Transplant of SARS-CoV-2-infected Living Donor Liver: Case Report.

Given the high community prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), transplant programs will encounter SARS-CoV-2 infections in living donors or recipients in the perioperative period. There is limited data on SARS-CoV-2 viremia and organotropism beyond the respiratory tract to inform the risk of transplant transmission of SARS-CoV-2. We report a case of a living donor liver transplant recipient who received a right lobe graft from a living donor with symptomatic PCR-confirmed SARS-CoV-2 infection 3 d following donation. The donor was successfully treated with remdesivir, dexamethasone, and coronavirus disease 2019 (COVID-19) convalescent plasma. No viral transmission was identified, and both donor and recipient had excellent postoperative outcomes.

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) pandemic have disrupted transplantation practices, forcing adaptive changes in national and institutional policies. Complete suspension or major reductions in transplantation volume were reported by many centers in the early months of the pandemic.[1,2] As testing for SARS-CoV-2 became more widely available and knowledge regarding therapeutics in solid organ transplant recipients expanded, institutions resumed transplantation including living donor transplantation, at normal to near-normal capacities.[3-6] However, because the risk of transmission of SARS-CoV-2 through organ tand ransplantation remains unknown, multiple national and international organizations advise against accepting organs from donors who test positive for SARS-CoV-2. These organizations recommend routine screening of deceased donors for SARS-CoV-2 in an effort to prevent inadvertent transplantation of organs from actively infected donors.[7-9] Based on national guidelines, most, if not all, transplant centers require living donors to test negative for SARS-CoV-2 RNA before donation, although testing algorithms and policies are heterogeneous across institutions.[6]

Little is known about the risk of donor-derived SARS-CoV-2 transmission. Currently, there are few reports of centers utilizing organs from SARS-CoV-2–positive donors. We report a case of a living donor liver transplant recipient who received a right lobe graft from a donor who became symptomatic and was found to be positive with SARS-COV-2 RNA on nasopharyngeal swab 3 d following donation. It is assumed the donor contracted the virus shortly before surgery given the timing of symptoms. No organ transmission was identified. The clinical courses of the donor and recipient are summarized.

CASE DESCRIPTION

Donor

A 24-y-old healthy male was evaluated and confirmed to be an appropriate candidate for nondirected right hepatic lobe donation. The donor traveled from out of state by car and arrived in Maryland on preoperative day 4. In addition to being reminded of distancing and masking practices, he had been advised to isolate 7 d before surgery. Per institutional protocol, he tested negative for SARS-CoV-RNA by nasal swab that was collected on preoperative day 3. The donor presented in his usual state of health on the morning of surgery. On arrival to the preoperative unit, his temperature was 36.6°C, heart rate 125 beats per minute (bpm), blood pressure 118/69 mm Hg, and oxygen saturation 98% on room air. The tachycardia was attributed to his reported anxiety about the procedure.

Tachycardia improved with induction of anesthesia to 90–100 bpm. The right lobectomy was performed without complication. The patient tolerated the operation well. Estimated blood loss was 1000 mL, and postoperative hemoglobin was 10.8 g/dL. Recovery from anesthesia was uncomplicated; the patient was extubated postoperatively and transferred to the surgical intensive care unit with normal hemodynamics except for tachycardia (120–130 bpm).

On postoperative day (POD) 1, the donor had sanguinous output from a surgical drain positioned at the cut surface and hilum of the liver. This was associated with a decline in hemoglobin from 10.8 g/dL to 7.2 g/dL and international normalized ratio of 1.9. An abdominal contrasted CT scan showed hematoma in the surgical bed but no active extravasation. He received 2 units of fresh frozen plasma, 10 mg intravenous Vitamin K, and 2 units of packed red blood cells to correct these derangements. On POD 3, the patient developed a fever of 39.4°C, heart rate 110–140 bpm; his oxygen saturation was 88% on room air prompting administration of 1–2 L/min of oxygen via nasal cannula. Other biochemical markers were unremarkable. A chest x-ray film demonstrated left retrocardiac and left basilar patchy opacity. Blood and urine cultures were obtained, and he was started empirically on vancomycin and piperacillin-tazobactam. SARS-CoV-2 RNA was detected in nasopharyngeal swab later that day. Inflammatory markers of COVID-19, including C-reactive protein (CRP), D-dimer, and lactate dehydrogenase, were elevated (Figure 1). Ferritin and troponin levels were unremarkable.

FIGURE 1.

Donor clinical and laboratory parameters from date of surgery to date of hospital discharge. SARS-CoV-2 diagnosis was confirmed, and therapeutics were initiated on POD 3. Temperature (A), heart rate (B), CRP (C), and D-Dimer (D) improved during the course of treatment. CRP, C-reactive protein; POD, postoperative day; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Given the diagnosis of COVID-19 and the requirement for oxygen, he was treated with 1 unit of COVID-19 convalescent plasma (CCP), a 10-d course of 6 mg IV dexamethasone, and 4 d of remdesivir (200 mg loading dose followed by 100 mg). The fifth and final dose of remdesivir was omitted due to concern for rising transaminases, which subsequently improved. Once hemoglobin was stable, deep vein thrombosis prophylaxis with low-molecular-weight heparin was initiated. Fever and tachycardia resolved, and CRP and D-Dimer declined following initiation of COVID-19 therapy (Figure 1). Blood and urine cultures remained negative. His antibacterial therapy was transitioned to a 7-d course of cefdinir for risk of secondary bacterial pneumonias. The donor was discharged from the hospital on POD 13 after 10 d of quarantine in the hospital and continues to recover well with normalization of aminotransferases and total bilirubin during the initial 26 d of follow-up (Figure 2).

FIGURE 2.

Donor aminotransferases (A) and total bilirubin (B) levels from date of surgery to outpatient follow-up. Aminotransferases and total bilirubin increased on POD 6 after 4 d of remdesivir. The fifth dose was subsequently omitted with improvements in aminotransferase and total bilirubin. POD, postoperative day.

Recipient

A 24-y-old male with a history of Crohn’s disease and primary sclerosing cholangitis developed progressive symptoms from cholestatic liver disease despite multiple prior endoscopic interventions and a common bile duct excision with roux-en-y hepaticojejunostomy. His model for end-stage liver disease score remained low, prompting evaluation for living donor liver transplantation. A suitable living donor was identified.

Per institutional protocol, nasopharyngeal testing was negative for SARS-CoV-RNA 3 d before transplantation. He had an uncomplicated hepatectomy and received induction immunosuppression of 1000 mg methylprednisolone. The right lobe allograft from the unrelated living donor was utilized and implanted without complication. Estimated blood loss was 650 mL. The patient tolerated anesthesia well. He was extubated postoperatively and transferred to the surgical intensive care unit with normal hemodynamics. His postoperative course was unremarkable. Postoperative immunosuppression included tacrolimus, mycophenolate mofetil, and tapering doses of methylprednisolone. He exhibited excellent allograft function with continued normalization of liver function tests by POD 3 (Figure 3).

FIGURE 3.

Recipient aminotransferases (A) and total bilirubin (B) levels from date of surgery to outpatient follow-up. Mild elevations of aminotransferases were seen on POD 9 due to presumed rejection, which improved following a methylprednisolone taper. POD, postoperative day.

In light of the donor’s positive SARS-CoV-2 RNA results, the recipient underwent SARS-CoV-2 via nasopharyngeal testing on POD 4 and POD 5, the results of which were both negative. Although a positive nasopharyngeal swab for SARS-CoV-2 was not expected because the route of possible transmission was not respiratory, the negative test did not rule out acquisition of SARS-CoV-2 from the donor. Unfortunately, viremia testing was not available. Given the patient’s immunosuppressed state, he was approved for prophylactic treatment with 1 unit of CCP on POD 4. Despite his negative IgA and IgG titers following this treatment, additional doses of CCP were not administered given his continued normal vital signs, negative testing, and excellent clinical condition.

On POD 9, the patient had a mildly elevated aminotransferases and alkaline phosphatase, which were presumed to be due to rejection. A methylprednisolone pulse and taper were initiated with good response. He remained on full immunosuppression including tacrolimus (targeting a level of 8–10), mycophenolate mofetil (1000 mg BID), and prednisone. The patient was discharged to home 13 d after transplantation with repeatedly negative SARS-CoV-2 tests and excellent allograft function during the initial 26 d of follow-up (Figure 3).

DISCUSSION

As the SARS-CoV-2 pandemic continues to evolve, transplant programs will be increasingly likely to encounter cases of COVID-19 diagnosed in either living donors or recipients in the perioperative period. In this case report of an unanticipated use of a SARS-CoV-2-infected living donor liver for transplantation, no donor-associated transmission was identified. We assumed the donor acquired COVID-19 shortly before surgery. In familial clusters, the incubation period of SARS-CoV-2 was found to be 3–6 d, whereas the mean incubation period of COVID-19 symptoms was found to be 6.4 d, ranging from 2.1 to 11.1 d.[10,11] It would have been unlikely for the donor to have contracted COVID-19 in the immediate preoperative or perioperative setting and become symptomatic on POD 3. Furthermore, the likelihood of transmission to a donor in a carefully controlled perioperative setting in which all personnel are wearing appropriate personal protective equipment and are trained to exercise strict universal precautions would be extremely low. We believe the donor may have become infected with SARS-CoV-2 before his negative SARS-CoV-2 nasal swab on preoperative day 3 but was not detected due to short incubation period or false negative result. In a systematic review of 5 studies involving 957 patients under suspicion of COVID-19 or with confirmed cases, false negative results ranged from 2% to 29%.[12] From an infectious disease standpoint, the source of this unsuspected infection was most likely attributable to an unnoticed exposure during travel or predonation stay, although in-hospital transmission cannot be completely ruled out.

The symptomatic donor was successfully treated with remdesivir, dexamethasone, and CCP according to our institutions’ current COVID-19 therapeutic guidelines. The recipient was prophylactically treated with CCP to provide an immediate dose of neutralizing antibodies, as this was the only targeted prophylaxis available to the recipient who did not meet our center’s criteria for remdesivir (which requires hypoxemia) nor monoclonal antibody therapy (which is given only to outpatients). Randomized trial data now demonstrate that CCP provided early in the course of infection can prevent severe disease.[13] Furthermore, published recommendations by the American Association of Blood Banks indicate that the risk of using CCP is comparable with standard (SARS-CoV-2 nonimmune) plasma, and CCP is optimally effective when transfused as close to symptom onset as possible. We elected to use CCP in the recipient in a manner similar to other instances such as use of hepatitis B immune globulin, in which there is peritransplant exposure to hepatitis B.[14] In this case report, both donor and recipient recovered well from their operations with normalization of liver function.

In retrospect, the preoperative and postoperative tachycardia may have been early signs of COVID-19 infection in the donor. Furthermore, intraoperative hemostasis during the donor hepatectomy was more challenging than anticipated and may have been explained by the immunological hyper-response characterized by endothelial damage associated with COVID-19.[15,16] Although postoperative elevations in D-dimer and CRP were evident in this donor, it is difficult to attribute this solely to COVID-19 in the perioperative setting, especially in the presence of a postoperative hematoma. Nevertheless, these inflammatory markers improved and normalized with COVID-19 treatment.

SARS-CoV-2 preferentially infects the respiratory tract and has direct affinity for the lungs. A case of donor-derived SARS-CoV-2 transmission has been described in a lung transplant recipient whose lung donor tested negative for SARS-CoV-2 by nasopharyngeal PCR but was retrospectively found to be positive on bronchoalveolar lavage fluid obtained at procurement.[17] Currently, there are no clinical data that accurately define the risk of transmission of SARS-CoV-2 with liver transplant. Several small studies do provide insight to SARS-CoV-2 viremia and organotropism beyond the respiratory tract. In a prospective series of 41 critically ill patients with confirmed COVID-19 infection, only 15% of patients were found to have viremia, albeit with low viral RNA levels as evidenced by high average cycle thresholds.[18] Another study of specimens from patients with severe COVID-19 found that SARS-CoV-2 RNA was detected by RT-PCR in blood from only 1% of patients with similar high average cycle threshold.[19] In a study quantifying SARS-CoV-2 viral load in autopsy tissue samples obtained from 22 patients who died from COVID-19, the highest levels of SARS-CoV-2 copies per cell were detected in the respiratory tract, and lower levels were detected in other organs including the liver.[20] Although hepatocellular injury has been documented in cases of severe COVID-19, it remains unclear whether injury is mediated primarily by direct viral injury or by drug-induced liver injury and associated systemic inflammatory syndromes.[21]

Since the pandemic, there have been few reports detailing the use of allografts from donors with unsuspected COVID-19 or unnoticed SARS-CoV-2 exposure and infection detected posttransplant. In one case of an adult liver transplant using an allograft from a mildly symptomatic SARS-CoV-2-infected living donor, there was no evidence of viremia or viral infection of the donor liver on histology. The recipient remained SARS-CoV-2 RNA negative without evidence of COVID-19 symptoms.[22] In another report, suspected COVID-19 hepatitis was detected in a pediatric living donor recipient whose donor subsequently tested positive for COVID-19. Liver biopsy obtained due to rising liver function tests showed moderate acute hepatitis with prominent clusters of apoptotic hepatocytes. Although findings were interpreted as acute cellar rejection, enzymes worsened after increase in immunosuppression but improved after fast steroid taper and discontinuation of mycophenolate mofetil.[23] In a similar case of a pediatric liver transplant recipient who was diagnosed with symptomatic SARS-CoV-2 after receiving a liver allograft from a living donor who subsequently tested positive, histology demonstrated moderate acute hepatitis and classical elements of mild to moderate acute cellular rejection. Interestingly, hepatitis and respiratory symptoms coincidentally improved with completing treatment with hydroxychloroquine, reduced immunosuppression, and intravenous gamma globulin.[24] In our case, the recipient never tested positive for SARS-CoV-2. Elevated liver functions tests were presumed to be secondary to rejection and improved with a course of steroids; therefore, no biopsy was obtained. Currently, histologic manifestations of hepatitis related to COVID-19 are not fully understood, and larger case series are needed to elucidate the spectrum of disease.

Beyond the donor and recipient of this case, the safety of the procurement and transplant surgical teams as well as perioperative staff was a major concern with the use of an infected donor. The Department of Hospital Epidemiology and Infection Control performed contact tracing and investigation of all staff members who were exposed to the donor and found no evidence of transmission. We have intensified our education on COVID-19 safety and prevention measures (distancing, masking, isolation), particularly for donors and recipients traveling from out of state. In potential live donors who have a history of COVID-19, we advise at least 1 mo between initiation of symptoms/positive PCR and negative testing before donation, as recommended by the American Society of Transplant Surgeons COVID-19 Strike Force Guidance.[25] This case has prompted an update in our SARS-CoV-2 testing guidelines for transplant donors and recipients at our center. For all donors and recipients both in or out of state, SARS-CoV-2 nasopharyngeal swab results must be negative 1 wk before donation, within 72 h of donation once they have arrived in Baltimore, and again on the morning of surgery. We also ask donors to quarantine for at least a week before surgery date. These protocols will continue to evolve as testing continues to improve and as we gain better understanding of the impact of prior infections and immunization status in transplant donors or recipients, which will potentially aid in the proper selection of donors and recipients.

This case illustrates the successful management and outcome of a donor and recipient pair after liver transplant from an unsuspected SARS-CoV-2 donor. It also underscores the importance of intensifying the preoperative testing protocols for all donors and recipients, as we continue to perform these life-saving operations.