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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Real-time transcription polymerase chain reaction cycle threshold values as criteria for utilization of incidental COVID-19 positive lung donors

Published:December 27, 2022DOI:https://doi.org/10.1016/j.healun.2022.12.016
      Shortage of organ donors is an ongoing limiting factor in lung transplantation (LT). Despite increasing prevalence of asymptomatic COVID-19 infection, positive COVID-19 testing from a potential donor remains a contraindication at many LT centers.
      In this report, we present the outcomes of LT utilizing an algorithm based on donor clinical presentation, and COVID-19 real-time reverse transcription polymerase chain reaction (RT-PCR) with cycle threshold (Ct) values evaluation. The Ct value threshold for organ acceptance was >35. A total of 8 COVID-positive donors were included. No donor-to-recipient transmissions of COVID-19 were observed. Short-term outcomes were comparable to those reported in pre-COVID literature. Survival-to-date is 100% with median POD of 161 days. Our findings support the safety and efficacy of utilizing our algorithm including Ct value threshold for selection of donors with incidental COVID-19 positive testing.

      Graphical abstract

      Keywords

      Abbreviations:

      LT (lung transplant), NP (nasopharyngeal), LRT (lower respiratory tract), Ct (cycle threshold), PGD (primary graft dysfunction), ACR (acute cellular rejection), DSN (donor sequence number)

      Brief communication

      The emergence of the COVID-19 pandemic placed significant strain on solid organ transplantation.
      • Valapour M
      • Lehr CJ
      • Skeans MA
      • et al.
      OPTN/SRTR 2019 annual data report: lung.
      ,
      • Bock MJ
      • Vaughn GR
      • Chau P
      • Berumen JA
      • Nigro JJ
      • Ingulli EG
      Organ transplantation using COVID-19-positive deceased donors.
      As a consequence of the pandemic in 2020, there was a decline in both the number of lung transplants (LTs) performed as well as the number of recovered lung donors.
      • Valapour M
      • Lehr CJ
      • Skeans MA
      • et al.
      OPTN/SRTR 2019 annual data report: lung.
      A potential explanation is related to the safety of utilizing of COVID-19 positive donors due to the risk of transmission of COVID-19 infection.
      • Shah MB
      • Lynch RJ
      • El-Haddad H
      • Doby B
      • Brockmeier D
      • Goldberg DS
      Utilization of deceased donors during a pandemic: argument against using SARS-CoV-2-positive donors.
      Outcomes have been reported in other solid organs, yet there remains paucity of LTs described.
      • Bock MJ
      • Vaughn GR
      • Chau P
      • Berumen JA
      • Nigro JJ
      • Ingulli EG
      Organ transplantation using COVID-19-positive deceased donors.
      ,
      • Eichenberger EM
      • Coniglio AC
      • Milano C
      • et al.
      Transplanting thoracic COVID-19 positive donors: an institutional protocol and report of the first 14 cases.
      Following 3 donor derived COVID-19 transmissions to LT recipients from donors with initial negative nasopharyngeal (NP) testing that retrospectively tested positive in lower respiratory tract (LRT) samples, the Organ Procurement and Transplantation Network (OPTN) required LRT SARS-CoV-2 testing for all potential lung donors. In its current iteration, the OPTN guidance on SARS-CoV-2 screening and donor organ acceptance identifies COVID-19 positive donors as low risk if the test was performed between 21 and 90 days after disease onset in the setting of resolved COVID-19.

      Organ Procurement and Transplantation Network. Summary of Current Evidence and Information-Donor SARS-CoV-2 Testing & Organ Recovery from Donors with a History of COVID-19. Version 6. Available at: https://optn.transplant.hrsa.gov/media/kkhnlwah/sars-cov-2-summary-of-evidence.pdf. Accessed November 15, 2022.

      For donors who test positive with no known history of infection, it is recommended that organs be considered for non-lung recipients only. However, these guidelines can decrease the number of organ acceptance without considering quality of the lungs and our evolving knowledge of COVID-19 risk of transmission and severe disease. Therefore, we present our center's experience utilizing an algorithm based on donor clinical presentation, and COVID-19 reverse transcriptase polymerase chain reaction (RT-PCR) with cycle threshold (Ct) values (Figure 1).
      Figure 1
      Figure 1Algorithm for organ evaluation for lung transplantation in donors with incidental positive COVID-19 testing. For donors with incidental positive COVID-19 testing by NP swab, evaluation of the Ct was completed. If Ct threshold was < 35, organ was declined. If Ct threshold was >35, LRT testing was performed. If LRT RT-PCR was positive, organs were declined. If the LRT RT-PCR was negative or met Ct threshold >35, organ would be accepted. LRT = lower respiratory tract; NP = nasopharyngeal swab; Ct = cycle threshold; RT-PCR = reverse transcriptase polymerase chain reaction.
      This is a single-center case series evaluating LT outcomes utilizing donors with incidental positive SARS-CoV-2 RT-PCR with Ct >35 via NP or LRT testing at any point during hospitalization between October 2021 and August 2022. SARS-CoV-2 RT-PCR testing per organ acceptance algorithm was ordered by the organ procurement organization as requested by our center and performed at the donor hospital facility. The primary outcome was COVID-19 transmission based on positive COVID-19 testing within 30 days of transplant. Secondary outcomes were primary graft dysfunction (PGD) grading at 72 hours, incidence of acute cellular rejection (ACR), 30-day survival, and 90-day survival. All LT recipients had received vaccination against COVID-19 prior to listing and signed informed consent to the use of lungs from donors with COVID-19 RT-PCR Ct values >35.
      As of October 30, 2022, there have been a total of 8 COVID-positive donors meeting criteria. Donor and recipient clinical characteristics are described in Table 1. All donors were male. Donor median age was 24.5 years (y) (range 17-32y) and median BMI was 27.9 (range 20.7-31.1). No donors had history of diabetes or smoking greater than 20 packs/y. The median donor sequence number (DSN), which represents the number of recipients to whom the organ had been offered prior to acceptance for transplantation, was 7.5 (range 1-75). All offers prior to acceptance (7 out of 8) had been declined due to NP COVID-19 positive testing. Median Ct value of SARS-CoV-2 RT-PCR testing was 36.4 (range 35.7-37.5), with 7 (87.5%) detected from NP sampling. Median number of days between positive donor testing and transplantation was 4 (range 3-5). Median number of chest imaging tests, including chest X-rays and at least 1 computed tomography, was 12 during donor admission. All images were reviewed by transplant surgeons and pulmonologist prior to acceptance. Cause of deaths included drug intoxication (2), motor vehicle accident (2), suicide (2), head trauma (1), and cardiovascular (1). All 8 LT recipients underwent bilateral lung transplants. The median age of LT recipients in years was 44.5 (range 34.5-50.3) and median lung allocation score (LAS) was 46 (range 37-85). There was no donor-derived COVID-19 transmission to recipients based on LRT SARS-CoV-2 RT-PCR testing post-transplant. At 72 hours, 3 (37.5%) developed Grade 1 PGD, 1 (12.5%) Grade 3 PGD, and 4 (50%) had no evidence of PGD. One recipient (12.5%) developed Grade A1 rejection. All recipients are alive to date, corresponding to 30-day survival of 100% for 8 recipients and 90-day survival of 100% for 7 thus far (Table 2).
      Table 1Donor and Recipient Characteristics
      DonorRecipient
      CaseAge (y)SexBMICause of deathP/F ratio at offerCT chestNP CtLRT CtTime to transplant (d)Age (y)SexDiseaseLASOffers prior to acceptance
      129M31.6Drug intoxication408Ground-glass and patchy alveolar opacities are present within RUL and bilateral lobes35.8Negative545MPF3811
      220M20.7MVA520Patchy infiltrate in LUL. Ground-glass infiltrate in LLL39.3Negative668MIPF3712
      317M25.6Suicide496Mild dependent aspiration and atelectasis.35.3Negative435MCOVID-19 PF9421
      419M31.1Suicide457Dependent atelectasis is present at RLL36.7Negative251FNSIP494
      532M25.0Cardiovascular539Minimal ground-glass density in RUL. Minimal atelectasis in LLLNegative35.12350MPH4375
      618M30.9Head trauma485Consolidation in RLL. A small dependent left basilar consolidation is also present.36.1Negative433FPF941
      730M23.3MVA419Minimal bilateral effusion, no opacities37.1Negative744MIPF374
      829M30.1Drug intoxication447Consolidation in RLL, scattered small consolidation LLL38.6Negative327FPH822
      Abbreviations: Ct, cycle threshold; IPF, idiopathic pulmonary fibrosis; LAS, lung allocation score; LLL, left lower lobe; LRT, lower respiratory tract; LUL, left upper lobe; MVA, motor vehicle accident; NP, nasopharyngeal; NSIP, nonspecific interstitial pneumonia; PF, Pulmonary fibrosis; PH, pulmonary hypertension; RLL, right lower lobe; RUL, right upper lobe.
      Table 2Outcomes After Lung Transplant
      Postoperative
      CaseSurgeryCOVID-19 transmissionPGD at 72 hACRICU LOSHospital LOSDays To dateStatus
      1BilateralN1A11113330Alive
      2BilateralN0N312205Alive
      3BilateralN0N426176Alive
      4BilateralN0N712146Alive
      5BilateralN3N1149120Alive
      6BilateralN0N305395Alive
      7BilateralN1N61264Alive
      8BilateralN1N1421225Alive
      Abbreviations: ACR, acute cellular rejection; ICU, intensive care unit; LOS, length of stay; PGD, primary graft dysfunction.
      There is currently no consensus for determining the safety of utilization of donors for LT with incidental positive COVID-19 testing. Only 2 LTs have been described at a single center, where donor eligibility required initial positive NP testing to be >20 days from procurement and a negative LRT testing.
      • Waudby-West R
      • Parcell BJ
      • Palmer CNA
      • Bell S
      • Chalmers JD
      • Siddiqui MK
      The association between SARS-CoV-2 RT-PCR cycle threshold and mortality in a community cohort.
      However, it does not include evaluation of the cycle threshold (Ct) value. In fact, Ct values are presently not recommended for assessment of infectivity by the Centers for Disease Control and Prevention and the Food and Drug Administration due to test variability.
      • Waudby-West R
      • Parcell BJ
      • Palmer CNA
      • Bell S
      • Chalmers JD
      • Siddiqui MK
      The association between SARS-CoV-2 RT-PCR cycle threshold and mortality in a community cohort.
      ,
      • Kute VB
      • Fleetwood VA
      • Meshram HS
      • Guenette A
      • Lentine KL
      Use of organs from SARS-CoV-2 infected donors: is it safe? A contemporary review.
      However, other single center experiences using Ct threshold greater than 35 have reported successful organ transplantations.
      • Kute VB
      • Fleetwood VA
      • Meshram HS
      • Guenette A
      • Lentine KL
      Use of organs from SARS-CoV-2 infected donors: is it safe? A contemporary review.
      ,
      • Dhand A
      • Gass A
      • Nishida S
      • et al.
      Successful transplantation of organs from a deceased donor with early SARS-CoV-2 infection.
      Ct values represent the number of amplification cycles needed on a RT-PCR sample to breach the threshold for positivity. They have been inversely correlated to viral load and mortality and used clinically to reduce isolation period for COVID-19 infected individuals.
      • Waudby-West R
      • Parcell BJ
      • Palmer CNA
      • Bell S
      • Chalmers JD
      • Siddiqui MK
      The association between SARS-CoV-2 RT-PCR cycle threshold and mortality in a community cohort.
      ,
      • Aranha C
      • Patel V
      • Bhor V
      • Gogoi D
      Cycle threshold values in RT-PCR to determine dynamics of SARS-CoV-2 viral load: an approach to reduce the isolation period for COVID-19 patients.
      Our experience based on an evaluation of the RT-PCR Ct values contributes to the available evidence of safety of utilizing donors with incidental positive COVID-19 testing. Across our 8 cases, all donors had Ct values greater than 35, a threshold that has been shown to correlate with inability to detect culturable virus.

      Organ Procurement and Transplantation Network. Summary of Current Evidence and Information-Donor SARS-CoV-2 Testing & Organ Recovery from Donors with a History of COVID-19. Version 6. Available at: https://optn.transplant.hrsa.gov/media/kkhnlwah/sars-cov-2-summary-of-evidence.pdf. Accessed November 15, 2022.

      Based on our algorithm, only 8 potential donors were evaluated. We believe that performing LRT COVID-19 RT-PCR to rule out infection in appropriate donors, such as those with incidental positive NP COVID-19 positive RT-PCR with a Ct greater than 30, normal P/F ratio and benign chest imaging, could potentially increase the donor pool even further. While most (7 of 8) tested positive by NP RT-PCR alone with negative LRT testing, it should be noted that 1 donor had negative NP testing and subsequent LRT positivity with Ct value above 35. We thus did not make a distinction between NP or LRT source if Ct value threshold >35 was met and did not decline donors due to lack of prior COVID testing data if initial RT-PCR positivity was within 20 days of procurement. We observed that the donors’ causes of death are attributed to circumstances that often pose a practical challenge to ensuring adequate time from initial positive testing to organ procurement as proposed under current OPTN guidelines. Ct may therefore represent a surrogate for consideration for donor organ risk stratification in case of incidental COVID-19 positive RT-PCR, as proposed in Figure 1. Since positive RT-PCR by LRT with negative NP testing was represented by only 1 donor during the study period, the donor selection algorithm we put forth in Figure 1 utilizes positive NP RT-PCR alone (Ct value >35) as initial criteria.
      Our study has limitations. First, our experience is small with only 8 LTs. Second, donor clinical information was limited to data obtained by organ procurement organizations . However, there were no cases of COVID-19 donor transmission and no mortality to date. Moreover, we noted similar rate of PGD to what is reported in literature.
      • Van Raemdonck D
      • Hartwig MG
      • Hertz MI
      • et al.
      Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: prevention and treatment: a 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      These results should be interpreted cautiously but they support a reassessment of current recommendations for donor lung acceptance to maximize donor utilization as incidental COVID-19 positive testing is expected to increase.

      Disclosure statement

      The authors of this publication have no conflicts of interest or financial considerations to disclose.
      J.H., A.Y., L.Z., and R.R. contributed to the analysis and drafted the manuscript. All other authors revised the manuscript and approved the final version. R.R., P.Z., P.D. and D.J.M. contributed to the planning of the study.

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