COVID-19: Issues related to solid organ transplantation

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".)

RISK OF TRANSMISSION

Potential for donor-derived infection — Donor-derived infection has been reported with lung transplantation but not with other organs [1]. For non-lung organ transplantation, data from case series have shown that transplantation of non-lung organs from SARS-CoV-2-infected donors can be safely performed [1-6]. While data are limited, there is no evidence that non-lung 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 — With declining rates of COVID-19 and the ending of the pandemic emergency, practices for organ donor and potential recipient screening are evolving, with some centers no longer routinely screening asymptomatic potential recipients and/or donors. It is likely that policies for donor and potential recipient screening will be tailored to COVID-19 activity, with enhanced screening at times of increased community activity.

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, during times of community COVID-19 activity. 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, according to local center guidelines and policies.

●Deceased donors

•Screening should include assessing for past COVID-19, vaccination history, recent exposures, and the timing of these events relative to the donation.

•A nucleic acid amplification test (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 not recommended. 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 non-lung 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 appears to be low. There are increasing reports of transplantation of non-lung 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 — Potential organ transplant recipients should be screened for COVID-19 by history, chest imaging, and microbiologic testing prior to transplantation, according to local center guidance and policies.

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 solid organ transplant recipients should undergo COVID-19 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 dose and interval of COVID-19 vaccination in transplant recipients is the same as that for other individuals with moderate to severe immunocompromising conditions and is detailed elsewhere. (See "COVID-19: Vaccines", section on 'Immunocompromised 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 [30]. However, some experts favor holding the antimetabolite (eg, mycophenolate mofetil [MMF]) around the time of vaccination to maximize the likelihood of developing protective immunity [31]; 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 [19,32]. 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 [33]. 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 [34], this finding was not confirmed in a larger study [32]. 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. Because the impact of depleting therapies, especially with rituximab, may be prolonged, suboptimal responses may still occur even after three months.

Available studies have not reported an increased rate of acute allograft rejection with vaccination.

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 [35-41]. Although the overall incidence of severe 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 'Protection against severe disease or death'.)

Preexposure prophylaxis — There are currently no FDA-approved options for preexposure prophylaxis (PrEP) because most circulating variants are resistant or have reduced susceptibility to these therapies. (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 [42-46]. 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 [43,44]. Lymphopenia is also common and may be more profound than in nontransplant patients with COVID-19 [44,46].

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 [47,48]. However, among those who require hospitalization, the risk for mortality appears to be similar to that for the general population when adjusted for comorbidities [48-54]. Severity of disease among solid organ transplant recipients appears to be attenuated with the Omicron variant compared with prior variants [55].

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 [56]. 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 [57,58]. 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 [59]. 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.

Like other immunocompromised patients, solid organ transplant recipients may "shed" virus for longer periods than the general population after an acute episode of COVID-19. Thus, the detection of RNA and/or antigen ("shedding") may not necessarily indicate active or transmissible disease. Clinical evaluation, exposure history, and serial testing may be helpful in distinguishing between active or transmissible infection versus prolonged, nontransmissible shedding. (See "COVID-19: Diagnosis", section on 'Persistent or recurrent positive NAAT during convalescence' and "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

Specific testing and screening methods are discussed in the table (table 1) and 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 [43,46,49,57,58,60-62].

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 [43,44,46,49,63,64]. 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 [59]. 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:

●(See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients who develop infection'.)

●(See "Maintenance immunosuppression following lung transplantation", section on 'Monitoring and adjusting maintenance therapy'.)

●(See "COVID-19: Evaluation and management of cardiac disease in adults", section on 'Cardiac transplantation'.)

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 [65].

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 or everolimus 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 5^th to 6^th 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 10^th to 12^th 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 non-lung 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, solid organ donor and transplant candidates should generally 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 monoclonal antibodies (eg, tixagevimab plus cilgavimab) was authorized for use as PrEP in patients (aged ≥12 years) with moderate to severe immunosuppression. However, most circulating variants are resistant or have reduced susceptibility to these therapies and are not available for routine use. (See 'Preexposure prophylaxis' above.)