key: cord-0833004-gzbmndnl
authors: Raveh, Yehuda; Simkins, Jacques; Vianna, Rodrigo; TEKIN, Akin; Nicolau-Raducu, Ramona
title: A LESS RESTRICTIVE POLICY FOR LIVER TRANSPLANTATION IN COVID-19 POSITIVE PATIENTS, BASED UPON CYCLE THRESHOLD VALUES.
date: 2021-01-20
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.01.035
sha: a3eec7e35d783dcc952bb4d1b33d12a7a3a2d03a
doc_id: 833004
cord_uid: gzbmndnl

The coronavirus disease 2019 drastically impacted solid organ transplantation. Lacking scientific evidence, a very stringent but safer policy was imposed on liver transplant (LT) early in the pandemic. Restrictive transplant guidelines must be reevaluated and adjusted as data become available. Prior to LT, the prevailing policy requires a negative SARS-Cov-2 real-time polymerase chain reaction (RT-PCR) of donors and recipients. Unfortunately, prolonged viral RNA shedding frequently hinders transplantation. Recent data reveal that positive test results for viral genome are frequently due to non-infectious and prolonged convalescent shedding of viral genome. Moreover, studies demonstrated that the cycle threshold of quantitative RT-PCR could be leveraged to inform clinical transplant decision-making. We present an evidence-adjusted significantly less restrictive policy for LT, where risk tolerance is tiered to recipient acuity. In addition, we delineate the pre-transplant clinical decision-making, intra- and postoperative management, and early outcome of two recipients of a liver graft performed while their RT-PCR of airway swabs remained positive. Convalescent positive RT-PCR results are common in the transplant arena, and the proposed policy permits reasonably safe LT in many circumstances.

At the onset of the pandemic, the absence of scientific evidence compelled transplant policymakers to impose stringent but safer policy for liver transplantation (LT). As such, the a priori approach for LT during the pandemic was delineated in a clinical algorithm that is primarily based on a binary positive or negative result of real-time reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 genome in airway samples [1, 2] , along with clinical and epidemiological screening [1, 2] . A recently update approach requires, prior to organs retrieval, a negative SARS-CoV-2 RT-PCR respiratory specimen from donors previously known to have had COVID-19, unless ≥21 days from onset of symptoms to donation evaluation [3] . For recipients previously known to have had COVID-19, a negative RT-PCR is required within 24 hours of LT; If positive, LT should be deferred [4] . Restrictive transplant guidelines must, however, be reevaluated as data become available, and when supported by scientific J o u r n a l P r e -p r o o f evidence, less restrictive criteria are to be carefully considered and executed. Indeed, recent data show that: i) Prolonged (up to 12 weeks) respiratory viral RNA shedding is common among adult patients, especially following severe illness [5, 6] . ii) In some cases early convalescent negative results became subsequently positive [7, 8] . And iii) Shedding of viral genome does not equate to infectivity, which depends on the replication-capability of the virus [9] [10] [11] [12] . In this this manuscript we propose an evidence-adjusted significantly less restrictive transplant policy for LT in RT-PCR positive patients, based on scientific data gained this far in the pandemic ( Figure   1 ). We introduce the proposed algorithm by delineating the pre-transplant clinical decisionmaking, post-transplant immunosuppression and monitoring for SARS-CoV-2 infection, and early outcome of two LT performed on recipients who recovered from a documented SARS-CoV-2 infection, while airway swabs remained RT-PCR positive.

A 55-year-old male presented with pyogenic arthritis of a prosthetic knee, and was treated with ceftriaxone 2 g IV daily for 6 weeks, during which acute on chronic liver failure developed (Table   1 ). Nasopharyngeal SARS-CoV-2 RT-PCR swabs on day 3 and 5 were negative, and he was listed for LT with a diagnosed of alcoholic cirrhosis. On day 9, a nasopharyngeal RT-PCR swab became positive with cycle threshold (Ct) of 14.6 and his listing was put on hold (status 7). Over the following weeks he developed respiratory distress, hemodynamic instability, and acute renal failure; he required respiratory support with high flow nasal cannula, vasopressors, and renal replacement therapy. Remdesivir was not given due to his severe liver disease. Subsequent A 37-year-old female on the LT-waitlist was admitted with fever, chills, cough, bilateral patchy opacities on chest X-ray, and SARS-CoV-2 RT-PCR positive from a nasopharyngeal swab with Ct value of 42. She did not require oxygen supplementation (Table 1) . Her mycophenolate mofetil was held and her prednisone was increased to 10 mg daily. She was discharged home after 72h. 

Some data indicate that despite ongoing shedding of viral genome, persons with mild to moderate SARS-CoV-2 RT-PCR are usually non-contagious 8-10 days after onset of symptoms [9, 10, 12, 13] , while a replicable virus may be isolated up to 20 days after onset of symptoms in severe cases and in immunocompromised patients [12, 14] . In addition, at least sixteen studies established a strong correlation between isolating replicable virus and the viral genome load, as measured by log copies detected or its semiquantitative proxy-Ct value [8, 9, 13, [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] . A 10fold decrease in target gene copies corresponds to a 3.3 increase in Ct [8, 13, 27] . Six studies reported Ct cut-off values denoting non-infectious shedding and ranging 24-35 [13, 17-19, 21, 23, 26] , and four additional studies identified CT cut-off values, between 23 and >35, associated with low probability (<8.5%) for cultivable virus [15, [20] [21] [22] 25] . This expanding data indicate that clinical and transplant strategies regarding an ongoing SARS-CoV-2 infection or its infectivity are better informed via the Ct value. Moreover, safer, more refined and less restrictive clinical decision-making is achieved when the Ct value is interpreted in the clinical context of days from symptom onset to test as well as illness severity [8, 15, 21, 26] . A conceivably riskier approach is justified in high acuity recipients, similar to our patient 1, where LT is their ultima ratio [2] . Accordingly, the critically ill patient 1 was deemed clear of an ongoing SARS-CoV-2 infection or infectivity preoperatively based on the clinical constellation of: a) twenty seven days since onset of symptoms; b) improvement of his respiratory status; and c) an increase in his Ct from 14 to 25 [13] . Likewise, a post-transplant reinfection [28] , or exacerbation of an ongoing SARS-CoV-2 should be suspected when new pulmonary infiltrates are accompanied by inflammatory markers, e.g. CRP, D-dimers, ferritin, or interleukin 6 [29] , along with low or decreasing Ct values. On admission for LT, patient 2 was asymptomatic but with a positive J o u r n a l P r e -p r o o f SARS-CoV-2 RT-PCR swab. Yet, despite having lower acuity end stage liver disease, she was cleared for transplantation in view of her mild SARS-CoV-2 illness 94 days earlier, and a Ct of 40. Serologic tests are helpful in cases with high clinical suspicion despite negative nucleic acid testing [30] . While seroconversion may offer temporary immunity [31], serology is not currently recommended to establish absence of infectivity [4, 12, 30, 32] .

During the pandemic our empirically modified post-LT immunosuppression induction regimen includes steroids in lieu of anti-thymocyte globulin [33] . Both recipients received the modified regimen, and did not appear to be negatively impacted by the prolonged shedding of viral genetic material. Undoubtedly, studies pursuing safe and efficacious regimens for induction of immunosuppression after SOT during this pandemic are necessary.

In view of the current resurgence of SARS-CoV-2 both world-wide and nationally, prolonged convalescent shedding of SARS-CoV-2 genome is becoming a common occurrence in the transplant arena, in both recipients and donors. An evidence-adjusted algorithm for LT is presented in Figure 1 . The new algorithm is guided primarily by Ct of RT-PCR and employs the previously proposed cut-off Ct values of 24 and 35, tiered to recipient acuity [8, 13] . There remains a small but real risk of grafting a liver to a recipient with an ongoing SARS-Cov-2 infection, despite Ct value ≥ 24. Personal protective equipment should be donned during the perioperative management, and recipients should be monitored closely. Likewise, no Ct cutoff value uniformly predicts good outcomes. Several factors of specimen collection and handling impact the RT-PCR detectable Viral RNA, SARS-Cov-2 Ct values may vary considerably between and within platforms, laboratories, and target genes [34] . Published Ct values should be compared to local RT-PCR assay reference values prior to clinical applicability [34, 35] . Our results support the gradual implementation of less restrictive criteria for LT. Additional data is The algorithm delineates evidence-based and less restrictive adjustments to previous transplant societies' recommendations, and is centered on the severity of symptoms, days since onset of symptoms, and the cycle threshold of a positive RT-PCR of a respiratory specimen. Noninfectious shedding of viral genome occurs 10 days and 20 days after mild-moderate, and severe COVID-19 disease, respectively.

Step 1: An asymptomatic candidate is one who lacks any clinical evidence suggestive of COVID-19 >21 days prior to screening. If symptomatic, days since onset of symptoms and disease severity should be determined. The candidate should have complete resolution of symptoms.

Step 2: Some experts recommend two negative RT-PCR tests at least 24 hours apart for asymptomatic candidates due to the limited sensitivity (~70%) of each test (Ref 3-4).

Step 

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