Version November 2023
INTRODUCTION — Solid organ transplant recipients may be at increased risk for coronavirus disease 2019 (COVID-19) because they are immunosuppressed and are less likely to mount effective immune responses to vaccination.
This topic reviews aspects of COVID-19 that are specific to solid organ transplantation, including screening prior to transplantation, distinct clinical features, managing immunosuppression, and important drug interactions. Other aspects of COVID-19 care are discussed separately:
●(See "COVID-19: Epidemiology, virology, and prevention".)
●(See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)
●(See "COVID-19: Management in hospitalized adults".)
●(See "COVID-19: Evaluation of adults with acute illness in the outpatient setting".)
●(See "COVID-19: Management of adults with acute illness in the outpatient setting".)
●(See "COVID-19: Vaccines".)
●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)
In addition, please refer to our COVID-19 homepage to view the complete list of UpToDate COVID-19 topics.
RISK OF TRANSMISSION
Potential for donor-derived infection — Donor-derived severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported with lung transplantation but not with other organs [1]. For nonlung organ transplantation, data from case series have shown that transplantation of nonlung organs from SARS-CoV-2-infected donors can be safely performed [1-6]. While data are limited, there is no evidence that nonlung organ transplantation from a SARS-CoV-2-infected donor leads to worse short-term outcomes. As an example, one single-center study of 220 deceased-donor kidney transplants found similar rates of delayed graft function, rejection, graft failure, mortality, and COVID-19 diagnoses among recipients of SARS-CoV-2-infected and SARS-CoV-2-uninfected donor kidneys at a median of 5.7 months [7].
Bloodborne transmission has not been reported and is not expected; the frequency, duration, and magnitude of SARS-CoV-2 viremia are low [8-11]. (See "Blood donor screening: Medical history", section on 'Active or prior COVID-19'.)
Posttransplantation risk — It is not known whether solid organ transplant recipients are at higher risk for acquiring SARS-CoV-2 infection than the general population. However, chronic immunosuppression may lower the infectious dose needed to cause infection and impair adequate immune control once infection is established.
Like other immunosuppressed persons, solid organ transplant recipients may shed greater amounts of virus for longer durations than otherwise healthy hosts. Thus, they may be more likely to spread infection to others. Further data are needed to confirm these theories and to quantify viral dynamics and the risk of transmission to others.
PRETRANSPLANTATION SCREENING — All organ donors and potential recipients should be screened for COVID-19 prior to organ procurement. This is to reduce the risk for progression to severe COVID-19 with potent immunosuppression and to initiate appropriate infection prevention measures (eg, airborne precautions) for the safety of the organ procurement team.
Reverse-transcriptase polymerase chain reaction (RT-PCR; primarily used to detect active infection) is the main assay used for screening. Results from RT-PCR can remain positive after clinical resolution and may not be associated with increased risk of transmission. Thus, decisions about proceeding to transplant should take into account when the onset of infection likely occurred and whether symptoms, laboratory, and radiographic findings associated with active COVID-19 are present. (See "COVID-19: Diagnosis", section on 'Choosing an initial diagnostic test'.)
Donor screening — All donors should be screened for SARS-CoV-2 infection [12]. We generally perform a careful history, obtain chest imaging, and perform microbiologic testing. In all cases the decision to proceed to transplantation should consider the urgency of the transplant and the risk and benefits in each individual. General principles adapted from the American Society of Transplantation (AST) guidelines and Organ Procurement and Transplantation Network (OPTN) on SARS-CoV-2 donor evaluation and testing are below [13,14]:
●Living donors
•Self-quarantine for 14 days prior to donation should be considered to reduce the risk of SARS-CoV-2 infection. At a minimum, we ask donors to avoid high risk activities and to mask and take other general precautions prior to donation.
•At the time of donation, donors should be screening for symptoms and potential exposures. Chest imaging and nucleic acid amplification testing (NAAT) for SARS-CoV-2 from a respiratory tract sample should be performed within 72 hours of donation (but ideally as close as possible to the time of donation).
●Deceased donors
•Screening should include assessing for past COVID-19, vaccination history, recent exposures, and the timing of these events relative to the donation.
•NAAT for SARS-CoV-2 should be performed on nasopharyngeal samples from deceased donors within 72 hours and, ideally, as close as possible to organ recovery. When lungs are recovered for transplantation, NAAT for SARS-CoV-2 should be performed on both nasopharyngeal and lower respiratory tract samples.
Lung transplantation from donors with active infection is generally avoided. Some centers have avoided the use of donors with active infection and death due to severe COVID-19 or donors with thrombotic complications due to COVID-19, even for non-lung organ transplantation.
For donors with resolved COVID-19 who test positive by NAAT, the decision to proceed to transplantation should be on a case-by-case basis and consider the urgency of transplantation and the risk of recipient mortality if transmission occurs. In general, for donors who recovered from COVID-19 21 to 90 days prior to donation, the likelihood of transmission via transplantation of nonlung organs is low and a positive NAAT is not thought to reflect active/transmissible virus [2]. For those who more recently recovered or who have no clear history of COVID-19, the risk for transmission is not fully known but appears to be low. There are increasing reports of transplantation of nonlung organs from donors with recent SARS-CoV-2 infection that do not lead to viral transmission and have good short-term patient and graft outcomes. Long-term outcomes are not well characterized.
Similarly, for donors who have been exposed but test negative, the safety of donation is not known. In all cases, consultation with an infectious disease expert can help with test interpretation and risk-benefit analysis [13]. The OPTN has provided a summary of the evidence to help guide decision-making.
Candidate screening — All potential organ transplant recipients should be screened for COVID-19 by history, chest imaging, and microbiologic testing prior to transplantation. Although data are lacking, COVID-19 can be asymptomatic, and there is concern that the intensive immunosuppression given at the time of transplantation could result in rapidly progressive and potentially fatal COVID-19:
●All potential organ recipients should be screened for COVID-19 prior to transplantation. At most transplant centers this includes NAAT of an upper respiratory tract specimen (eg, nasopharyngeal swab), a thorough symptom and exposure history, and chest imaging. A chest radiograph is usually sufficient for patients who lack respiratory symptoms, however, for those with respiratory symptoms (even if minor), computed tomography (CT) of the chest is appropriate.
●Candidates with active COVID-19 should generally be deferred for transplantation.
For patients with active COVID-19 and patients who screen positive, the optimal deferral period is not known. The AST suggests waiting until all symptoms have resolved and at least one NAAT for SARS-CoV-2 has been negative [12,15]. Some centers prefer to have two negative NAATs for enhanced sensitivity. However, as with any transplantation, the risk of transplantation must be balanced with the risk of not transplanting a patient with acute or recent COVID-19.
PREVENTION
General measures — Preventive measures for organ transplant recipients are similar to those defined for the general population. However, we continue to advise vaccinated transplant recipients to maintain personal measures to minimize exposure to SARS-CoV-2 (eg, masking, distancing, avoiding crowds when possible) because early data suggest that vaccine response is suboptimal and that newer omicron variants are more readily transmitted, regardless of vaccination status. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)
One additional consideration is that solid organ transplant recipients who have COVID-19 may shed greater amounts of virus for longer durations than nonimmunosuppressed patients [16,17]. Thus, a longer duration of isolation and/or testing may be needed to document viral clearance to help reduce the likelihood of spreading the infection to others [18]. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the home setting' and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)
Centers for Disease Control and Prevention (CDC) guidance on the duration of isolation and quarantine for immunocompromised patients can be found here.
Vaccination — All transplant recipients are eligible for vaccination, unless contraindicated (eg, hypersensitivity to the vaccine or its components). Although the immunogenicity and efficacy of COVID-19 vaccines are lower in solid organ transplant recipients than the general population [19,20], the benefit from vaccination outweighs risk. Solid organ transplant recipients should continue to adhere to protective measures (such as masking and social distancing) despite vaccination, based upon data suggesting a suboptimal immune response among transplant recipients [21-25] and studies suggesting lower efficacy against severe disease [26,27].
●Timing – The ideal timing of vaccination in the posttransplantation setting is not known. In all cases, we weigh the likelihood of contracting COVID-19 (based on community prevalence) against the probability of developing a protective immune response to vaccination.
•Whenever possible, vaccination should occur prior to transplantation (ideally with completion of a vaccine series a minimum of two weeks prior to transplant).
•If vaccination prior to transplantation is not possible, we delay vaccination for at least one month from the time of transplantation and for at least three months after use of T cell-depleting agents (eg, anti-thymocyte globulin) or specific B cell-depletion agents (eg, rituximab) [28].
•For patients who are transplanted between vaccine doses, we delay the second dose until at least one month after transplantation (if induction did not include a T or B cell-depleting agent) and for three months when a T or B cell-depleting agent was used for induction.
These recommendations are consistent with expert guidance from International Society for Heart and Lung Transplantation (ISHLT) [28]; the American Society of Transplantation (AST) also recommends vaccinating at least two weeks before transplantation but does not specify whether vaccination should be delayed when T or B cell-depleting agents are used [29].
●Dose and interval – The humoral immune response to COVID-19 vaccination is impaired in solid organ transplant recipients [21-23,25]. Several studies have found that the antibody response to a two-dose mRNA vaccine is substantially lower in solid organ transplant recipients when compared with the general population [21,22,25,30]. Poor immune response was associated with the use of antimetabolite immunosuppression in one study [22]. However, observational studies assessing the "real-world" impact of vaccination among transplant recipients have shown that receipt of mRNA vaccine is associated with a lower risk of SARS-CoV-2 infection, although these studies predated the emergence of the Omicron variant [31-35].
Administering a third dose to solid organ transplant recipients is associated with improved immunogenicity in a significant number of individuals and appears to be safe. The US Food and Drug Administration (FDA) approved third doses of mRNA COVID-19 vaccine for many immunosuppressed patients, including solid organ transplant recipients, based upon multiple studies showing improved immune response [36-41]. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)
Response to vaccination among solid organ transplant recipients may be determined by measuring antibody responses, cellular immune responses (not commercially available), and overall effectiveness. While antibody responses are diminished compared with those in healthy controls [42], T cell responses may be present in the absence of humoral immunity (and vice versa) [43-46], and although breakthrough infections occur in fully vaccinated solid organ transplant recipients, the severity of illness appears to be diminished. We do not perform routine antibody testing to assess vaccine response.
●Booster doses – Following completion of a primary vaccine series and any booster doses of the monovalent vaccine, a booster dose of the bivalent mRNA vaccine is recommended at least two months after the last vaccine dose or three months after COVID-19 infection.
Further details on the indications and approach to booster vaccinations are discussed separately. (See "COVID-19: Vaccines", section on 'Dose and interval (for immunocompetent individuals)'.)
●Immunosuppression and vaccine response – The optimal approach to managing immunosuppression around the time of vaccination is not known, and approaches vary among experts:
•For transplant recipients outside of the early posttransplantation period, there are insufficient data to guide modifications of immunosuppression in anticipation of, or preparation for, vaccination, and society guidelines do not recommend routine modification of immunosuppression [47]. However, some experts favor holding the antimetabolite (eg, mycophenolate mofetil [MMF]) around the time of vaccination to maximize the likelihood of developing protective immunity [48]; there is no specific evidence to guide how best to adjust immunosuppression with respect to timing, duration, or specific medication adjustment. MMF has been associated with a lower odds of positive antibody response to vaccination among solid organ transplant recipients [19,49]. However, in one trial in kidney transplant recipients who did not develop an antibody response after two of three doses of mRNA vaccine, temporary discontinuation of MMF prior to immunization did not improve seroconversion [50]. Although one study of kidney transplant recipients found an association between mammalian (mechanistic) target of rapamycin (mTOR) inhibitor therapy and improved humoral and cellular immune response to a two-dose mRNA vaccine [51], this finding was not confirmed in a larger study [49]. A clinical trial evaluating the effects of immunosuppression reduction on vaccine response is in progress (NCT05060991).
•For those receiving B or T cell-depleting therapy for rejection or other indications, we may delay vaccination for one to three months depending on the agent used.
Available studies have not reported an increased rate of acute allograft rejection with vaccination, but longer-term follow-up and assessment of donor-specific antibodies are needed.
Specific details on vaccine administration (eg, intervals between vaccination, lack of need for serologic testing) are similar to those for the general population. (See "COVID-19: Vaccines".)
●Breakthrough infections after vaccination – Breakthrough infections among vaccinated solid organ transplant patients, including cases requiring hospitalization and mechanical ventilation, have been reported [52-58]. Although the overall incidence of breakthrough infections among vaccinated transplant patients is low, it appears to be greater than that among vaccinated individuals in the general population. (See "COVID-19: Vaccines", section on 'Breakthrough infections after vaccination'.)
Preexposure prophylaxis — Preexposure prophylaxis (PrEP) with tixagevimab plus cilgavimab was authorized for use as PrEP in patients (aged ≥12 years) with moderate to severe immunosuppression [59]. One cohort study comparing PrEP with tixagevimab-cilgavimab with no PrEP in vaccinated solid-organ transplant found a lower risk of breakthrough COVID-19 infection (5 versus 14 percent, respectively) during the omicron wave [60]. However, the risk of breakthrough infection with the omicron variant appears to be higher when the lower dose (150 mg of tixagevimab plus 150 mg of cilgavimab) is used [60,61].
However, the proportion of variants with reduced susceptibility to tixagevimab plus cilgavimab is growing; concordantly, its effectiveness appears to be increasingly limited. At this time, tixagevimab plus cilgavimab is no longer available in the United States for PrEP. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis'.)
ACTIVE COVID-19 IN SOLID ORGAN TRANSPLANT RECIPIENTS
Clinical presentation
Clinical features — Clinical features of COVID-19 among solid organ transplant recipients are variable and similar to those in immunocompetent patients. However, fever appears to be less common, possibly as a consequence of the effects of immunosuppressive therapy on the systemic inflammatory response [62-66]. As an example, in two case series of solid organ transplant recipients in New York City, fever was a presenting symptom in only 58 to 70 percent [63,64]. Lymphopenia is also common and may be more profound than in nontransplant patients with COVID-19 [64,66].
Severity of illness — The incidence of COVID-19 infection is similar or slightly higher among solid organ transplant recipients compared with the general population. Hospitalization rates are also higher among solid organ transplant recipients [35,67]. However, among those who require hospitalization, the risk for mortality appears to be similar to that for the general population when adjusted for comorbidities [67-73]. Severity of disease among solid organ transplant recipients appears to be attenuated with the Omicron variant compared with prior variants [74].
Risk factors for severe COVID-19 are discussed in detail elsewhere. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness'.)
Effect of immunosuppression — The impact of immunosuppression in the solid organ transplant population on COVID-19 disease severity remains unclear. The pathogenesis of COVID-19 appears to represent an interplay between direct virally mediated injury and the associated host response, with experimental data suggesting that a dysregulated and hyperintense immune response may mediate more severe disease [75]. Since immunosuppressive agents modulate several aspects of the host immune response, the severity of COVID-19 could potentially be affected by the type, combinations, and intensity of immunosuppression. As an example, certain immunosuppressive medications can either directly (eg, lymphocyte-depleting antibodies) or indirectly (eg, antimetabolites) cause lymphopenia, which is a reported risk factor for severe COVID-19 illness [76,77]. Specific agents that have been independently associated with decreased immune responses to vaccines (eg, mammalian [mechanistic] target of rapamycin [mTOR] inhibitors, mycophenolate) could theoretically impair the ability to develop an adequate immune response to natural infection. Conversely, some experimental data suggest that mTOR inhibitors may have some biological activity against SARS-CoV-2 [78]. Additional studies are required to determine the impact of specific immunosuppressive agents on the course of COVID-19.
Diagnosis — Criteria for testing for COVID-19 in solid organ transplant recipients are similar to those for the general population. However, clinicians should have a higher index of suspicion of infection, as is generally recommended for immunosuppressed individuals (table 1):
●For solid organ transplant recipients with suspected COVID-19 who are hospitalized, testing is recommended.
●For solid organ transplant recipients with mild symptoms, optimal practice is not defined. While some favor testing all such patients based upon the potential for rapid disease progression and early treatment, others favor making a clinical diagnosis and monitoring the patient at home. Thus, the decision is often individualized based upon local COVID-19 prevalence, available resources, and patient-provider preference. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)
●Routine screening of asymptomatic solid organ transplant recipients is not recommended.
Specific testing and screening methods are discussed separately. (See "COVID-19: Diagnosis", section on 'Clinical suspicion' and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)
Management
General considerations — The approach to the management of acute COVID-19 in solid organ transplant recipients is similar to that for nontransplant patients; however, because of their immunosuppressed status, the threshold to treat early and mild infections and provide post- or preexposure prophylaxis is lower (algorithm 1). In addition, careful attention should be paid to drug-drug interactions. (See 'Drug-drug interactions' below.)
These issues are discussed in more detail separately:
●(See "COVID-19: Management of adults with acute illness in the outpatient setting".)
●(See "COVID-19: Management in hospitalized adults".)
●(See "COVID-19: Clinical manifestations and diagnosis in children".)
●(See "COVID-19: Management of the intubated adult".)
Adjusting immunosuppression — Adjustments to the immunosuppressive regimen are necessarily individualized, based upon disease severity, the specific regimen used, type of organ transplanted, time posttransplant, and the risk of acute allograft rejection [63,66,68,76,77,79-81].
Although the optimal approach is not defined, we usually reduce immunosuppression in patients with moderate to severe COVID-19 (eg, those requiring hospitalization):
●As a first step, we often reduce or hold the antimetabolite (eg, mycophenolate mofetil/sodium), particularly for patients with lymphopenia (eg, absolute lymphocyte count <700 cells/mL).
●We generally continue the calcineurin inhibitor (CNI) because CNIs inhibit interleukin (IL) 6 and IL-1 pathways; these cytokines may contribute to the development of the severe, dysregulated immune response seen in some patients with severe COVID-19.
In all cases the decision to reduce immunosuppression must be carefully weighed against the risk for acute rejection, particularly in transplant recipients who generally require high levels of maintenance immunosuppression (eg, lung or heart recipients). Data supporting our approach and any other are limited to observational studies [63,64,66,68,82,83]. In addition, this approach does not preclude the use of high-dose glucocorticoids and other immunomodulators for severe COVID-19 infection.
There are also concerns that COVID-19 itself may increase the risk for acute rejection and that an overly intense inflammatory host immune response might contribute to overall disease severity. Thus, attenuating the immune response by maintaining low-dose immunosuppression could theoretically be beneficial. In addition, experimental data suggest that certain immunosuppressive agents such as mTOR inhibitors may have some biological activity against SARS-CoV-2 [78]. Additional studies are required to confirm these findings.
Additional guidance on adjusting immunosuppression in transplant recipients with active infection can be found in the following topic reviews:
Recommendations from specific medical societies are listed separately. (See 'Society guideline links' below.)
Drug-drug interactions — Several new antiviral medications are being evaluated or have already been approved for treatment of COVID-19 (see "COVID-19: Management in hospitalized adults", section on 'Specific treatments'). Clinicians should be aware that these medications have potential drug-drug interactions with immunosuppressive medications that are commonly used among solid organ transplant recipients (such as CNIs) (table 2). If these immunosuppressive agents are continued during COVID-19 infection, their blood levels should be frequently monitored [84].
As an example, nirmatrelvir-ritonavir has been authorized for emergency use by the United States Food and Drug Administration (FDA) for the treatment of mild to moderate COVID-19 in adults and children at high risk for progression to severe disease. Nirmatrelvir-ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. Concomitant use with sirolimus should be avoided, and blood levels of other immunosuppressive agents (such as CNIs) should be monitored. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Nirmatrelvir-ritonavir as preferred therapy' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Challenges for organ transplantation – COVID-19 poses challenges for individual solid organ transplant candidates and recipients and the process of organ transplantation. (See 'Introduction' above.)
●Risk of transmission – Donor-derived SARS-CoV-2 infection has been reported through lung transplantation but not via nonlung transplantation. (See 'Potential for donor-derived infection' above.)
●Screening before transplantation – Because of the risk for progression to severe disease and the potential for transmitting SARS-CoV-2 to health care providers, all solid organ donor and transplant candidates should be screened for COVID-19 by history, chest imaging, and microbiologic testing. (See 'Pretransplantation screening' above.)
●Posttransplant risk – Posttransplantation, solid organ transplant recipients may be at increased risk for acquisition of infection, progression to symptomatic infection, and/or development of more severe COVID-19. (See 'Posttransplantation risk' above.)
●Clinical manifestations – The clinical manifestations of COVID-19 in solid organ transplant recipients are variable and generally similar to those observed in nonimmunocompromised patients. However, fever appears to be less common. (See 'Clinical presentation' above and 'Severity of illness' above.)
●Diagnosis – The approach to diagnosis is similar to that for the general population. Because signs and symptoms of COVID-19 may be subtle in transplant recipients and disease progression can be rapid, some clinicians have a lower threshold for evaluating and testing transplant recipients. (See 'Diagnosis' above.)
●Management approach – The approach to management (eg, use of antivirals, supportive care) is also similar to that for the general population. Careful attention should be paid to potential drug-drug interactions and effects on the immunosuppressive regimen. (See 'General considerations' above and 'Drug-drug interactions' above.)
●Adjusting immunosuppression – Adjustments to the immunosuppressive regimen are necessarily individualized, based upon disease severity, the specific regimen used, type of organ transplant, time posttransplant, and the risk of acute allograft rejection. Some organ transplant recipients recover without reduction in immunosuppression, which carries the risk of rejection and immune reconstitution. Conversely, continued immunosuppression may enhance the risk of uncontrolled infection. (See 'Adjusting immunosuppression' above.)
●Vaccination – All transplant recipients are eligible for vaccination with an extended dose vaccine series, unless contraindicated (eg, hypersensitivity to the vaccine or its components). The ideal timing in the posttransplantation setting is uncertain. Because early data suggest that vaccine response is suboptimal, we continue to advise that vaccinated transplant recipients maintain personal measures to minimize exposure to SARS-CoV-2 (eg, masking, distancing, avoiding crowds when possible). (See 'Vaccination' above and 'General measures' above.)
●Preexposure prophylaxis – Preexposure prophylaxis (PrEP) with tixagevimab plus cilgavimab is authorized for solid organ transplant patients (aged ≥12 years) who are receiving immunosuppressive treatment. However, the proportion of variants with reduced susceptibility is rising; concordantly, its efficacy appears to be increasingly limited. (See 'Preexposure prophylaxis' above.)
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