A new chapter in an evolving pandemic: Successful pediatric liver transplantation with SARS‐CoV‐2+ donors

Abstract

Background

Amid a viral pandemic with poorly understood transmissibility and pathogenicity in the pediatric patient, we report the first pediatric liver transplants utilizing allografts from SARS‐CoV‐2+ donors.

Methods

We describe the outcomes of two pediatric liver transplant recipients who received organs from SARS‐CoV‐2 nucleic acid test‐positive (NAT+) donors. Data were obtained through the respective electronic medical record system and UNet DonorNet platform.

Results

The first donor was a 3‐year‐old boy succumbing to head trauma. One of four nasopharyngeal (NP) swabs and 1 of 3 bronchoalveolar lavage (BAL) NAT tests demonstrated SARS‐CoV‐2 infection before organ procurement. The second donor was a 16‐month‐old boy with cardiopulmonary arrest of unknown etiology. Three NAT tests (2 NP swab/1 BAL) prior to procurement failed to detect SARS‐CoV‐2. The diagnosis was made when the medical examiner repeated 2 NP swab NATs and an archive plasma NAT, all positive for SARS‐CoV‐2.

Both 2‐year‐old recipients continue to do well 8 months post‐transplant, with excellent graft function and no evidence of SARS‐CoV‐2 transmission.

Conclusions

This is the first report to describe successful pediatric liver transplantation from SARS‐CoV‐2+ donors. These data reinforce the adult transplant experience and support the judicious use of SARS‐CoV‐2+ donors for liver transplantation in children. With SARS‐CoV‐2 becoming endemic, the concern for donor‐derived viral transmission must now be weighed against the realized benefit of life‐saving transplantation in the pediatric population as we continue to work toward donor pool maximization.

Abbreviations

BAL

bronchoalveolar lavage

COVID‐19

coronavirus disease 2019

NAT

nucleic acid test

NP

nasopharyngeal

POD

post‐operative day

PVT

portal vein thrombosis

SARS‐CoV‐2

severe acute respiratory syndrome coronavirus 2

1. INTRODUCTION

There is an evolving experience with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and coronavirus disease 2019 (COVID‐19) that is now informing organ procurement and transplantation of organs from SARS‐CoV‐2+ donors. The Organ Procurement Transplant Network (OPTN) Disease Transmission Advisory Committee published a Summary of Evidence reviewing the data nearly 2 years into the current pandemic as it pertains to organ recovery from donors with a history of COVID‐19. The most current version released on September 22, 2021, advocated for risk–benefit assessment concerning candidate‐specific morbidity and mortality likelihood while on the waitlist, understanding that data regarding viral transmission were encouraging though based on limited experience to date. ¹ With the pandemic stretching beyond 2 years and evolving into endemicity, transplant programs have begun accepting extrapulmonary organs from SARS‐CoV‐2+ donors. In a report by Koval et al. ² 10 adult kidney transplants were successfully performed using allografts from five actively SARS‐CoV‐2‐infected donors; none of the donors had clinical evidence of COVID‐19. There was no evidence of adverse allograft outcomes or SARS‐CoV‐2 transmission between 2 and 4 months of follow‐up. Notably, all organs had been rejected by multiple other centers and would have otherwise been discarded. Favorable outcomes were subsequently described by Romagnoli et al. ³ who reported the first 10 liver transplants from an Italian multicenter series using organs from SARS‐CoV‐2+ donors or donors with a history of COVID‐19 for urgent need transplant candidates. Five of the ten donors had no known symptoms compatible with COVID‐19 and were nucleic acid test positive (NAT+) via bronchoalveolar lavage (BAL) within 24 h of organ recovery. There was no clinical or laboratory evidence of new SARS‐CoV‐2 infection with weekly testing for the first month of follow‐up. One pediatric recipient was included, though the donor had a remote history of COVID‐19 and tested negative for SARS‐CoV‐2 prior to procurement. Additional case reports/series demonstrate transmission‐free adult liver transplants with donors testing positive for SARS‐CoV‐2 at the time of procurement. ⁴ , ⁵ , ⁶ , ⁷

Evolving data suggest non‐lung organs may be safely transplanted from SARS‐CoV‐2+ donors in adults, though data regarding pediatric transplantation in this context are limited. We report the first two successful pediatric liver transplants from SARS‐CoV‐2+ donors.

2. MATERIALS AND METHODS

This is a review of two pediatric liver transplant recipients and their donors who tested positive for SARS‐CoV‐2 just prior to or at the time of procurement. Clinical, laboratory, and outcome data were obtained through the respective electronic medical record system and UNet DonorNet platform.

3. RESULTS

The first donor is a 3‐year‐old boy (16.1 kg) who died after a motor vehicle accident (MVA). The donor's parents reported that the donor developed a nonproductive cough accompanied by rhinorrhea ~17 days before organ procurement with the date of symptom resolution unable to be verified. In the 4 days preceding procurement, 1 of 4 nasopharyngeal (NP) swab NATs was positive for SARS‐CoV‐2, parainfluenza 3, rhinovirus, and adenovirus, and 1 of 3 BAL NATs was positive for SARS‐CoV‐2 and parainfluenza 3 infection. The recipient was a 2‐year‐old girl with alpha‐1‐antitrypsin deficiency (ZZ genotype) who weighed 13.9 kg and tested negative for SARS‐CoV‐2 by NAT at the time of transplant. She was not tested for SARS‐CoV‐2 antibodies but had no history of COVID‐19 prior to transplant. Her course was complicated by portal vein thrombosis (PVT), requiring intra‐operative thrombectomy followed by catheter‐directed thrombectomy/angioplasty via interventional radiology with successful recanalization on post‐operative day (POD) 5. She tested negative for SARS‐CoV‐2 via NP swab NAT on POD 7 and was discharged on POD 20. She was later found to have a clinically silent middle hepatic vein thrombus 2‐month post‐transplant through surveillance ultrasonography not requiring intervention.

The second donor was a 16‐month‐old boy (11.4 kg) with upper respiratory illness symptoms for multiple weeks and recent treatment of presumed sinusitis with amoxicillin before cardiopulmonary arrest of unknown etiology. Out of nine respiratory NAT assays in the week prior to procurement, the donor tested positive for adenovirus in three qualitative tests without evidence of infection in urine and stool sampling. Two NP swab NATs (6 days prior to procurement) and a BAL NAT (2 days prior to procurement) failed to detect SARS‐CoV‐2 infection. The diagnosis was made after transplant when the medical examiner repeated 2 NP swab NATs and an archive plasma NAT, obtained at the time of organ procurement, which were all found to be positive for SARS‐CoV‐2. The recipient was a 2‐year‐old boy with Alagille syndrome weighing 12.4 kg at the time of transplant who tested negative for SARS‐CoV‐2 via NAT on admission. On the day of transplant, testing for SARS‐CoV‐2 antibodies was nonreactive; he had no history of COVID‐19. Given the donor's unknown SARS‐CoV‐2 infection at the time of transplant and delayed medical examiner results, there was no screening for SARS‐CoV‐2 during his uncomplicated post‐operative course prior to discharge on POD 12.

No donors or recipients had received COVID‐19 vaccination(s) prior to transplant per Centers for Disease Control and Prevention (CDC) guidelines at the time. Standard immunosuppression consisting of Prograf and steroids without modification was used in both recipients, and no COVID‐19‐specific prophylactic or antiviral therapies were administered. Both recipients continue to do well 8‐month post‐transplant, with excellent graft function and no evidence of transplant‐associated SARS‐CoV‐2 transmission.

4. DISCUSSION

Apart from lungs, ⁸ , ⁹ SARS‐CoV‐2 transmission from transplanted organs and tissues has not been reported. ¹⁰ Nonetheless, potential donors with detectable SARS‐CoV‐2 RNA continue to be generally excluded. This is understandable considering the systems‐level risk of transmission to not only the recipient but also the transplant team, Organ Procurement Organizations (OPOs), and associated hospital workforce. Furthermore, emerging data demonstrate increased peri‐operative mortality in the first 6 weeks after COVID‐19 diagnosis, ¹¹ though most applicable to transplant recipients or living donors with recent COVID‐19. However, strategies to transplant extrapulmonary organs are now timely as the pandemic and chronic organ shortage continue to coincide, with ~17 daily deaths from end‐stage organ failure, while the risk of SARS‐CoV‐2 transmission has thus far remained scant.

To our knowledge, this is the first description of successful pediatric liver transplantation from SARS‐CoV‐2+ donors. Neither recipient experienced clinical or laboratory evidence of donor‐derived SARS‐CoV‐2 infection up to 8 months after transplantation, and there were no known transmission events to ancillary healthcare teams.

It is important to address the clarity of evidence of infection in our two donors. Both donors were recently though mildly symptomatic before procurement. Translation of the seemingly low transmissibility risk to the acutely ill donor with severe COVID‐19, particularly in the pediatric patient, requires further investigation. In regard to laboratory evidence, donor 1 was positive for SARS‐COV‐2 in 1 of 4 NP swabs and 1 of 3 BAL NATs. Serial testing prior to procurement for donor 2 failed to detect SARS‐CoV‐2 while repeat specimens obtained by the medical examiner during organ procurement indicated infection. Infectious disease specialists may attribute this intermittent positivity to false negatives or positives and/or remote infection leading to discordant results due to sampling error in the presence of a low viral load. ¹² , ¹³ While these testing discrepancies limit the ability to confirm safety of using livers from SARS‐CoV‐2+ donors, our experience begins building the literary evidence for extension of utilizing these allografts in the generally risk‐averse field of pediatric transplantation.

It is worth noting that our first recipient suffered from PVT, which resolved after catheter‐directed therapies. ¹⁴ While she had a very small native portal vein that most likely accounted for the development of thrombosis, we cannot be certain that hypercoagulability associated with theoretical donor‐derived SARS‐CoV‐2 transmission did not contribute to her risk for PVT or subsequent middle hepatic vein thrombus, ¹⁵ though no such events have been reported due to transplant‐derived infection.

We have previously published the largest case series on the pediatric experience with post‐transplant SARS‐CoV‐2 infection suggesting similar prognoses to immunocompetent children. ¹⁶ SARS‐CoV‐2 transmission with extrapulmonary organ transplant is currently a theoretical concern, and the existing evidence demonstrates unlikely clinical significance in children in the event of post‐transplant infection. ¹⁶ It is imperative to weigh associated risks against high waitlist mortality.

Our cases reinforce case reports/series in the adult transplant population of successful use of organs from SARS‐CoV‐2+ donors. ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ As we learn to best serve our patients amid an unprecedented, lingering pandemic, research describing success with organs from SARS‐CoV‐2+ donors will inform evolving policy and organ utilization. As there are now better therapeutic options, increased access to vaccines or immunity from prior infection, and an improved understanding of transmission, the risks of accepting SARS‐CoV‐2+ donors to the recipient and transplant centers are likely less compared with early in the pandemic. This report provides new data to serve as the starting point in support of the use of SARS‐CoV‐2+ donors for pediatric liver transplantation. Individual assessment of the risk vs. survival benefit of extrapulmonary organ transplant may offset the risk of SARS‐CoV‐2 transmission.

AUTHOR CONTRIBUTIONS

Matthew B. Goss spearheaded the conception and design of work; acquisition and analysis of data; drafting, revision, and final approval. Daniel H. Leung, Stephanie M. Pouch, Flor M. Munoz, Tyler Lambing, Nicolas F. Moreno, and Christine A. O'Mahony contributed to the conception and design of work; analysis of data; drafting, revision, and final approval. Elizabeth A. Moulton contributed to the design of work; analysis of data; drafting, revision, and final approval. Sarah Koohmaraie contributed to the design of work; acquisition and analysis of data; drafting, revision, and final approval. John A. Goss, MD contributed to the conception and design of work; acquisition and analysis of data; drafting, revision, and final approval. N. Thao N. Galván oversaw conception and design of work; acquisition and analysis of data; drafting, revision, and final approval.

FUNDING INFORMATION

No funding was received to produce this study.

CONFLICT OF INTEREST

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

Goss MB, Leung DHB, Pouch SM, et al. A new chapter in an evolving pandemic: Successful pediatric liver transplantation with SARS‐CoV‐2+ donors. Pediatric Transplantation. 2022;26:e14407. doi: 10.1111/petr.14407

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.