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Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell Transplant, and Cellular Therapy Candidates, Donors, and Recipients

Last Updated: July 17, 2020

Summary Recommendations
Summary Recommendations

Potential Transplant and Cellular Therapy Candidates

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends diagnostic molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for all potential solid organ transplant (SOT), hematopoietic cell transplant (HCT), and cell therapy candidates with signs and symptoms that suggest acute COVID-19 infection (AIII).
  • The Panel recommends following the guidance from medical professional organizations that specialize in providing care for SOT, HCT, or cell therapy recipients when performing diagnostic molecular testing for SARS-CoV-2 in these patients (AIII).
  • If SARS-CoV-2 is detected or if infection is strongly suspected, transplantation should be deferred, if possible (BIII).

Potential Transplant Donors

  • The Panel recommends assessing all potential SOT donors for signs and symptoms that are associated with COVID-19 according to guidance from medical professional organizations (AIII).
    • The Panel recommends performing diagnostic molecular testing for SARS-CoV-2 if symptoms are present (AIII).
    • If SARS-CoV-2 is detected or if infection is strongly suspected, donation should be deferred (BIII).
  • The Panel recommends assessing all potential HCT donors for signs and symptoms that are associated with COVID-19 according to guidance from medical professional organizations (AIII).
    • The Panel recommends performing diagnostic molecular testing for SARS-CoV-2 when symptoms are present (AIII).
    • If SARS-CoV-2 is detected or if infection is strongly suspected, donation should be deferred (BIII).

Transplant and Cellular Therapy Recipients with COVID-19

Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies; III = Expert opinion

Introduction

Treating COVID-19 in solid organ transplant (SOT), hematopoietic cell transplant (HCT), and cellular immunotherapy recipients can be challenging due to the presence of coexisting medical conditions, transplant-related cytopenias, and the need for chronic immunosuppressive therapy to prevent graft rejection and graft-versus-host disease. Transplant recipients may also potentially have increased exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) given their frequent contact with the health care system. Since immunosuppressive agents modulate several aspects of the host’s immune response, the severity of COVID-19 could potentially be affected by the type and the intensity of the immunosuppressive effect of the agent, as well as by specific combinations of immunosuppressive agents. Some transplant recipients have medical comorbidities that have been associated with more severe cases of COVID-19 and a greater risk of mortality, which makes the attributable impact of transplantation on disease severity difficult to assess.

The American Association for the Study of Liver Diseases (AASLD),1 the International Society for Heart and Lung Transplantation, the American Society of Transplantation, the American Society for Transplantation and Cellular Therapy (ASTCT), the European Society for Blood and Marrow Transplantation (EBMT), and the Association of Organ Procurement Organizations provide guidance for clinicians who are caring for transplant recipients with COVID-19, as well as guidance for screening potential donors and transplant or cell therapy candidates. This section of the Guidelines complements these sources and focuses on considerations for managing COVID-19 in SOT, HCT, and cellular therapy recipients. The optimal management and therapeutic approach to COVID-19 in these populations is unknown. At this time, the procedures for evaluating and managing COVID-19 in transplant recipients are the same as for nontransplant patients (AIII). See Management of Persons with COVID-19, Potential Antiviral Drugs Under Evaluation for the Treatment of COVID-19, and Immune-Based Therapy Under Evaluation for Treatment of COVID-19 for more information. The medications that are used to treat COVID-19 may present different risks and benefits to transplant patients and nontransplant patients.

Assessment of SARS-CoV-2 Infection in Transplant and Cellular Therapy Candidates and Donors

The risk of transmission of SARS-CoV-2 from donors to candidates is unknown. The probability of donor or candidate infection with SARS-CoV-2 may be estimated by considering epidemiologic risk, obtaining clinical history, and testing with molecular techniques. No current testing strategy is sensitive enough or specific enough to totally exclude active infection. Living solid organ donors should be counseled on strategies to prevent infection and monitored for exposures and symptoms in the 14 days prior to scheduled transplant.2 HCT donors should practice good hygiene and avoid crowded places and large group gatherings during the 28 days prior to donation.3

Assessment of Transplant and Cellular Therapy Candidates

Diagnostic molecular testing for SARS-CoV-2 is recommended for all potential SOT candidates with signs and symptoms that suggest acute COVID-19 infection (AIII). All potential SOT candidates should be assessed for exposure to COVID-19 and clinical symptoms that are compatible with COVID-19 before they are called in for transplantation and should undergo diagnostic molecular testing for SARS-CoV-2 shortly before SOT in accordance with guidance from medical professional organizations (AIII).

Clinicians should consider performing diagnostic testing for SARS-CoV-2 in all HCT and cellular therapy candidates who exhibit symptoms. All candidates should also undergo diagnostic molecular testing for SARS-CoV-2 shortly before HCT or cell therapy (AIII).

Assessment of Donors

The COVID-19 Treatment Guidelines Panel (the Panel) recommends following the guidance from medical professional organizations and assessing all potential HCT donors for exposure to COVID-19 and clinical symptoms that are compatible with COVID-19 before donation (AIII). Deceased donors should undergo screening for known symptoms and exposure to others with COVID-19 before transplantation, and decisions about using such organs should be made on a case-by-case basis (BIII). Recommendations for screening are outlined in the ASTCT and EBMT guidelines.

If SARS-CoV-2 Infection Is Detected or Strongly Suspected

If SARS-CoV-2 is detected or if infection is strongly suspected in a potential SOT donor or candidate, transplant should be deferred, if possible (BIII). The optimal disease-free interval before transplantation is not known. The risks of viral transmission should be balanced against the risks to the candidate, such as progression of the underlying disease and risk of mortality if the candidate does not receive the transplant. This decision should be continually reassessed as conditions evolve. For HCT and cellular therapy candidates, current guidelines recommend deferring transplants or immunotherapy procedures, including peripheral blood stem cell mobilization, bone marrow harvest, T cell collection, and conditioning/lymphodepletion in recipients who test positive for SARS-CoV-2 or who have clinical symptoms that are consistent with infection. Final decisions should be made on a case-by-case basis while weighing the risks of delaying or altering therapy for the underlying disease.

Transplant Recipients with COVID-19

SOT recipients who are receiving immunosuppressive therapy should be considered to be at increased risk for severe COVID-19.1,4 A national survey of 88 U.S. transplant centers conducted between March 24 and 31, 2020, reported that 148 SOT recipients received a diagnosis of COVID-19 infection (69.6% were kidney recipients, 15.5% were liver recipients, 8.8% were heart recipients, and 6.1% were lung recipients).5 COVID-19 was mild in 54% of recipients and moderate in 21% of recipients, and 25% of recipients were critically ill. Modification of immunosuppressive therapy during COVID-19 and the use of investigational therapies for treatment of COVID-19 varied widely among recipients. Initial reports of transplant recipients who were hospitalized with COVID-19 suggest mortality rates of up to 28%.6-9

Risk of Graft Rejection

There have been no published reports of graft rejection in SOT recipients who received a diagnosis of COVID-19, although this may be due to a limited ability to perform biopsies. Acute cellular rejection should not be presumed in SOT recipients without biopsy confirmation in individuals with or without COVID-19. Similarly, immunosuppressive therapy should be initiated in recipients with or without COVID-19 who have rejection confirmed by a biopsy.1

There is a lack of data on the incidence and clinical characteristics of SARS-CoV-2 infection in HCT and cellular therapy recipients. Experience with other respiratory viruses suggests that this population is at a high risk for severe disease, including increased rates of lower respiratory tract infection and mortality.10 Factors that may determine clinical severity include degree of cytopenia, time since transplant, intensity of the conditioning regimen, graft source, degree of mismatch, and the need for further immunosuppression to manage graft-versus-host disease. For other respiratory viruses, HCT recipients often exhibit prolonged viral shedding,11-14 which can have implications for infection prevention and for the timing of potential interventions.

Treatment of COVID-19 in Transplant Recipients

Currently, no drug has been approved by the Food and Drug Administration (FDA) for the treatment of COVID-19, although preliminary data suggest that the investigational antiviral drug remdesivir can be used in those with severe disease. Remdesivir is available for use in these patients under the FDA’s Emergency Use Authorization.15

Preliminary data from a large randomized controlled trial have shown that a short course of dexamethasone (6 mg once daily for up to 10 days) can improve survival in patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen.16 At this time, the risks and benefits of using dexamethasone in transplant recipients with COVID-19 who are receiving immunosuppressive therapy, which may include corticosteroids, are unknown.

The Panel’s recommendations for the use of remdesivir and dexamethasone in patients with COVID-19 can be found in the Remdesivir and Corticosteroids sections.

A number of other investigational agents and drugs that are approved by the FDA for other indications are being evaluated for the treatment of COVID-19 (e.g., antiviral therapies, COVID-19 convalescent plasma) and its associated complications (e.g., immunomodulators, antithrombotic agents). In general, the considerations when treating COVID-19 are the same for transplant recipients as for the general population. When possible, treatment should be given as part of a clinical trial. The safety and efficacy of investigational agents and drugs that have been approved by the FDA for other indications are not well defined in transplant recipients. Moreover, it is unknown whether concomitant use of immunosuppressive agents to prevent allograft rejection in the setting of COVID-19 affects treatment outcome.

The use of antiviral or immune-based therapies for the treatment of COVID-19 can present additional challenges in transplant patients. Clinicians should pay special attention to the potential for drug-drug interactions and overlapping toxicities with concomitant medications, such as immunosuppressants that are used to prevent allograft rejection (e.g., corticosteroids, mycophenolate, and calcineurin inhibitors such as tacrolimus and cyclosporine), antimicrobials that are used to prevent opportunistic infections, and other medications. Dose modifications may be necessary for drugs that are used to treat COVID-19 in transplant recipients with pre-existing organ dysfunction. Adjustments to the immunosuppressive regimen should be individualized based on disease severity, the specific immunosuppressants used, the type of transplant, the time since transplantation, the drug concentration, and the risk of graft rejection.7 Clinicians who are treating COVID-19 in transplant patients should consult with a transplant specialist before adjusting immunosuppressive medication (AIII).

Certain investigational or off-label therapeutics (e.g., remdesivir, tocilizumab) are associated with elevated levels of transaminases. For liver transplant recipients, the AASLD does not view abnormal liver biochemistries as a contraindication to using investigational or off-label therapeutics, although certain elevation thresholds may exclude patients from trials of some investigational agents.17 Close monitoring of liver biochemistries is warranted in patients with COVID-19, especially when they are receiving agents with a known risk of hepatotoxicity.

Calcineurin inhibitors, which are commonly used to prevent allograft rejection, have a narrow therapeutic index. Medications that inhibit or induce cytochrome P450 enzymes or P-glycoprotein may put patients who receive calcineurin inhibitors at risk of clinically significant drug-drug interactions, increasing the need for therapeutic drug monitoring and the need to assess for signs of toxicity or rejection.18 Similarly, transplant patients may be at a higher risk of adverse effects, particularly when their concomitant medications have overlapping toxicities. Specific concerns about the use of potential antiviral medications and immune-based therapy for COVID-19 in transplant patients are noted below. See Tables 2b and 3b for additional details.

Table 4. Special Concerns for Drugs That Are Being Evaluated for COVID-19 Treatment in Transplant Patients

Table 4. Special Concerns for Drugs That Are Being Evaluated for COVID-19 Treatment in Transplant Patients
Drugs That Are Being Evaluated for COVID-19 Treatment Concerns in Transplant Patients

Azithromycin

  • Hepatotoxicity (cholestatic hepatitis, rare)
  • Additive effect with other drugs that prolong the QTc interval.

Chloroquine and Hydroxychloroquine

  • Moderate inhibition of CYP2D6.
  • Inhibition of P-gp may increase levels of calcineurin inhibitors and mTOR inhibitors.
  • Additive effect with other drugs that prolong the QTc interval.

Dexamethasone

  • Moderate CYP3A4 inducer
  • Potential for additional immunosuppression and increased risk of OIs.

HIV Protease Inhibitors

  • RTV and other PIs are strong inhibitors of CYP3A4. Coadministration will increase concentrations of tacrolimus, cyclosporine, everolimus, sirolimus, and prednisone.
  • TDM and dose adjustment of immunosuppressant is necessary. Monitor for calcineurin inhibitor-associated toxicities.

Interleukin-6 Inhibitors

  • Use of IL-6 inhibitors may lead to increased metabolism of drugs that are CYP substrates. Effects on CYP may persist for weeks after therapy.
  • AEs include neutropenia and an increase in transaminases. See Table 3b.

Remdesivir

  • Strong P-gp inducers (e.g., rifampin) may reduce RDV exposure. Coadministration is not recommended.
  • Increase in levels of serum transaminases.
  • Accumulation of drug vehicle cyclodextrin in patients with kidney dysfunction.

Ribavirin

  • Significant toxicities, including anemia, bradycardia, and an increase in serum transaminases levels.

References

  1. Fix OK, Hameed B, Fontana RJ, et al. Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD Expert Panel consensus statement. Hepatology. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32298473.
  2. American Society of Transplantation. COVID-19 resources for transplant community. 2020. Available at: https://www.covid19treatmentguidelines.nih.gov/contact-us/. Accessed June 26, 2020.
  3. American Society for Transplantation and Cellular Therapy. ASTCT interim patient guidelines April 20, 2020. 2020. Available at: https://www.astct.org/viewdocument/astct-interim-patient-guidelines-ap?CommunityKey=d3949d84-3440-45f4-8142-90ea05adb0e5&tab=librarydocuments. Accessed July 2, 2020.
  4. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): groups at higher risk for severe illness. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html. Accessed June 1, 2020.
  5. Boyarsky BJ, Po-Yu Chiang T, Werbel WA, et al. Early impact of COVID-19 on transplant center practices and policies in the United States. Am J Transplant. 2020;20(7):1809-1818. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32282982.
  6. Akalin E, Azzi Y, Bartash R, et al. COVID-19 and kidney transplantation. N Engl J Med. 2020;382(25):2475-2477. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32329975.
  7. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant. 2020;20(7):1800-1808. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32330343.
  8. Alberici F, Delbarba E, Manenti C, et al. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int. 2020;97(6):1083-1088. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32354634.
  9. Montagud-Marrahi E, Cofan F, Torregrosa JV, et al. Preliminary data on outcomes of SARS-CoV-2 infection in a Spanish single center cohort of kidney recipients. Am J Transplant. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32368838.
  10. Ison MG, Hirsch HH. Community-acquired respiratory viruses in transplant patients: diversity, impact, unmet clinical needs. Clin Microbiol Rev. 2019;32(4). Available at: https://www.ncbi.nlm.nih.gov/pubmed/31511250.
  11. Ogimi C, Xie H, Leisenring WM, et al. Initial high viral load is associated with prolonged shedding of human rhinovirus in allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2018;24(10):2160-2163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30009982.
  12. Ogimi C, Greninger AL, Waghmare AA, et al. Prolonged shedding of human coronavirus in hematopoietic cell transplant recipients: risk factors and viral genome evolution. J Infect Dis. 2017;216(2):203-209. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28838146.
  13. Milano F, Campbell AP, Guthrie KA, et al. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088-2094. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20042728.
  14. Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M. Differences in clinical outcomes after 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood. 2011;117(19):5050-5056. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21372154.
  15. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—preliminary report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.
  16. Horby P, Shen Lim W, Emberson J, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1.
  17. American Association for the Study of Liver Diseases. Clinical insights for hepatology and liver transplant providers during the COVID-19 pandemic. 2020. Available at: https://www.aasld.org/sites/default/files/2020-04/AASLD-COVID19-ClinicalInsights-4.07.2020-Final.pdf. Accessed: June 26, 2020.
  18. Elens L, Langman LJ, Hesselink DA, et al. Pharmacologic treatment of transplant recipients infected with SARS-CoV-2: considerations regarding therapeutic drug monitoring and drug-drug interactions. Ther Drug Monit. 2020;42(3):360-368. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32304488