key: cord-0847957-3uep12ei
authors: Axelrod, David A.; Ince, Dilek; Harhay, Meera N.; Mannon, Roslyn B.; Alhamad, Tarek; Cooper, Matthew; Josephson, Michelle A.; Caliskan, Yasar; Sharfuddin, Asif; Kumar, Vineeta; Guenette, Alexis; Schnitzler, Mark A.; Ainapurapu, Sruthi; Lentine, Krista L.
title: Operational challenges in the COVID era: Asymptomatic infections and vaccination timing
date: 2021-07-23
journal: Clin Transplant
DOI: 10.1111/ctr.14437
sha: a1ebf58d8a2d6997c2ff32b5d294c721af96d870
doc_id: 847957
cord_uid: 3uep12ei

The coronavirus disease 2019 (COVID‐19) pandemic has created unprecedented challenges for solid organ transplant programs. While transplant activity has largely recovered, appropriate management of deceased donor candidates who are asymptomatic but have positive nucleic acid test (NAT) for COVID‐19 is unclear as this may reflect active infection or prolonged viral shedding. Furthermore, candidates who are unvaccinated or partially vaccinated continue to receive donor offers. In the absence of prospective data, transplant professionals at U.S. adult kidney transplant centers were surveyed to determine community practice (N: 92 centers, capturing 40.8% of centers and 56.6% of transplants performed). The majority (96.8%) of responding centers declined organs for asymptomatic NAT+ patients without documented prior infection. However, 31.6% of centers proceeded with kidney transplant in NAT+ patients who were at least 30 days from initial diagnosis with negative chest imaging. Less than 7% of programs reported inactivating patients who were unvaccinated or partially vaccinated. In conclusion, despite national recommendations to wait for negative testing, many centers are proceeding with transplant in patients with positive tests due to presumed viral shedding. Furthermore, very few centers are requiring COVID‐19 vaccination prior to transplantation despite early evidence suggesting reduced immunogenicity in transplant patients on immunosuppression. This article is protected by copyright. All rights reserved

The coronavirus disease 2019 (COVID-19) has substantially impacted organ donation, transplantation, and the management of the post-transplant patient population. Two meta-analysis have shown higher hospitalization rates and intensive care and hospital mortality rates due to COVID-19 in solid organ transplant recipients when compared to the general population. 1, 2 The COVID-19 pandemic initially led to a rapid decline in deceased organ donation and near cessation of living donor transplantation out of caution. 3, 4 Importantly, in addition, increased waitlist mortality rates in kidney transplant candidates were observed at the onset of the national emergency period of COVID-19. When compared with transplant recipients with similar demographics and comorbidities who developed COVID-19, waitlisted patients who developed COVID-19 were more likely to require hospitalization. 5, 6 To help guide the community during the pandemic, American Society of Transplantation (AST) has developed recommendations on how and when to test deceased and living donors for SARS-CoV-2, as well as transplant practices during the pandemic. 7, 8 Serum antibody testing has not been This article is protected by copyright. All rights reserved. recommended given variability in specificity based on prevalence of SARS-CoV-2 in the region. With these recommendations, solid organ transplantation has recovered to almost pre-COVID-19 levels and the total number of transplants was only slightly decreased in 2020. 4, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] currently available in the United States under Emergency Use Authorization confer significant protection (66%-95%) against COVID-19 in persons 16 years of age and older based on studies carried out in mostly immunocompetent hosts. 10, 11 In the absence of data on efficacy and safety in solid organ transplant recipients, but based on prior knowledge on other vaccines, AST has made recommendations on safety and pre-and post-transplant timing of COVID-19 vaccinations. 12 Despite available guidance, transplantation in the COVID-19 era is complex with areas of ongoing uncertainty. Prolonged, asymptomatic shedding of viral RNA for up to 90 days has been reported, leading to uncertainties in candidate management. The decision to transplant patients with asymptomatic SARS-CoV-2 nucleic acid testing (NAT) positivity has been evolving, with some centers requiring one to two negative NAT results prior to transplantation and others transplanting more quickly. Similarly, management of waitlist candidates who are not yet transplanted is unclear. While pre-transplant vaccination is optimal, it is not clear how centers should treat candidates who are not fully vaccinated but remain active on the deceased donor transplant list. To better elucidate these issues and current practice patterns, we designed and administered an electronic survey. Herein we report the findings based on responses at U.S. adult kidney transplant programs from 2/13/2021 to 4/29/2021.

The survey instrument was developed by the study investigators. The final survey instrument comprised of 10 questions addressing the management of kidney transplant candidates with asymptomatic COVID-19 infection who receive an organ offer as well as deceased donor transplant candidates who are not yet vaccinated (SDC, Table 1 ). The survey also queried information on the OQiT posting was approved by the AST Education Committee, and email to ASTS members was approved by the council. The first page of the survey notes that the decision to proceed indicates consent to participate. Up to two reminders were provided for non-respondents.

Each program was represented only once in the analysis. For programs with multiple respondents, we selected a single participant to represent the program using a hierarchical algorithm. First, we prioritized responses with the most complete information (i.e., least unanswered items). Next, we prioritized surveys submitted by surgeons or nephrologists, over those from coordinators, social workers, administrators, or others. Lastly, we prioritized the earliest submitted questionnaire.

Responses to each survey question were described with percentages and frequencies. To obtain rates, we divided the number of program responses by the total number of programs who responded to the question, such that percentages reflect proportions of respondents, as per previous methods. [13] [14] [15] For questions where participants were asked to "select all that apply," the denominator for calculating percentages was the number of participants responding to that question. All analyses were performed using R for windows version 1.2.5042 (RStudio Inc., Boston, MA).

This report describes responses from 92 unique kidney transplant centers in the United States (SDC, Table 1) .

Management of candidates called in for transplant who have no clinical evidence of documented COVID-19 infection but were found to have a positive test with a nasopharyngeal swab differed across programs (Figure 1 ). The majority of programs declined the organ and delayed transplantation. The length of delay varied, with 69.6% of centers requiring delay until the candidate tests negative and 27.2% delaying for a fixed period of at least 30 days without retesting. In 4.3% of centers, patients with reassuring adjunctive testing including CT scans or antibody tests were assumed to have a resolved infection and proceed with transplant.

Among candidates with documented COVID-19 infection more than 30 days prior to admission who have persistently positive testing, practices were more varied. The majority (55.4%) of centers continued to decline the organ and wait for negative testing. However, 31.6% of centers proceeded with transplant, either with negative pulmonary imagining (19.6%) or positive pre-transplant antibody testing (12.0%). Other, unspecified protocols, were followed in 23.9% of centers to allow transplantation. This article is protected by copyright. All rights reserved.

Nearly all centers (93.5%) currently encourage vaccination for all candidates on the waiting list and prior to living donation ( Table 2) . Only one center reported that they have decided to inactivate unsensitized candidates (cPRA<80%) until they are vaccinated, and five centers report inactivating This article is protected by copyright. All rights reserved.

The COVID-19 pandemic has significantly changed healthcare delivery across the world, [16] [17] [18] including profound impacts on organ transplantation. 19 

may reduce the efficacy of the vaccine. Based on a recent report of 187 solid organ transplant recipients, the first dose of two dose vaccine series were shown to be safe, with no reports of rejection, rare systemic reactions such as fevers and chills, and slightly more than baseline headache, fatigue and myalgias. 23 However, immunogenicity after a single dose of mRNA vaccine was low, with spike protein antibodies detectable in only 17% of transplant recipients versus 100% of healthy subjects 14-21 days after vaccination. 24 Two studies showed anti-spike protein response rates of 37.5% and 58.8% following two doses of the mRNA vaccine BNT162b2, with both studies showing significantly lower antibody titers in organ transplant recipients. 25, 26 The low immunogenicity after transplant supports AST recommendations on preferential vaccination of potential transplant recipients prior to transplantation. However, this recommendation needs to be balanced against the risk of delaying transplant. As less than 50% of the US population has received one dose to date, it is likely that this will be an issue for many additional months.

Prolonged viral shedding in patients with end-stage kidney disease presents a clinical management challenge for transplant clinicians. In a recent study of routine screening of patients in a dialysis facility, 33% of patients with a positive test were completely asymptomatic. 27 Thus, these patients would not be recognized by clinical signs prior to presenting for transplant. Initially, out of caution, the AST and others recommended delaying transplant until the candidate (or living donor) had two negative tests. 28 With increased knowledge of the clinical course and evidence that viral shedding alone does not appear to correlate with adverse outcomes in asymptomatic non-transplant patients, one third of centers are proceeding with transplant after a predefined waiting period. The safety of this practice has not been firmly established. This article is protected by copyright. All rights reserved.

Our study has limitations inherent to the survey study design, such as potential for recall bias. The findings represent practices as they are reported; we cannot verify how accurately the reports represent actual practice at each program. Respondents were identified by online outreach to U.S. transplant professionals, and not all programs are represented. However, the 37.2 % response rate is higher than many contemporary studies of transplant program practices (where response rates in 30%-range are common), 15, 29, 30 vaccinations for transplant candidates and recipients, and to optimize COVID testing practices that provide safe access to transplantation for fully vaccinated and was well as unvaccinated patients, but do not unnecessarily delay transplant procedures.

Data availability is limited to aggregate summaries as reported, based on IRB requirements. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

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The authors thank survey respondents, including members of the American Society of This article is protected by copyright. All rights reserved.

'N=' Indicates the item denominator, based on number of respondents, and accounting for contingent responses