipient 2.

Practically, recently updated guidance documents from major transplant societies recommend not performing heart transplantation if the donor or the recipient is screened positive for SARS-CoV-2 [16, 17]. However, as illustrated in our cases, the lack of a rapid diagnostic test, the high proportion of asymptomatic carriers [18] capable of transmitting the infection among patients’ acquaintance, the high rate of false negative tests [19], the possibility of donor-recipient transmission, and the absence of massive COVID-19 testing all currently contribute to the impossibility of timely identification of patients who should not receive an emergency transplant.

The decision to perform two heart TP in the midst of a pandemic with no rapid preoperative testing available to rule out COVID-19 infection could be seriously questioned. However, at the time of both TP, all Belgian transplant centers were still pursuing their program. We were at the beginning of the pandemic in Belgium with 1486 COVID-19 confirmed cases and 14 deaths in the whole country (Additional file 3) [20]. There were 500 patients with COVID-19 hospitalized with 100 in the ICU in the whole country. In addition, our hospital’s prevalence of COVID-19 cases was low (28 patients). The two patients were transplanted just before the beginning of the nationwide lockdown (18th March 2020), and there was no indication that they were infected. At that period (17th March 2020), the ISHLT suggested proceeding with transplantation in waitlisted patients as long as there was no recent exposure or symptoms compatible with COVID-19 in the previous 2 weeks. Furthermore, RT-PCR for SARS-Cov-2 was also recommended depending on timing and testing availability [16]. Despite the fact that the first patient was called in from home, he had experienced recurrent episodes of life-threatening arrhythmia with a worsening of his clinical status the weeks before his transplant, and the second patient was in the cardiologic ward for a new episode of heart failure requiring inotropic support.

Questions remain on the optimal management of immunosuppression in transplant recipients with Covid-19. Current guidelines from expert associations recommend considering holding MM, mammalian target of rapamycin inhibitors or azathioprine in cases of moderate/severe COVID-19 infection, though specific data are still lacking at this time in the literature [16]. However, whether immunosuppression therapy can modify the course of the disease with either the benefit of a reduced immunological reaction or a greater risk of severe manifestation remains uncertain. In a literature review of published cases of COVID-19 in HTR performed at the beginning of the pandemic, Decker et al. found that immunosuppressive agents have been partially discontinued or reduced in dose in 71.8% of patients [21]. The elevated mortality rate in several case series of COVID-19 among HTR on chronic immunosuppressive therapy does not suggest a protective effect of the immunosuppressive drugs on the course of the infection [6, 8, 9]. However, further studies are needed to evaluate the impact of immunosuppressive therapy on the pathogenesis and outcomes of COVID-19 infection among HTR. In our two asymptomatic patients, we initially continued immunosuppressive drugs without any particular adjustment of the dose while prescribing HCQ known to improve viral clearance. Despite this, the evolution was unfavorable with the appearance of symptoms within 15 days, the standard incubation period for the virus. Even worse, the viral load remained high in both patients despite the interruption of MM in both cases. As confirmed by several recent clinical trials [22, 23], antiviral monotherapy with HCQ was ineffective in both cases. We did not observe any toxicity of that drug in either patient. The potential benefit of other antiviral and immunomodulator drugs has not been tested. The two patients eventually died. Mortality rates associated with COVID-19 increase sharply with age and in patients with underlying cardiovascular diseases such as heart failure [24‐26]. Therapy for an overt disease is seriously lacking at the moment, although several promising molecules are still under active clinical investigations. Nonetheless, potential interactions between these medications and immunosuppressive drugs and the choice of the appropriate molecules according to clinical phenotype could add other challenges.

These two cases illustrate very well the severity and poor prognosis of COVID-19 infection in the immediate aftermath of a heart transplant. Moreover, our report highlights the problematic of asymptomatic carriers and of the delay in turnover time for COVID-19 testing results in HT. As transplant clinicians, we must be very careful about continuing the transplant program in this COVID-19 period. After these two cases, our heart transplant program was temporarily suspended. Our center has now increased its testing capacity as well as the use of serological testing. Our transplant policy is now in accordance with updated recommendations of major transplant societies. Donors and recipients are thoroughly screened to exclude infection and rule out any close contact with a person at risk or diagnosed with COVID-19 in the days preceding the transplant. The TP is not performed before obtaining the RT-PCR test results. In addition, after the procedure, patients should be regularly tested for COVID-19.