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Solid Organ Transplant & Immunosuppressive Medications

Last updated: November 9, 2020

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Overview

Individuals who are immunocompromised appear to be at higher risk for severe illness with COVID-19 (Centers for Disease Control and Prevention, May 2020; Giannakoulis, June 2020). Here we review current clinical information related to COVID-19 in patients who have received solid organ transplant and/or who take prescribed immunosuppressive medications; for information on other immunocompromised populations, see our reviews for patients with HIV and cancer. In general, immunocompromised patients appear to have similar COVID-19 clinical presentations to the general population. However, it has been suggested that some patients with solid organ transplants may present with atypical findings and a lack of fever due to immunosuppression.

Here we review select key epidemiologic literature relating to COVID-19 in patients who are recipients of solid organ transplants or who are receiving immunosuppressive medications, focusing on the largest studies/studies with the highest level of evidence and the most generalizable results. 

 

Testing and Isolation

IDSA recommends:

  • Testing immunocompromised patients who are symptomatic or who have been exposed to someone with COVID-19; and
  • Testing asymptomatic immunocompromised patients at the time of hospital admission or before initiation of immunosuppressive therapy or transplantation (within 48-72 hours).

CDC guidance on discontinuation of transmission-based precautions in patients with severe immunocompromise differs from guidance for the general population. Among most patients with mild to moderate disease, SARS-CoV-2 can no longer be cultured starting from 10-12 days after symptom onset, and in 95% of patients, SARS-CoV-2 cannot be cultured after 15 days of symptoms (see Isolation & Infection Control). However, in one unpublished study, SARS-CoV-2 was cultured 20 days after symptom onset in an immunocompromised patient (van Kampen, June 2020). Patients with immune compromise may shed viral RNA longer than other populations (Zhu, June 2020).

Transmission-based precautions for immunocompromised patients can be discontinued if at least 10 to 20 days have passed since symptoms first appeared AND (if symptomatic) at least 24 hours have passed since the last fever without antipyretics AND (if symptomatic) respiratory symptoms have improved. A test-based strategy can also be considered; this involves resolution of fever and symptoms (if symptomatic) and 2 consecutive negative respiratory SARS-CoV-2 RT-PCR tests at least 24 hours apart. Consultation with infection control experts is also recommended.

 

Treatment Guidance

Current data on management of COVID-19 in patients who are immunocompromised is limited to observational studies and extrapolation of data about other respiratory viruses. Treatment recommendations do not differ from non-immunocompromised populations. However, the safety and efficacy of available investigational agents are not well-defined among immunocompromised patients. Clinicians should pay special attention to potential drug-drug interactions between investigational agents, immunosuppressants (corticosteroids, mycophenolate, calcineurin inhibitors such as tacrolimus and cyclosporine), prophylactic antimicrobials and other medications.

Considerations for patients on immunosuppressive medications other than chemotherapy

Patients with autoimmune conditions may require immune suppressing therapies such as corticosteroids, TNF-alpha inhibitors, JAK-inhibitors, etc. At this time it is not clear if patients with underlying autoimmune diseases have an increased risk of acquiring SARS-CoV-2 or developing severe disease due to their condition (Gianfrancesco, May 2020; Haberman, July 2020; Pablos, August 2020). Comorbidities and increasing age may play a role in disease outcome. Data are also mixed on whether immune suppressing agents such as biologics and steroids increase the risk of acquiring SARS-CoV-2 or developing more severe disease (Ye, May 2020; Conticini, May 2020; Damiani, May 2020; Gianfrancesco, May 2020).

The American College of Rheumatology recommends that hydroxychloroquine, chloroquine and sulfasalazine can be continued in patients with active COVID-19, but other immune suppressing medications should be withheld. If the risks of withholding IL-6 inhibitor therapy are significant, then these may be continued. NSAIDs can be continued unless severe respiratory symptoms are present, and glucocorticoids can be continued as per standard of care.

Considerations for patients with solid organ transplants

It is not currently known if patients who have received solid organ transplants are at increased risk of acquiring COVID-19, and data are variable on if these patients are at increased risk for developing severe disease due to their transplanted state, or due to their increased comorbidities and age (Yi, June 2020; Caillard, August 2020; Kates, August 2020; Peirera, August 2020). Current data are also often limited by lack of a non-transplant group and failure to account for provider decision-making regarding escalating care. Some transplant centers have deferred non-urgent transplants.

The American Society of Transplantation recommends that providers consider decreasing immunosuppression (except for corticosteroids) for solid organ transplant recipients with active COVID-19 who have not had recent rejection episodes and notes the decision to reduce immunosuppression should be based on severity of COVID-19 disease in comparison with rejection risk.

For patients with liver transplants, the American Association for the Study of Liver Diseases recommends discontinuing antimetabolite medications such as mycophenolate mofetil and azathioprine and maintaining calcineurin inhibitors.

 

Key Literature

In summary: It is not currently clear if COVID-19 occurs at a higher incidence in patients with solid organ transplants or immune suppressing medications compared with the general population. Observational studies suggest a higher risk of severe disease in these groups, but whether this is due to underlying immune suppressing condition versus comorbidities or increasing age is not clear. COVID-19 disease management for these patients does not differ from that of the general population.

COVID-19 in solid organ transplant: A multi-center cohort study (Kates, August 2020).

Patient population:

  • Multi-center prospective cohort study of 482 solid organ transplant from >50 transplant centers with confirmed COVID-19.
  • Patients included kidney, kidney/pancreas, liver, heart and lung transplant recipients.
  • The median age was 58 (IQR 46-57); median time post-transplant was 5 years (IQR 2-10).
  • 66% of the cases were patients who received a kidney or kidney/pancreas transplant, followed by liver or liver/kidney (15.2%) and heart or heart/kidney (11.8%).
  • 92% had >1 underlying comorbidity.
  • 91% of the cohort was receiving calcineurin inhibitor-based maintenance immunosuppression.

Primary endpoint:

  • 28-day mortality.

Key findings:

  • Among the 376 (78%) hospitalized, 117 (31%) required mechanical ventilation and 77 (20.5%) died within 28 days of diagnosis.
  • Mortality among hospitalized solid organ transplant patients with COVID-19 was 20.5%.
  • Age >65 (aOR 3.0, p<.001), congestive heart failure (aOR 3.2, p=.004), chronic lung disease (aOR 2.5, p=.018), obesity (aOR 1.9, p=.039) and presenting findings (lymphopenia [aOR 1.9, p=.033] and abnormal chest imaging [aOR 2.9, p=.027]) were independently associated with mortality.
  • Multiple measures of immunosuppression intensity were not associated with mortality.

Limitations:

  • Treatment regimens and immunosuppression management varied by transplant center and geographical region, making it difficult to analyze which investigational agents or interventions were associated with lower mortality.
  • The cohort was heterogeneous in terms of types of solid organ transplant patients; only 6% had undergone lung transplant.
  • The study relied on clinician-reported cases, which may lead to subject bias.

Overall, in this prospective cohort study, mortality among patients who were recipients of solid organ transplant was high. Specific comorbidities were associated with mortality, but degree of immune suppression was not.


An initial report from the French solid organ transplant COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants (Caillard, August 2020).

 

Patient population:

  • 279 COVID-19 patients with kidney transplants listed in the French nationwide Registry of Solid Organ Transplant Recipients.
  • 87% of the patients were admitted; those who were not were predominantly young and with more mild symptoms.
  • Of the hospitalized patients, median age was 61.6 years (IQR 50.8−69.0); 75% were men.
  • 63.8% were overweight, 90.1% had hypertension, 36.1% had cardiovascular disease, 41.3% had diabetes and 14.8% had a history of lung disease.

Primary endpoint:

  • To describe the disease presentation, immunosuppression management, clinical outcomes and independent prognostic variables in kidney transplant recipients with COVID-19.

Key findings:

  • SARS-CoV-2 infection was identified after a median of 74.1 months (IQR 27.6−138.7) from transplant.
  • The median delay between the onset of symptoms and hospital admission was 5 days (IQR 3−8).
  • Severe COVID-19 occurred in 106 patients (46%).
  • 43 hospitalized patients died (30-day mortality 22.8%).
  • 9 patients lost their graft during hospitalization.
  • Multivariable analysis identified overweight (HR 1.65, p=.03), fever (HR 2.01, p=.03) and dyspnea (HR 2.23, p<.001) as independent risk factors for severe disease, whereas age over 60 years (HR 3.81, p=.003), cardiovascular disease (HR 2.04, p=.031) and dyspnea (HR 2.35, p=.01) were independently associated with mortality.

Limitations:

  • The study was retrospective; bias is possible.
  • The cohort includes only symptomatic patients; the results may not be generalizable to all kidney transplant recipients with COVID-19.
  • 7% of the patients were diagnosed based on clinical status and imaging.
  • Data on the non-hospitalized patients is not well-described.

Overall, in this retrospective study, kidney transplant recipients with COVID-19 had high mortality; old age, cardiovascular disease and dyspnea were associated with mortality.


COVID-19 in solid organ transplant recipients: Initial report from the U.S. epicenter (Pereira, May 2020).

Patient population:

  • 90 solid organ transplant recipients with COVID-19 presenting to 2 centers in New York City.
  • The overall median age was 57 years, and 59% were men.
  • There were 46 (51%) kidney transplant recipients, 17 (19%) lung recipients, 13 (14%) liver recipients, 9 (10%) heart recipients, 3 (3%) heart‐kidney recipients, 1 (1%) liver‐kidney recipient and 1 (1%) kidney‐pancreas recipient.

Primary endpoint:

  • To describe the clinical characteristics of solid organ transplant recipients with COVID-19.

Key findings:

  • The median time from transplant to COVID‐19 diagnosis was 6.64 years.
  • 22 (24%) patients had mild COVID-19, 41 (46%) had moderate COVID-19 and 27 (30%) had severe COVID-19.
  • The most common symptoms reported were fever by 63 patients (70%), cough in 53 (59%) and dyspnea in 39 (43%).
  • Immunosuppressive therapy was reduced in the majority of patients. Overall, 42 patients (88%) had antimetabolite doses reduced or held, 3 (7%) had steroids decreased or held and 10 (18%) had calcineurin inhibitor doses decreased or held.
  • 62 (91%) patients received hydroxychloroquine and 45 patients (66%) received azithromycin.
  • 16 patients died (18% overall, 24% of those hospitalized, 52% of those in ICU)  and 37 (54%) were discharged.

Limitations:

  • Small sample size in a single city.
  • Most of the patients received hydroxychloroquine. There has been a change in clinical practice with use of this drug.

Overall, in this small retrospective study of solid organ transplant recipients, the rate of severe COVID-19 was higher than in the general population.

 

COVID-19 in Immune-Mediated Inflammatory Diseases — Case Series from New York (Haberman, July 2020).

Patient population:

  • 86 patients at a single institution in New York City with immune-mediated inflammatory disease with confirmed (59 patients) or highly suspected (27 patients) symptomatic COVID-19 infection, who were receiving anticytokine biologics, other immunomodulatory therapies or both.
  • 72% of the cohort were receiving JAK inhibitors.

Primary endpoint:

  • Describing the clinical characteristics and outcomes of the cohort.

Key findings:

  • The overall incidence of hospitalization was 16%.
  • The hospitalized patients were older than the ambulatory patients.
  • A higher percentage of admitted patients had rheumatoid arthritis.
  • More of the patients for whom hospitalization was warranted had coexisting hypertension, diabetes or chronic obstructive pulmonary disease.
  • The percentage of patients who were receiving biologics or JAK inhibitors at baseline was higher among the ambulatory patients than among the hospitalized patients (76% vs. 50%).
  • The overall incidence of hospitalization among patients who had received these medications on a long-term basis was 11%.
  • After multivariate analysis, the use of oral glucocorticoids (29% of hospitalized patients, 6% of ambulatory patients), hydroxychloroquine (21% and 7%, respectively) and methotrexate (43% and 15%, respectively) was higher among patients with immune-mediated inflammatory disease for whom hospitalization was warranted.

Limitations:

  • Small case series from a single center; the results may not be generalizable.

Overall, in this small case series, receipt of biologic agents or JAK inhibitors was not more likely in hospitalized versus ambulatory patients with rheumatologic conditions and COVID-19.

 

Characteristics associated with hospitalization for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry (Gianfrancesco, June 2020).

Patient population:

  • Case series of 600 patients (from 40 countries) with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry.
  • 71% were female, and the median age was 56 (IQR 45–67).
  • The most common rheumatic disease was rheumatoid arthritis (38%), followed by lupus (14%) and psoriatic arthritis (12%).
  • The most common comorbidities were hypertension (33%), lung disease (21%), diabetes (12%), cardiovascular disease (11%) and chronic renal insufficiency/end-stage renal disease (7%).

Primary endpoint:

  • Hospitalization for COVID-19.

Key findings:

  • 46% of the cases were hospitalized, and 9% died.
  • In multivariable-adjusted models, prednisone dose of ≥10 mg/day was associated with higher odds of hospitalization (OR 2.05, 95% CI, 1.06-.96).
  • Use of conventional disease-modifying antirheumatic drug alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalization (OR 1.23, 95% CI, 0.70-2.17 and OR 0.74, 95% CI, 0.37-1.46, respectively).
  • Non-steroidal anti-inflammatory drug use was not associated with hospitalization status (OR 0.64, 95% CI, 0.39-1.06 ).
  • Tumor necrosis factor inhibitor (anti-TNF) use was associated with reduced odds of hospitalization (OR 0.40, 95% CI, 0.19-0.81).
  • No association with antimalarial use (OR 0.94, 95% CI, 0.57-1.57) was observed.

Limitations:

  • 9% of cases were presumptively diagnosed.
  • The registry is voluntary and does not capture all cases of COVID-19 in patients with rheumatic disease.
  • There was selection bias due to geographic location, hospitalization status and higher disease severity.
  • There was no data on the duration of treatment, medication dose or additional historical treatments.

Overall, in this case series, a prednisone dose of 10 mg/day or more was associated with higher odds of hospitalization, but use of biologic agents was not.

COVID-19 pneumonia in a large cohort of patients treated with biological and targeted synthetic antirheumatic drugs (Conticini, May 2020).

Patient population:

  • 859 patients with rheumatologic conditions treated with disease modifying agents at a single center in Italy.

Primary endpoint:

  • Incidence of COVID diagnosis.

Key findings:

  • Of the cohort, 2 patients developed active COVID-19; one was treated with rituximab and one was treated with tocilizumab.

Limitations:

  • There was no comparator arm to help determine the risk of COVID-19 in patients without rheumatologic diagnoses in the region.
  • It is not clear if testing occurred in asymptomatic patients, which could lead to an undercounting of cases.

Overall, in a single cohort of patients with rheumatologic conditions on disease modifying agents, only 2 patients developed COVID-19 over an approximately 1.5-month timeframe.

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