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

Last Updated: April 21, 2021

Summary Recommendations
Summary Recommendations

Vaccination for SARS-CoV-2

  • Given the effectiveness of SARS-CoV-2 vaccines in the general population and the increased risk of worse clinical outcomes of COVID-19 in transplant and cellular therapy recipients, the COVID-19 Treatment Guidelines Panel (the Panel) recommends SARS-CoV-2 vaccination for potential transplant and cellular therapy candidates, potential donors, and recipients (AIII). See the text below for information on the appropriate timing for SARS-CoV-2 vaccination in these patients.

Potential Transplant and Cellular Therapy Candidates

  • The Panel recommends diagnostic molecular testing for 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 and 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 if 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

  • Clinicians should follow the guidelines for evaluating and managing COVID-19 in nontransplant patients when treating transplant and cellular therapy recipients (AIII). See Therapeutic Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of Hospitalized Adults With COVID-19 for more information.
  • The Panel recommends that clinicians who are treating COVID-19 in transplant and cellular therapy patients consult with a transplant specialist before adjusting immunosuppressive medications (AIII).
  • When treating COVID-19, clinicians should pay careful attention to potential drug-drug interactions and overlapping toxicities with immunosuppressants, prophylactic antimicrobials, and other medications (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = 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 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 COVID-19 Treatment 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 those for nontransplant patients (AIII). See Therapeutic Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of Hospitalized Adults With 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.

Vaccination for SARS-CoV-2 in Solid Organ Transplant, Hematopoietic Stem Cell Transplant, and Cellular Therapy Candidates, Donors, and Recipients

The clinical trials that have evaluated the SARS-CoV-2 vaccines that have received Emergency Use Authorizations from the Food and Drug Administration have excluded severely immunocompromised patients.2-4 The Advisory Committee on Immunization Practices notes that the currently authorized COVID-19 vaccines are not live vaccines; therefore, they can be safely administered to immunocompromised people.5 The efficacy rates for the available vaccines may be lower in immunocompromised patients than in the general population, and the relative efficacy of the different vaccines for transplant candidates or recipients is currently unknown. Given the effectiveness of SARS-CoV-2 vaccines in the general population and the increased risk of worse clinical outcomes of COVID-19 in transplant and cellular therapy recipients, the COVID-19 Treatment Guidelines Panel (the Panel) recommends SARS-CoV-2 vaccination for potential transplant and cellular therapy candidates, potential donors, and recipients (AIII).

When determining the timing of SARS-CoV-2 vaccination in SOT, HCT, and cell therapy recipients, clinicians should consider the following factors:

  • Ideally, SOT candidates should receive SARS-CoV-2 vaccines while they are awaiting transplant.
  • In general, vaccination should be completed at least 2 weeks prior to SOT or started 1 month after SOT.
  • In certain situations, it may be appropriate to delay vaccination until 3 months after SOT, such as when T cell or B cell ablative therapy (with antithymocyte globulin or rituximab) is used at the time of transplant.6
  • At this time, reducing the dose of immunosuppressants and holding immunosuppressants prior to SARS-CoV-2 vaccination are not recommended.
  • SARS-CoV-2 vaccines can be offered as early as 3 months after a patient receives HCT or chimeric antigen receptor T cell (CAR-T) therapy, although the efficacy of the vaccines may be reduced compared to the efficacy observed in the general population.7,8 Patients who are scheduled to receive cytotoxic or B cell–depleting therapies should complete their SARS-CoV-2 vaccination prior to initiation or between cycles of cytotoxic or B cell–depleting therapies if possible.
  • After completing SARS-CoV-2 vaccination, immunocompromised persons should be advised to continue to exercise precautions to reduce their risk of SARS-CoV-2 exposure and infection (e.g., they should continue wearing a mask, maintain a distance of 6 feet from others, and avoid crowds and poorly ventilated spaces).9

It is unknown whether the immune responses to SARS-CoV-2 vaccination can increase the risk of graft-versus-host disease or other immune-related complications. Outside of a clinical study, antibody testing is not recommended to assess immunity to SARS-CoV-2 following COVID-19 vaccination in transplant patients. For people who received COVID-19 vaccines during treatment with immunosuppressive drugs, revaccination after they regain immune competence is currently not recommended.

Vaccination of household members, close contacts, and health care providers who provide care for immunocompromised patients is imperative to protect immunocompromised patients from infection. All close contacts are strongly encouraged to get vaccinated as soon as possible.

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 that a donor or candidate may have SARS-CoV-2 infection can be estimated by considering the epidemiologic risk, obtaining a 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 a scheduled transplant.10 HCT donors should practice good hygiene and avoid crowded places and large group gatherings during the 28 days prior to donation.11

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 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-19.1,12 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).13 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%.14-18

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, regardless of whether the individual has COVID-19. Similarly, immunosuppressive therapy should be initiated in recipients with or without COVID-19 who have rejection confirmed by a biopsy.1

There are limited data on the incidence and clinical characteristics of SARS-CoV-2 infection in HCT and cellular therapy recipients. Recent data from the Center for International Blood and Marrow Transplant Research demonstrated a mortality rate of approximately 30% within a month of COVID-19 diagnosis among a cohort of 318 HCT recipients.19 This mortality rate was observed in both allogeneic and autologous recipients. Older age (≥50 years), male sex, and receipt of a COVID-19 diagnosis within 12 months of transplantation were associated with a higher risk of mortality among allogeneic recipients. In autologous recipients, patients with lymphoma had a higher risk of mortality than patients who had plasma cell disorder or myeloma.

A smaller study demonstrated a slightly lower mortality rate among HCT and cellular therapy recipients than earlier reports. This study found that the number of comorbidities, the presence of infiltrates on initial chest imaging, and neutropenia were predictors for increased disease severity.20 Additional factors that have been used to determine the clinical severity of other respiratory viral infections include the degree of cytopenia, the intensity of the conditioning regimen, the graft source, the degree of mismatch, and the need for further immunosuppression to manage graft-versus-host disease. Prolonged viral shedding has been described in SOT and HCT recipients; this can have implications for infection prevention and for the timing of potential therapeutic interventions.21

Treatment of COVID-19 in Transplant Recipients

Currently, the antiviral agent remdesivir is the only drug that is approved by the Food and Drug Administration (FDA) for the treatment of COVID-19. Outpatient transplant recipients who are immunosuppressed or who have certain underlying comorbidities are candidates for the anti-SARS-CoV-2 monoclonal antibodies that are available through Emergency Use Authorizations (see Anti-SARS-CoV-2 Monoclonal Antibodies). Transplant recipients who are hospitalized with mild to moderate COVID-19 may be considered for anti-SARS-CoV-2 monoclonal antibodies that are available through expanded access programs.

Data from a large randomized controlled trial found that a short course of dexamethasone (6 mg once daily for up to 10 days) improved survival in hospitalized patients with COVID-19 who were mechanically ventilated or who required supplemental oxygen.22 Tocilizumab used in combination with dexamethasone is recommended for some patients with severe or critical COVID-19 who exhibit rapid respiratory decompensation (see Interleukin-6 Inhibitors).23,24 The risks and benefits of using both dexamethasone and tocilizumab in transplant recipients with COVID-19 who are receiving immunosuppressive therapy are unknown. Because both dexamethasone and tocilizumab are immunosuppressive agents, patients who receive this combination should be closely monitored for secondary infections.

The Panel’s recommendations for the use of remdesivir, dexamethasone, and tocilizumab in patients with COVID-19 can be found in Therapeutic Management of Hospitalized Adults With COVID-19.

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 for 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.

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.15 Clinicians who are treating COVID-19 in transplant patients should consult a transplant specialist before adjusting immunosuppressive medication (AIII).

Certain therapeutics (e.g., remdesivir, tocilizumab) are associated with elevated levels of transaminases. For liver transplant recipients, the AASLD does not consider abnormal liver biochemistries a contraindication to using remdesivir.25 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 (CYP) 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.26 Among the drugs that are commonly used to treat COVID-19, dexamethasone is a moderate inducer of CYP3A4, and interleukin-6 inhibitors may lead to increased metabolism of CYP substrates. Close monitoring of serum concentration of calcineurin inhibitors should be considered when these drugs are used.

Additional details about the adverse effects and drug interactions of antiviral medications and immune-based therapy for COVID-19 are noted in Tables 2e, 3c, and 4d.

  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;72(1):287-304. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32298473.
  2. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020;384(5):403-416. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33378609.
  3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383(27):2603-2615. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33301246.
  4. Food and Drug Administration. Vaccines and related biological products advisory committee meeting. 2021. Available at: https://www.fda.gov/media/146217/download. Accessed March 26, 2021.
  5. Centers for Disease Control and Prevention. COVID-19 ACIP vaccine recommendations. 2020. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. Accessed January 6, 2021.
  6. American Society of Transplantation. COVID-19 vaccine FAQ sheet. 2021. Available at: https://www.myast.org/sites/default/files/2021%2003%2018%20COVID19%20VACCINE%20FAQS_update.pdf. Accessed April 8, 2021.
  7. Khawaja F, Chemaly R, Dadwal S, et al. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell recipients: frequently asked questions. 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-vaccination-for-hct-and-car-t-cell-recipients. Accessed April 8, 2021.
  8. Ljungman P, Avetisyan G. Influenza vaccination in hematopoietic SCT recipients. Bone Marrow Transplant. 2008;42(10):637-641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18724396.
  9. Centers for Disease Control and Prevention. When you’ve been fully vaccinated: how to protect yourself and others. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.html. Accessed April 8, 2021.
  10. American Society of Transplantation. COVID-19 resources for transplant community. 2020. Available at: https://www.myast.org/covid-19-information. Accessed June 26, 2020.
  11. 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.
  12. Centers for Disease Control and Prevention. People with certain medical conditions. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed April 20, 2021.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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;20(10):2958-2959. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32368838.
  18. Kates OS, Haydel BM, Florman SS, et al. COVID-19 in solid organ transplant: a multi-center cohort study. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32766815.
  19. Sharma A, Bhatt NS, St. Martin A, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185-e193. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33482113.
  20. Shah GL, DeWolf S, Lee YJ, et al. Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation. J Clin Invest. 2020;130(12):6656-6667. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32897885.
  21. Aydillo T, Gonzalez-Reiche AS, Aslam S, et al. Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer. N Engl J Med. 2020;383(26):2586-2588. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33259154.
  22. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
  23. Horby PW, Pessoa-Amorim G, Peto L, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021;preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.
  24. Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.
  25. American Association for the Study of Liver Diseases. Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus statement. 2021. Available at: https://www.aasld.org/sites/default/files/2021-03/AASLD-COVID19-ExpertPanelConsensusStatement-March92021.pdf. Accessed April 12, 2021.
  26. 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.