key: cord-312036-5867bc6i
authors: Decker, Annegrit; Welzel, Markus; Laubner, Katharina; Grundmann, Sebastian; Kochs, Georg; Panning, Marcus; Thimme, Robert; Bode, Christoph; Wagner, Dirk; Lother, Achim
title: Prolonged SARS‐CoV‐2 shedding and mild course of COVID‐19 in a patient after recent heart transplantation
date: 2020-06-09
journal: Am J Transplant
DOI: 10.1111/ajt.16133
sha: 
doc_id: 312036
cord_uid: 5867bc6i

In the coronavirus disease 2019 (COVID‐19) pandemic, organ transplant recipients are considered to be at high risk for unfavorable outcome. However, in particular the role of immunosuppression in patients infected with SARS‐CoV‐2 remains undetermined. Here, we present a 62‐year old male COVID‐19 patient with recent heart transplantation who developed only mild symptoms, but had prolonged virus shedding, and summarize the available data on COVID‐19 in cardiac allograft recipients. Initially the patient presented with a transient episode of fever and sore throat but no other symptoms, in particular no cough or dyspnea at rest. After diagnosis, immunosuppression was continued unchanged. On day 7, temperature increased again with concurrent mild rise of CRP, IL‐6 and proBNP levels. Hydroxychloroquine was started and continued for 7 days. While the patient had no clinical symptoms anymore 20 days after initial presentation, virus culture of throat swabs on days 18 and 21 confirmed active virus replication and SARS‐CoV‐2 PCR remained positive on day 35 with copy numbers similar to the onset of infection. In conclusion, immunosuppression regimen in transplant recipients with mild COVID‐19 associated symptoms may be continued unchanged. However, it may contribute to delayed virus PCR conversion and thus possible prolonged infectivity.

In the emergence of the Corona Virus Disease 2019 (COVID-19) pandemic, organ transplant recipients require particular consideration. COVID-19 is typically associated with lung injury, triggering a hyperinflammatory response involving myeloid cells and T cells and excessive production of inflammatory cytokines. 1 It has been hypothesized that immunosuppression could increase susceptibility to SARS-CoV-2 infection in transplanted patients. On the other hand, the anti-inflammatory effects of immunosuppression might modify presentation, course and outcome of COVID-19. 2, 3 Since many patients with COVID-19 develop cardiovascular complications 4 , heart transplant recipients may be at particular risk. Angiotensin-converting enzyme 2 (ACE2), which has been identified as the SARS-CoV-2 cell entry receptor, is expressed in cardiac myocytes and virus particles have been localized in myocardial biopsy from a patient with COVID-19 complicated by myocarditis. [5] [6] [7] Here, we report a mild course of SARS-CoV-2 infection with prolonged virus persistence in a patient only five months after heart transplantation.

The 62-year old male patient underwent heart transplantation on November 2 nd , 2019 for arrhythmogenic cardiomyopathy of the right ventricle. After transplantation, he remained hospitalized due to a series of complications including pneumonia and acute respiratory distress syndrome. He required 56 days of mechanical ventilation and was in need of intermittent renal replacement therapy. Echocardiography revealed a left ventricular ejection fraction of 55 % with no signs of transplant rejection. Immunosuppression regime consisted of cyclosporine A (target range 135 ± 30 ng / ml), mycophenolate mofetil 500 mg b.i.d. and prednisone 10 mg q.d.. No antilymphocyte globulins had been used as induction therapy. Blood count revealed anemia and leucopenia, the latter likely being caused by immunosuppressive medication, yet not improving significantly under dose reduction. He received cotrimoxazole and due to cytomegalovirus highrisk constellation (D+R-), ganciclovir had been administered for 4 months after transplantation and was then switched to valganciclovir prophylaxis. Concurrent medication did not include ACE inhibitors or angiotensin receptor blockers.

This article is protected by copyright. All rights reserved On March 13 th , 2020 (day 1), the patient developed fever (39,9°C), tachycardia (105 bpm) and a sore throat. PCR from throat swab revealed SARS-CoV-2 infection. Body temperature quickly normalized within the first 12 hours. Blood oxygen saturation levels remained stable in the range of 96-100% without oxygen supplementation at a respiratory rate of 16 breaths per minute.

Besides mild rhinorrhea and impaired exercise capacity, the patient showed no other symptoms, in particular no cough or dyspnea at rest. On day 7, a second increase in temperature up to 38,4°C was observed which resolved spontaneously. This episode went along with a mild rise and peak of CRP, IL-6 and proBNP levels and lymphopenia ( Figure 1A and still on day 35. Concurrent with the second onset of fever we observed an increased viral load after day 7 that slowly returned to the level of infection onset. Whereas the patient already was asymptomatic, virus culture on days 18 and 21 still confirmed active virus replication ( Figure   1E ).

As proBNP levels increased and decreased simultaneously with the inflammation parameters, we considered a COVID-19 related myocardial affection, yet did not confirm it by myocardial biopsy.

No signs of clinical deterioration, notably no signs of cardiorespiratory impairment, were observed. Weaning from hemodialysis was successful (day 1) and urine output and body weight remained stable. Cyclosporine A dose was adjusted several times over the course of infection to achieve therapeutic range of 135 +/-30 ng/ml ( Figure 1F ). Otherwise, medication including immunosuppression was continued unchanged except for an increase of prednisone dose to 50 mg for three days and 25mg for another three days from day 14 on for treatment of acute gout in the left knee.

Here, we report a case of mild nosocomial COVID-19 in a heart transplant recipient. Though the patient had been considered to be at high risk due to immunosuppression and a complicated course after recent transplant surgery, including respiratory and renal failure, he showed only mild

This article is protected by copyright. All rights reserved symptoms. Increase in inflammation markers at day 7 were accompanied by a transient raise in proBNP, however, no clinical signs of cardiorespiratory deterioration were observed during the whole course of infection and increase in proBNP might as well have been associated with weaning from haemodialysis. Our experiences in this case underscore the particularities in management of COVID-19 in heart transplant recipients.

Few registries or case series describe course and management of COVID-19 in heart transplant recipients. In a Chinese registry, upper airway infection was reported in 4 out of 87 cardiac allograft recipients but none of them was tested positive for SARS-CoV-2. 8 Among 803 heart transplant recipients from New York (USA), retrospective analysis revealed 28 cases of COVID- 19. 9 In total, we have identified 54 cases of COVID-19 in heart transplant recipients from registries or case reports, with full relatable data available for 38 patients (Table 1 ). 9-16 To date, out of these evaluable cases including our case reported here, 33 (84.6 %) have been hospitalized; 9 of them required invasive ventilation In total, 24 patients (61.5%) had recovered from infection or were discharged from hostpital at time of reporting while 10 patients had died (Table 1) . 9-11,13-16

As non-CMV infections are the leading cause of death after recent heart transplantation 17 , reducing immunosuppressive drugs has been discussed to improve outcomes in COVID-19. In fact, in 71.8 % of patients with COVID-19 after heart transplant, immunosuppressive agents have been (partially) discontinued or reduced in dose (Table 1) , thus potentially increasing the risk of organ rejection. 9-16 On the other hand, immunosuppressive therapies have been suggested to prevent organ damage caused by hyperinflammation 1,3, 18 and it has been shown that tacrolimus and a non-immunosuppressive derivative of Cylcosporin A inhibited replication of SARS-CoV-1 and thus possibly decreased viral load. 19 In our case, continuation of the immunosuppressant regime was associated with a mild course of COVID-19, though we observed a transient increase in CRP and IL-6. However, retrospective analysis is prone to bias since treating physicians may tend to discontinue immunosuppression in patients presenting with more severe symptoms. Thus, potential benefits of continued immunosuppression require prospective evaluation and need to be carefully balanced against the risk of bacterial superinfection.

Importantly, it has been hypothesized earlier that immunosuppression may impair viral clearance. 2, 20 However, no data is available from heart transplant recipients. We show here that under continued immunosuppression SARS-CoV-2 was still detectable by RT-PCR from oropharyngeal swab up to day 35 of infection. Interestingly, we observed a rapid increase but slow decline in SARS-CoV-2 copy numbers in quantitative RT-PCR after day 7: Despite a Table 1 ). 9-11,13-16 In our case, hydroxychloroquine treatment might have contributed to the persistent mild course of disease after the first week of infection, however, this remains uncertain. We observed some variance in cyclosporine A levels during the course of treatment, eventually associated with the recovery of renal function. In another case, tacrolimus had to be stopped due to uncontrollable high levels after treatment with hydroxychloroquine, remdesivir and lopinavir/ritonavir. 15 Due to multiple potential interactions with immunosuppressive drugs, serum levels should be closely monitored when hydroxychloroquine or antiviral agents, especially lopinavir/ritonavir are used in heart transplant recipients.

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This report highlights the particularities of COVID-19 in heart transplant recipients. Although the cardiovascular system seems to be a critical target site of SARS-CoV-2 infection, a mild course of COVID-19 is possible even in a high-risk patient after recent heart transplantation. We conclude that in mild symptomatic transplant recipients immunosuppression regimen may be continued unchanged unless prospective data recommend otherwise. Importantly, we demonstrate 

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Data sharing is not applicable to this article as no new data were created or analyzed in this study. 

This article is protected by copyright. All rights reserved infection (7 days after symptom onset) revealed residues of previous bacterial pneumonia (111 days before symptom onset) but no typical signs of COVID-19 (D). SARS-CoV-2 was detected in throat swabs by RT-PCR (quantitiy shown as log 10 copies/ml) and by positive virus culture (dashed black lines) before and after hydroxychloroquine treatment (blue area, E). Administered daily doses (solid black line), serum levels (blue discs), and target range (blue area) of cyclosporine A are indicated (F). Dashed red lines indicated date of first symptoms and detection of SARS-CoV-2 in throat swab in each panel. Pereira et al. 12 Li et al. 14 Holzhaus er et al. 15 Hsu et al. 10 Hoek et al. 16 Decker et al. 

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This article is protected by copyright. All rights reserved Need of oxygen supply

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