This is the fifth update of Coronavirus Disease 2019 (COVID-19) Guidance from the TID Section of TTS. It is important to note that information about this disease and our understanding of this virus and its impact on transplantation is evolving rapidly so the guidance may change over time. We plan to regularly update the guidance as new information becomes available.
Additionally, we have added some focused reviews on key topics that we hope the community finds as an easier way to access data. These sections will be updated regularly while this master document will not be updated extensively after this update. Focused updates include:
TID COVID-19 Guidance Focused Review:
Update on Epidemiology of COVID-19 in Transplant Patients
Date of Update: 30 June 2020
The COVID-19 pandemic continues to expand, with infection rates increasing most in South and Central America and in the United States, Africa and the Indian Subcontinent. As some countries began to resume pre-COVID activities, continued vigilance is necessary to identify new cases and provide mitigation strategies. Moreover, as healthcare institutions increase elective surgeries and outpatient activities, transplant programs will need to be informed by community incidence data to ensure safety for listed and transplanted patients.
More epidemiologic data of COVID-19 in transplant patients are becoming available; however, data on incidence rates and comparisons to non-transplant patients with COVID-19 remain limited. Recent case series have investigated COVID-19 in transplant patients, focusing on clinical presentation and outcomes1-8. A summary of recent selected studies is provided below:
TID COVID-19 Guidance Focused Review:
Update on SOT Recipient Advice to Prevent COVID-19
Date of Update: 30 June 2020
As COVID-19 continues to spread around the world, protecting solid organ transplant (SOT) patients, who appear to be at higher risk for severe SARS-CoV-2 infection, remains critical. Published case series suggest that SOT recipients are frequently hospitalized, and the majority have moderate to severe disease. Since no vaccine or effective antiviral is yet widely available, the best way to prevent infection is to avoid exposure to the virus by implementing strict hygienic and behavioral measures. Advice for SOT patients to protect themselves according to the information available in the literature include:
Summary - General
Summary - Recipients
Summary - Donors
Nucleic Acid Tests (NATs)
Molecular based tests for the detection of SARS-CoV-2 nucleic acid include reverse transcription polymerase chain reaction (RT-PCR) and other nucleic acid amplification tests (NAATs), especially isothermal amplification methods, such as loop-mediated isothermal amplification (LAMP).(1)
Although NATs are the gold standard, questions remain regarding the sample that will give the best yield, the number of samples that gives the best sensitivity, the timing of sampling in relation to symptoms, the duration of shedding and the implications of prolonged shedding. It is important to point out that the bulk of the available data come from studies that were not focused on solid-organ transplant (SOT) candidates/recipients.
Many published studies on COVID-19 in SOT have used RT-PCR to confirm the diagnosis. (2 – 6) While testing is generally applied to nasopharyngeal (NP) and oropharyngeal (OP) swabs, other samples like sputum, nasal swabs, and saliva have also been used. (4 – 6) Although there is general consensus that NP samples give the best sensitivity, with the Omicron variant, saliva has again been suggested.(7)
In the general population, infection with SARS-CoV-2 ranges from being clinically silent (asymptomatic) to severe. SOT recipients, too, have a similarly wide range of manifestations. Patients with severe disease (ventilator-requiring pneumonia) have usually progressed through milder stages.
Accordingly then, the World Health Organization (WHO) recommends using upper respiratory samples to be submitted for NAT testing in patients with early stage illness (eg, the asymptomatic or the mildly symptomatic).(7) The sample that provides the best yield remains controversial. Several studies support the NP swab as giving the best yield; some studies suggest combining NP with OP swabs for improved sensitivity.
Lower respiratory samples are advised later in the course of the disease.(7) An aspirate from the endotracheal tube (ETT) is appropriate and straightforward in an intubated patient.(7) For evaluation of donors, NP swab results are acceptable for decision-making regarding non-lung donors but lower respiratory samples are deemed safer for potential lung donors.(8) The United Kingdom National Health Service Blood and Transplant mandates testing for SARS-CoV-2 RNA in upper respiratory tract (URT) and lower respiratory tract (LRT) specimens in all potential deceased donors, and this strategy minimized the risk of SARS-CoV-2 transmission to lung transplant recipients.(8) In the United States, UNOS only requires BAL SARS-COV-2 PCR of the lower respiratory tract when lungs are being allocated. The best donor sample to decide on suitability of a potential small-bowel donor is unknown.
Information on the use of non-respiratory organs from SARS-CoV-2-infected donors is increasing and there are some reported case series showing that it may be feasible and successfully performed.(9, 10)
There are several reports of false-negative RT-PCR results.(9) These may be related to sampling techniques, eg, skill of the swabber, cooperativeness of the patient, or certain laboratory techniques. (11,12) Whenever COVID-19 is suspected, patient isolation should continue and repeat sampling should be performed.(13, 14) False-negative results are of concern in transplantation as NATs are used to rule out COVID-19 in potential donors. However, depending on the informed consent process between the transplant team and the recipient, duration since onset of COVID-19 in the potential donor, and the urgency and type of transplant, COVID-19 in a donor may longer considered an absolute contraindication (please see above paragraph, plus section on COVID-19 in donors).
There is much concern that mutations may lead to negative PCR results with current kits.(15) It is useful to check with the laboratory if the kit it uses detects variants that emerge.
The Omicron variant has a large number of mutations on the spike (S) protein. NAT assays that combine the S gene with one other target may demonstrate “S-gene target failure”.(16) This S-gene target failure or dropout is being used as a simple means of preliminarily identifying the Omicron variant.(17, 18) The alpha (the B1.1.7 variant) similarly demonstrated S-gene target gene failure.(19) Note that the BA variant of omicron does not exhibit S-gene target failure. (eCDC Update 20 Dec 2021)
Like all tests, NAT assays may also be associated with false-positives. (20) There is a possibility that with ramped up testing, and hence a lower pre-test probability, the number of false-positives may increase. As the PCR is taken as the gold standard, picking up false-positives will be a challenge.
Several articles describe positive results for SARS-CoV-2 PCR from faeces and blood. (21) Viral changes have been noted either pathologically or physiologically with multiple end organs, including the heart, kidney, liver and GI tract. The importance of these for donors and recipients requires further study.
It is now well established that even immunocompetent persons may be PCR-positive in respiratory samples for prolonged periods, up to and beyond 70 days.(22) The very low limit of detection employed by many PCR kits possibly contributes to this phenomenon.(23) However, Perera et al were unable to find subgenomic RNA (which provides evidence viral replication) after day 8 of symptoms, a finding identical to that of Wolfel et al.(24, 25) Bullard et al also were unable to culture virus after Day 8 of symptoms; they correlated cycle threshold (Ct) values with viral isolation and found that live virus could not be cultured when the Ct value was > 24.(26) Other groups have found different cut-offs – Singanayagam found that no viable virus could be isolated when the Ct value was above 35.(27) This is not surprising as Ct values from different assays in different laboratories are not directly comparable.(28)
Point-of-care (POC) or rapid molecular tests are available, but sensitivity varies by test.(29)The development of these POC tests is of relevance to the field of transplantation. The combination of high sensitivity and specificity with a rapid turn-around time should be particularly useful when COVID-19 needs to be ruled out in a potential donor, and in the potential recipient called in for transplant.(30)
In summary, testing of URT samples by RT-PCR is currently the most common means of establishing the diagnosis of SARS-CoV-2 infection and is screening and diagnostic method of choice in transplantation. Physicians may combine specimens to optimize yields. Some centres require several negative PCRs before accepting an organ.(31) When recovering lungs for transplantation, testing for SARS-CoV-2 RNA by NAT in a lower respiratory specimen significantly reduces the risk of transmission of an unrecognized infection. (8)
Serologic (antibody) Testing
Antibody tests measure various types of antibodies - neutralizing antibodies (nAB) or binding antibodies. Coronaviruses are comprised of four structural proteins: spike (S), envelope (E), membrane (M) and nucleocapsid (N). Current serologic tests detect antibodies that target the S and N proteins. Neutralization is defined as the loss of infectivity that occurs when nAB binds to a viral particle, thereby preventing the binding of the virus to its receptor. The gold standard virus neutralization assay to detect neutralizing antibodies – the plaque reduction neutralization test - requires live virus and hence skilled personnel and a biosafety level 3 (BSL 3) laboratory. More recently, the c-PASSTM technology, a surrogate viral neutralization assay, has been approved and can be performed without need for BSL 3 containment.(1)
Serological assays, as might be expected, take several days to become positive. A review of 23 published studies found that ELISA-based assays detecting IgG to nucleoprotein became positive at a mean of 13.3 days post symptoms and that ELISA-based assays detecting IgM to spike protein became positive at a mean of 12.6 days post symptoms (2). The time to seroconversion is not markedly different for papers reporting serology results using magnetic chemiluminescence assays.(2) There are individuals who mount an antibody response within the first week of symptoms, but these tend to be in the minority.(3)
Serology after SOT recipient vaccination
The exact measurable correlates and thresholds of protection from infection and/or severe COVID-19 disease have not been established yet. Therefore, routine testing for antibodies after vaccination is not recommended. Multiple studies, however, have been performed on the serological response to vaccination in SOT recipients, and these have shaped current guideline recommendations (See Vaccine Section for full details).
Vaccinated individuals may test positive for antibodies to antigens present in the vaccine [S and S subunits, including the receptor binding domain (RBD)] but not for antibodies against other non-target proteins. Hence, vaccination with spike-based preparations should give positive results for tests that utilize the S antigen or subunits like RBD, but not for tests that use the N antigen.(5) This implies that an antibody test that targets the S antigen is unable to differentiate between vaccine-induced versus post-disease immune response.
Antigen tests detect the presence of a viral antigen, typically the N antigen. Most antigen kits in the market are lateral flow assays. They are easy to use, and may be self-administered, but are intrinsically less sensitive than NATs for establishing the diagnosis of SARS-CoV-2 infection.(1 – 4)
Many studies have attempted to determine the sensitivity and specificity of the rapid antigen test (RAT) kits. They are hard to compare one against another as they use varying methodology. In general, however, sensitivity can be improved by the use of NP swabs obtained by trained healthcare professionals, and in symptomatic patients early in the course of the illness.(1, 2)
For example, a Japanese team found that the sensitivity of the RAT from self-collected saliva was only 12%.(1) Among close contacts of confirmed COVID-19 patients, the Dutch public health service found a sensitivity of 63% and 64% (two different assays).(2) They swabbed every patient at 2 sites – NP and OP or OP plus nasal. If, however, the patient was symptomatic at the time of the test, sensitivity rose to 78% and 83% (two different assays). This correlation with symptoms has also been found by other authors.(3)
A Belgian study found that RAT and PCR were concordant when the Ct values were below 26.(4) Hence, from an infection control viewpoint, positive RAT results need to be taken seriously, and the patient isolated.(5) On the other hand, Pekosz et al showed that the RAT, and not so much the PCR, correlated with a positive viral culture, and suggested that by tracking RAT results serially, one could determine the point at which a patient might be de-isolated.(6) In support of this, McKay et al also found that the RAT agreed better with viral culture positivity than with PCR positivity.(3)
Because of the low sensitivity of RATs, patients who are symptomatic but are RAT-negative should be tested by NAT. Confirming the diagnosis early is critically important as large studies have shown that early treatment improves clinical outcomes (see section on treatment).
Given the poor sensitivity of RAT assays at low viral loads, and the correlation between positive results and culture-positivity, one possible way to use these tests emerges.(7) In a patient known to have been recently positive for COVID-19, a negative RAT (performed on an NP sample obtained by a trained professional) may signify lack of infectiousness, and hence suitability for management in the usual care areas rather than in an isolation area. In the field of transplantation, a waitlisted candidate who has been temporarily suspended may be reinstated on the waiting list when the RAT becomes negative, which will occur sooner than conversion to PCR-negativity. These approaches have not yet been studied.
References (Antigen tests)
Authored by : Ban Hock Tan, Wanessa Trindade Clemente
TID COVID-19 Guidance Focused Review:
Update on SARS-CoV-2 and Organ Donation
Date of Update: 30 June 2020
With the global spread of COVID-19, the balance between risk of donor-derived or post-transplant infection has to be balanced with the risk of not undergoing organ transplant. Decisions to proceed with organ transplant locally must balance existing capacity of the center, availability of testing for donors and candidates and sufficient capacity to the healthcare workers and patients.(1)
Available data clearly demonstrate that the ongoing COVID-19 pandemic has had a meaningful impact on donor evaluation and procurement.(2)
Testing of deceased donor
The mainstay of donor screening begins with review of donor history – it is important to assess for recent travel, exposure to anyone known or suspected of COVID-19 and any presenting symptoms that could be considered consistent with COVID-19.
All transplant societies strongly recommend universal screening (nucleic acid testing - NAT) of potential deceased organ donors before procurement (https://cdtrp.ca/en/covid-19-international-recommendations-for-odt/). Test performance of routine SARS-CoV-2 NAT has not been evaluated and false negative results are known to occur with poor sample collection and early and late in the disease course. Yield is better from lower respiratory tract specimens, especially in patients with abnormal chest imaging. There appears to be no clear role currently for serologic testing of donors and antigen detection has not been studied in organ donors and is therefore not recommended unless it is the only available test.(3)
Routine imaging may provide help in risk stratifying donors, although lung abnormalities are common in donors without COVID-19.
Use of Donors with Positive Testing for SARS-CoV-2
Potential negative consequences of use of a SARS-CoV-2 infected donors include: 1) the risk of blood transmission of SARS-CoV-2; 2) involvement of donor organs; 3) lack of effective therapies; 4) exposure of health care and recovery teams; 5) disease transmission and propagation and 6) hospital resource utilization.(4)
On the other hand, these theoretical risks must be balanced against the known life-saving and quality of life-improving benefits of organ transplantation. Consideration of the risks and benefits of accepting specific non-lung organs from SARS-CoV-2 infected deceased donors are: 1) No report of successful culture from non-respiratory specimens; 2) there are no documented instances of transfusion or transplantation transmission of SARS-CoV-2 in the first 4 months of the SARS- CoV-2 pandemic; 3) SARS-CoV-2 has not been detected from liver tissue; 4) SARS-CoV-2 has only been detected from cardiac tissue in one patient with severe cardiac dysfunction, who would not be a candidate for transplantation.(5)
On balance, the current recommendation is to not utilize donors who have detectable SARS-CoV-2.
Use of Donors who have Recovered from COVID-19
Recent study demonstrated that SARS-CoV-2 Vero cell infectivity was only observed for RT-PCR cycle threshold (Ct) less than 24 and with symptom onset to test (STT) less than 8 days among 90 samples (nasopharyngeal swab, endotracheal aspirates) collected from day 0 – 21 from Covid-19 patients.(6) Another study with a wider range of disease severity, found culturable virus through day 10. Absolute cut-off values need to be determined by the PCR method used at an individual hospital as they will vary from assay to assay and run to run; there is no international standard for SARS-CoV-2. In another study, with 106 respiratory samples from patients with mild and severe Covid-19, viral infectivity was demonstrated until day 10 from symptoms onset and even 32 days in severe cases. There is a possibility that asymptomatic donors with positive PCR and mild Covid-19 have viable viruses for 10 days or more.(7)
In general, most groups recommend that donors who have had a history of COVID-19 should be at least 14 days since symptom onset and ideally have 2 negative SARS-CoV-2 PCR tests.
TID COVID-19 Guidance Focused Review:
Update on Therapeutic Agents for COVID-19
Date of Update: February 10, 2022
There is limited data on the specific role of any therapy for the treatment of COVID-19 in transplant patients. As such, recommendations are based on data in the general population. Attention should be paid to the potential drug interactions with current immunosuppression and the potential for increased risk of infectious complications when immunomodulatory agents are added to existing immunosuppressive therapy. A summary of the current evidence review for most of the agents listed below with links to key data are found in Table 1.
Therapeutics for Hospitalized, Severe COVID-19
While well-established therapeutic options are limited, remdesivir, an investigational antiviral, has been largely studied as a potential treatment against COVID-19. With known activity against Ebola, MERS, SARS-CoV-1, and SARS-CoV-2, remdesivir was shown to be clinically efficacious compared to the standard of care in patients with severe COVID-19, requiring hospitalization and supplemental oxygenation, including mechanical ventilation. Results from the double-blind, randomized, controlled NIAID ACTT-1 trial found that among 1062 patients, remdesivir (n=541) compared to placebo (n=521) resulted in a shortened median time to recovery (10 days vs. 15 days), a higher rate of clinical status improvement at day 15 (OR 1.5, 95% CI 1.2-1.9 , after adjustment for actual disease severity), and a numerically lower rate of 15-day mortality (6.7% vs. 11.9%) (1). Another randomized, open-label, phase 3 trial evaluated the efficacy and safety of 5 days versus 10 days of remdesivir in 397 hospitalized patients with COVID-19. Among patients receiving supplemental oxygen not on mechanical ventilation, 5 days of remdesivir compared to 10 days of therapy resulted in similar rates of clinical improvement, measured by 2 points on a 7-point ordinal scale (64% vs. 54%) and duration of hospitalization (7 days vs. 8 days).(2) A post hoc analysis to determine a subpopulation might have benefitted from receipt of ≥ 5 days of remdesivir was conducted. Of the patients receiving mechanical ventilation or ECMO at day 5, 40% (10 of 25) in the 5-day group had died by day 14 in contrast with 17% (7 of 41) in the 10-day group. However, treatment with remdesivir beyond 5 days did not appear to improve outcomes among patients who were receiving non-invasive positive pressure ventilation or high flow oxygen, receiving low-flow oxygen, or breathing in ambient air. Reported adverse events include hepatic transaminase elevations, reduced eGFR or CrCl, nausea, constipation, and hyperglycemia. While there are limited data on the safety of remdesivir in patients with eGFR < 30 ml/min, preliminary data suggests that it may be used in patients with acute kidney injury or chronic kidney disease with careful monitoring.(3, 4) Optimal duration of therapy has not been established for highly immunocompromised patients who may experience clinical or virologic rebound after stopping therapy.(5)
In severe COVID-19, the cytokine release syndrome (CRS) response to SARS-CoV-2 can result in lung injury and multi-system organ dysfunction. The use of anti-inflammatory agents such as corticosteroids and immunomodulators may have a role in mitigating the CRS. Initial retrospective cohort or case series studies have reported conflicting results on the benefit of using corticosteroids in novel coronaviruses. (6-10) In the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, a controlled, open-label study in the United Kingdom, participants receiving corticosteroids had lower mortality, in contrast to those receiving usual care. Mortality in COVID-19 patients receiving invasive mechanical ventilation and corticosteroids vs. in those receiving usual care was 29.3% vs. 41.4%rate ratio, 0.64 and those receiving oxygen supplementation without invasive mechanical ventilation and corticosteroids vs. usual care it was 23.3% vs. 26.2%, RR 0.82.(11) This finding was also confirmed by the meta-analysis of the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working group in critically ill patients with COVID-19.(12) The Infectious Diseases Society of America (IDSA) and National Institute of Health (NIH) recommended in their respective guidelines the use of corticosteroids only in patients with severe COVID-19.(13, 14)
Early studies have shown that elevated IL-6 levels were associated with increased rates of more severe disease. Tocilizumab, a monoclonal anti- IL-6 inhibitor approved for various rheumatologic diseases and CRS associated with CAR T-cell therapy, has emerged as a potential treatment option to mitigate CRS due to SARS-CoV-2 infection. Initial studies on tocilizumab had conflicting results.(15-19) However, the results from the RECOVERY and Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) have led to the recommendations in both NIH and IDSA guidelines.(13, 14) There is limited data on the safety or efficacy of tocilizumab in immunocompromised hosts.(20)
The REMAP-CAP (21) randomized adult patients with COVID-19 within 24 hours after starting invasive mechanical ventilation (IMV), non-invasive mechanical ventilation (NIMV), or high flow nasal cannula (HFNC) in the intensive care unit to receive one of the following: tocilizumab (n=353), sarilumab (n=48), or standard of care (n=402) Mortality was lower in the IL-6 inhibitor groups (tocilizumab 28%, sarilumab 22%) compared to control (36%). Most of these patients were enrolled after the RECOVERY trial on dexamethasone was released. Of the enrolled patients, 93% (610/654) received glucocorticoids at enrollment or within the following 48 hours. The treatment effect in patients who received combined IL-6 inhibitor and dexamethasone was greater than the estimates of individual intervention.
The RECOVERY trial (22) randomized their enrolled 4,116 patients with hypoxemia (O2 saturation of 92% on ambient air or those requiring O2 supplement) and C-reactive protein ≥ 75 mg/dl to standard of care alone or standard of care plus tocilizumab. Eighty-two percent of patients were receiving corticosteroids at the time of randomization. Patients who received tocilizumab were more likely to be discharged from the hospital alive within 28 days (54% vs. 47%, RR 1.22, 95% CI 1.12-1.34, p < 0.0001). Of the patients not receiving IMV at baseline, the tocilizumab group was less likely to reach the composite endpoint of IMV or death (33% vs. 38%, RR 0.85, 955 CI 0.78-0.93, p= 0.0005).
ACTT-2 (remdesivir + baricitinib vs. remdesivir + placebo) trial found that combination therapy resulted in a shorter median time to recovery (7 days v 8 days), a 30% higher odds of clinical improvement by day 15, and a numerically lower 28-day morality rate (5.1% v 7.8%).(23) A double-blind, randomized, placebo-controlled trial (COV-BARRIER) evaluated the baricitinib versus placebo in addition to standard of care (i.e., remdesivir and/or dexamethasone) among hospitalized adults with COVID-19.(24) The composite primary endpoint was the proportion who progressed to high flow oxygen, non-invasive ventilation, mechanical ventilation of death by day 28. 1525 participants were randomly assigned to baricitinib (n=764) or placebo (n=761). Two hundred four (79·3%) of 1518 participants were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Proportion of patients who progressed to meet the primary endpoint were comparable between baricitinib and placebo groups ( 27.8% vs 30.5%, absolute risk difference -2.7%; 95% CI -7.3 to 1.9). The 28-day all-cause mortality was lower in the baricitinib group ( 8% vs 13%, HR 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality.
Baricitinib is emergency use authorized in the United States for treatment of COVID-19. Data on its use in transplant patients has not been reported.
Therapeutics for Mild to Moderate COVID-19 in Ambulatory setting
Treatment of mild to moderate COVID-19 can be provided in ambulatory setting or in-hospital setting as per local/regional practices.
Anti-SARS-CoV-2 Monoclonal antibodies
Neutralizing monoclonal antibodies (mAb) isolated from B cells of patients who recovered from COVID-19 can target the receptor-binding domain of the SARS-CoV-2’s spike protein. There are three anti-SARS-CoV-2 mAb (bamlanivimab plus etesevimab, casirivimab plus imdevimab and sotrovimab) that have received emergency use authorization from the Food and Drug Administration in the United States for the treatment of mild to moderate COVID-19 in non-hospitalized patients who are at risk for progression to severe disease and/or hospitalization.
The role of mAb in management of mild to moderate COVID-19 were based on earlier studies of mAb, some no longer available due to lack of efficacy against the predominant variant. Existing data on monoclonal antibody use in solid organ transplant recipients (SOTr) are limited to retrospective single center studies and to prior monoclonal antibodies that do not have activity against the Omicron variant. A study of 73 SOTr (25) mostly received bamlanivimab (75%) between November 2020 until January 2021. Of these 73 SOTr, 11 (15%) had an ER visit within 28-days, 9 (12%) were hospitalized but none required mechanical ventilation, died, or experienced rejection. A similar study observed 8.7% 30-day hospitalization rate for COVID-19 directed therapy in a cohort of 93 SOTr.(26) In this study, a comparator group of 72 SOTr with COVID-19 who did not receive mAb had higher 30-day hospitalization rate of 15.3%.
With the emergence of variants across the globe, activity of the various monoclonal antibodies needs to be factored into decisions as to which agent to use based on local variant circulation. Details of impact of mutations in variants on the available agents is listed in Table 2. Bamlanivimab plus etesevimab are not authorized for use in areas of the United States, where the combined frequency of variants resistant to bamlanivimab and etesevimab exceeds 5% as of December 15,2021.(27) The FDA updated the Health care Provider Fact Sheets for bamlanivimab/etesevimab, casirivimab/imdevimab and sotrovimab on December 23,2021 with specific information regarding activity against the Omicron variant.(28) At present, only sotrovimab appears to retain activity against the Omicron variant due to its ability to target highly conserved epitope in the receptor binding domain of the SARS-CoV-2 spike protein.
Early initiation of antivirals may reduce hospitalization and poor outcomes. This was the premise of the double-blind randomized control study of remdesivir (3 days given intravenously) versus placebo in non-hospitalized, unvaccinated patients with COVID-19 who had symptom onset within the previous seven days and at risk for disease progression.(29) COVID-related hospitalization or death from any cause within 28 days was significantly lower in the RDV group (0.7% v 5.3%, P=0.008; RRR 87%, 95% CI 41-99%). No deaths occurred in either group at day 28. Adverse events occurred in 42.3% of patients in remdesivir group compared to 46.3% in the placebo group.
Currently under review by the FDA, molnupiravir (MOV) is an investigational oral drug for the treatment of mild to moderate COVID-19 in adults who are at risk for progressing to severe COVID-19 and/or hospitalization. MOV is a prodrug that is rapidly metabolized to N-hydroxycytidine (NHC) in plasma. NHC is phosphorylated inside the cell to form active ribonucleoside triphosphate (NHC-TP), which is later incorporated into the viral RNA by viral polymerase, subsequently resulting in (30) accumulation of errors in the viral genome and inhibition of replication.(31) Recommended dosing in adult patients is 800 mg every 12 hours with or without food for 5 days started as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset. In a double-blind randomized controlled trial comparing 5 days of MOV (n=716) versus placebo (n=717) among non-hospitalized, unvaccinated individuals with mild to moderated COVID-19 within 5 days of symptom onset with 1 or more risk factor for disease progression, hospitalization, or death at day 29 was lower in MOV group versus placebo group ( 6.8% vs 9.7%, HR 0.69, 95% CI 0.48-1.01). Adverse events in MOV and placebo groups were comparable (30.4% vs 33%, respectively). Of note, MOV is not recommended for use during pregnancy based on findings from animal reproduction studies. There is no available human data to date on the use of this antiviral to evaluate for birth defects, miscarriage, or maternal/fetal outcomes. Individuals of childbearing potential are advised to use effective method of contraception during MOV treatment and for 4 days after the last dose.(32)
An oral, SARS-COV-2 protease inhibitor antiviral therapy, nirmatrelivir/ritonavir, was recently given EUA by the US FDA. The nirmatrelvir blocks the activity of the SARS-CoV-2-3CL protease, which is an enzyme essential for viral replication. Low dose ritonavir is co-administered to slow the metabolism of nirmatrelvir which allows for longer half-life of the drug. Based on the interim analysis of the phase 2/3 randomized, double blind study of non-hospitalized patients with COVID-19 and at risk for progression to severe illness, an 89% reduction of COVID-19 hospitalization or death compared to placebo in patients treated within 3 days of symptoms.(33) A similar effect was observed amongst patients treated within 4 days of symptom onset. The recommended dosing for individuals age ≥ is 300 mg po nirmatrelvir and 100 mg po ritonavir BID for 5 days. The biggest challenge with the use of a ritonavir containing regimen is the drug-drug interaction with calcineurin inhibitor in SOTr. Dose adjustment and drug level monitoring should be carefully approached if prescribed.(34)
In mid-2021, the US FDA has expanded the emergency use authorization (EUA) for bamlanivimab/etesevimab and casirivimab/imdevimab for post-exposure prophylaxis of individuals at high risk for acquiring SARS-CoV-2 infection or for developing severe COVID-19.(35, 36) A recent combination mAb, tixagevimab/cilgavimab, was given EUA by the US FDA for pre-exposure prophylaxis of individuals who are moderately to severely immunocompromised due to either a medical condition or immunosuppressive medication and many not mount an adequate immune response to COVID-19 vaccination OR any individual who cannot complete COVID-19 vaccination due to a history of adverse reaction to COVID-19 vaccine and/or component of those vaccines.(37) The primary data supporting the EUA was from the PROVENT Phase III pre-exposure prevention trial that demonstrated a 83% reduction in the risk of developing symptomatic COVID-19 over a 6-month period among patients who received tixagevimab/cilgavimab compared to placebo.(38) There are a number of in vitro studies of tixagevimab/cilgavimab that demonstrate an increase in IC50 against the Omicron variant; some of the values are achievable clinically while others were at levels that are not clinically achievable.(39) There are limited clinical data on the protective efficacy against Omicron.
Potential agents in COVID-19 may have drug-drug interactions that can increase the risk for adverse events. A useful resource for drug-drug interactions can be found online at www.covid19-druginteractions.org. This website includes an interaction checker to detect interactions reliably.
Drugs Studied in COVID-19 that Are Not Recommended for Use
Refer to Table 1. TID EVIDENCE REVIEW FOR ANTIVIRAL TREATMENT OPTIONS FOR COVID-19
Due to lack of definitive evidence supporting efficacy of hydroxychloroquine and reports of increased risk of adverse events including QT prolongation and cardiac arrhythmias, particularly among those receiving concurrent azithromycin, hydroxychloroquine is not recommended for treatment nor prophylaxis of COVID-19.(40-48)
Despite in vitro inhibition of the 3CL protease enzyme responsible for viral replication of SARS-CoV-2, lopinavir/ritonavir has not demonstrated efficacy against COVID-19 in randomized, controlled trials compared to standard of care, and is no longer recommended for treatment of COVID-19.(47, 49, 50)
Despite significant enthusiasm and global availability of ivermectin, available studies do not support the use of ivermectin for the treatment of outpatients or inpatients with COVID-19.(51)
The listed agents represent potential treatments for inpatient cases of COVID-19 largely based on limited evidence. Careful clinical consideration should be applied when deciding to use the agents listed in this select evidence review. This document should not be used as empiric or definitive treatment guidelines. Evidence is continuing to evolve, as such this document will be updated accordingly.
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|AGENTS||PLACE IN THERAPY||DRUG INTERACTIONS||CONTRAINDICATIONS/ADVERSE EVENTS|
Antiviral with activity against Ebola, MERS, SARS
Prodrug nucleotide analog of adenosine triphosphate; incorporates into nascent viral RNA chains and results in premature termination.Gilead
Emergency Use Authorization (EUA) available in US with limited supply.
Avoid co-administration with:
AE: Abnormal LFTs, hepatotoxicity, abnormal INR, PT & PTT, reversible kidney injury, nausea, vomiting, diarrhea, headache, rash
Contraindications/Precautions: Monitor for hepatotoxicity, monitor for nephrotoxicity as IV formulation contains cyclodextrinFDA MedWatch Adverse Event Reporting for patients receiving EUA remdesivir
|AGENTS||PLACE IN THERAPY||DRUG INTERACTIONS||CONTRAINDICATIONS/ADVERSE EVENTS|
Increases pH of acidic intracellular vesicles that may lead to inhibition of endosome-mediated fusion, viral entry and pH dependent steps in viral replication. Anti-inflammatory and immunomodulatory properties that may inhibits release of inflammatory cytokines INFγ, IL-6, IL-1, TNF-α
HCQ: Hydroxyl analog of chloroquine. Similar activity and properties to chloroquine w/ ↓tox
FDA EUA no longer available (US)
Not recommended for COVID-19 due to lack of definitive evidence differentiating outcomes benefit with HCQ compared to supportive care and increased risk of adverse events
Not recommended outside of clinical trials, due to concerns about safety and efficacyFDA cautions against use for COVID-19 outside of hospital setting or clinical trial
Drug-drug interaction checker available here
Avoid co-administration with:
Caution used for co-administration with:
Avoid use with concurrent azithromycin (esp in pts with acute renal failure) due to QTc prolongation and risk of cardiac arrhythmias (Chorin, NIH Guidelines)
For patients with underlying CV disease or on concurrent QT prolonging medications, obtain baseline EKG and monitor QTc. Avoid use if baseline QTc > 500ms or in pts with known congenital QT prolongation.
AE: QT prolongation, nausea, vomiting, cardiomyopathy, pancytopenia, hepatotoxicity, irreversible retinopathy, extrapyramidal reaction, pruritus
Contraindications/Precautions: Caution in pts with QT prolongation, underlying cardiac disease, seizure history, severe hypoglycemia, proximal myopathy or neuromyopathy, retinal toxicity, GI disorders, hepatic impairment, G6PD deficiency
|AGENTS||PLACE IN THERAPY||DRUG INTERACTIONS||CONTRAINDICATIONS/ADVERSE EVENTS|
AntiretroviralHIV protease inhibitor that may provide activity against 3CL protease enzyme of SARS-CoV-2 to prevent cleavage of large polyproteins during viral replication
Limited availability and current level of evidence (CAO, NEJM 2020) does not support current use of lopinavir/ritonavir for COVID-19
Drug-drug interaction checker available here – Major CYP450 substrate (3A4), inhibitor (3A4, 2D6), inducer (2C19, 2C9, 1A2, 2B6), and transporter inhibitor
Avoid co-administration with:
Caution used for co-administration with:
AE: nausea, vomiting, diarrhea abdominal pain, dyspepsia, dysgeusia, hepatotoxicity, pancreatitis, diabetes, QT prolongation, torsades de pointes, dyslipidemia, peripheral lipoatrophy, and visceral adiposity
Contraindications/Precautions: Contraindicated with co-administration of potent CYP3A inducers, and in patients who demonstrated hypersensitivity to any of its ingredients. Major CYP450 substrate (3A4), inhibitor (3A4, 2D6), inducer (2C19, 2C9, 1A2, 2B6), and transporter inhibitor
Favipravir (T-705, Avigan®)
|AGENTS||PLACE IN THERAPY||DRUG INTERACTIONS||CONTRAINDICATIONS/ADVERSE EVENTS|
Purine nucleoside analog that competitively inhibits RNA-dependent RNA polymerase resulting in chain termination thus preventing viral replication. Activity against influenza A and B, Ebola, and SARS-CoV-2 in vitro
Investigational – not commercially available in US
Mild CYP2C8 inhibitor
AE: AST/ALT elevations, GI toxicity, hyperuricemia, neutropeniaContraindications/Precautions: teratogenic, avoid use in pregnancy
TID COVID-19 Guidance Focused Review:
Prevention and Management of COVID-19 in HSCT Recipients
Date of Update: 14 July 2020
As the situation of COVID-19 varies greatly between and within countries, we recommend that hematopoietic stem cell transplant (HSCT) centers follow guidelines, policies and procedures defined by national authorities, as well as local and institutional policies. Currently, the main prevention strategy is to avoid exposure to SARS CoV-2. HSCT recipients, candidates and donors should avoid higher-risk exposures that may put them at risk of becoming infected, including group gatherings, especially in closed environments. All should adhere to prevention practices including consistently wearing masks in public, during interactions with other people, habitual hand hygiene, mask wearing and social distancing.
COVID-19 cases have been increasingly diagnosed in HSCT recipients. Although still uncertain, some preliminary information of COVID-19 in HSCT recipients suggests that immunocompromised patients may develop a different form of the disease (1). According to the EBMT COVID-19 registry, the disease seems to be less severe in children compared to adults and lethality rates of up to 30% have been observed (https://www.ebmt.org/covid-19-webinars).
Although the risk factors for unfavorable outcomes in HSCT recipients have not been established, special attention should be given to patients with comorbidities, such as hypertension, cardiovascular disease, diabetes, and pulmonary disease (2). So far, the classification of disease severity should follow that recommended in the general population: Mild (mild symptoms, no radiologic images); moderate (fever, respiratory symptoms, radiologic images); severe (oximetry ≤93%, or respiratory rate >30rpm, or PaO2/FiO2 <300 mmHg); or critical (mechanical ventilation, or septic shock, or multiple organ failure) (3).
HSCT centers should have separate staff and areas for COVID-positive and COVID-negative patients. Non-urgent transplants should be postponed, especially for non-malignant diseases. Ensure availability of stem-cell products by by providing access freezing the product before conditioning begins. If not possible, have an alternative donor as a back-up. Prefer peripheral blood as a stem-cell source, unless there is a strong indication for bone marrow.
Telemedicine is encouraged for visits, if appropriate and possible. Visitors should be prohibited or restricted as much as possible. Parents of transplanted children should be tested for SAR-CoV-2 before entering the ward.
Health Care Workers
Provide personal protective equipment (PPE) and staff training to manage suspected or confirmed COVID-19 cases. Masks are important to limit the spread and to reduce the risk for HCW to become infected. The correct selection and proper use of the masks are crucial.
Staff with respiratory symptoms should follow institutional policies for SARS CoV-2 testing and quarantine guidance. If COVID-19 is diagnosed, return to work should follow national recommendations, usually requiring the resolution of symptoms with or without negative PCR testing. As a large number of health professionals have acquired COVID-19, HSCT centers should have a plan for any staff shortages due to leave (4).
Candidates should minimize the risk of SARS CoV-2 infection through physical distancing, ideally through home isolation, 14 days prior to conditioning. Avoid unnecessary hospital visits.
Candidates should be tested for SARS CoV-2 pre-admission, regardless of symptoms. Result must be negative before starting conditioning.
HSCT should be postponed in candidates with SARS-CoV-2 infection or clinical COVID-19. In case of high-risk disease, the transplant should be postponed for 3 to 4 weeks and have 2 negative tests with an interval of 24 hours before admission. In case of contact with a suspect or confirmed case of COVID-19, any procedure (mobilization, collection, conditioning) should be postponed for 14 days (preferably 21), and the candidate monitored for the appearance of symptoms. PCR test must be negative before transplantation.
At this time, there is not clear guidance when such donor can be cleared for donation. Donors with COVID-19 must be excluded from donation given the risk to others, including the hospital staff. Donation should be delayed until symptoms have resolved and SARS-CoV-2 PCR are negative. In case of urgency, case-specific considerations should be made. In case of close contact with a person diagnosed with SARS-CoV-2, the donor will be excluded from the donation for at least 28 days. The donor must be monitored for the diagnosis of COVID-19.
Donors within 28 days prior to donation should pay attention to good hygiene, avoid crowded places and large group meetings. Unnecessary travel should be avoided. Donors should be tested for COVID-19 before starting the mobilization procedure.
HSCT recipients should avoid travel. If necessary, preference should be given to private car instead of any public transportation (metro, bus, train and airplane).
All patients, regardless the presence of symptoms, should be tested for SARS CoV-2 before entering HSCT ward. Patients should also be tested in case of contact with a confirmed or suspected case of COVID-19, and whenever respiratory symptoms are present. The PCR test should be repeated if there is a strong suspicion of COVID19 and the test is negative (false negative).
Patients with a positive test for SARS CoV-2 or another respiratory virus should be removed from rooms with laminar flow or rooms with HEPA filter and positive pressure, unless the ventilation can be turned off.
Patients who test positive for SARS Cov-2 in an upper respiratory tract sample should undergo chest CT and evaluation of oxygenation impairment. Due to the risk of transmission to the healthcare professional, bronchoalveolar lavage (BAL) is not recommended in case of COVID-19, unless co-infection is suspected.
At this point, no clear recommendations can be made about specific therapies in severe cases due to limited data and unknown risk versus benefit. Also, it is not known whether HSCT recipients with asymptomatic infection or mild cases of COVID-19 can benefit from any specific treatment. Supportive care is crucial including non-invasive ventilation and anti-coagulants to prevent thromboembolic complications. Immunosuppression and treatment of bacterial, fungal or viral co-pathogens should be maintained. Remdesivir should be used for treatment for HSCT recipients with clinical COVID-19 where the drug is available. Dexamethasone treatment should be considered for patients on high-flow oxygen or mechanical ventilation.
Date of Update: 1 December 2021
So far, 10 different platforms have been used in the development of these vaccines: 1) protein subunit (PS); 2) inactivated virus (IV); 3) non-replicating viral vector (VVnr); 4) RNA; 5) DNA; 6) virus-like particle (VLP); 7) replicating viral vector (VVr); 8) live attenuated virus (LAV); 9) VVnr + antigen-presenting cell (APC); and 10) VVr + APC. Dashboards of vaccines under development, under cliical trials and authorized for emergency use in various regions of the globe, can be accessed here: www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccinesv.
Vaccine role out has progressed considerably but continues to lag in low- and middle-income countries. In the healthy population, projected clinical efficacy based on phase 2 and phase 3 studies varies from more than 50% to 95%.1-8
Despite the achievements in such a short time, many questions remain unanswered, such as the titers of neutralizing antibodies for a COVID-19 vaccine to protect humans, the duration of vaccine-induced immunity, and the need for booster vaccines. These and other queries that may arise with the expanded use of the COVID-19 vaccines will likely be clarified over time.
COVID-19 vaccines in transplant recipients
While prioritization of vaccines is generally determined by the federal, state and local health authorities, transplant recipients should be included in groups for earlier vaccination due to the risk for severe COVID-19. Immunocompromised patients, including transplant recipients, have not been included in studies performed to date. As these are not live virus vaccines, it is unlikely that these vaccines would pose additional risks. Transplant recipients have decreased vaccine responses compared to the general population, and thus should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination, including continuing to use masks, focus on hand hygiene and social distancing. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when available to them to protect the patient.
Inactivated vaccines, protein subunit recombinant or virus-like vaccines are considered safe to be administered to transplant populations. Particle vaccines have been used for decades in transplant vaccination programs (e.g., influenza, hepatitis B and HPV vaccines). RNA vaccines (BioNTech/Pfizer, Moderna) and non-replicating viral vector vaccines (Oxford/AstraZeneca, Janssen/Johnson & Johnson, Gamaleya) are also considered safe vaccines.
Preliminary data of 741 SOT recipients who received both doses of mRNA SARS-CoV-2 vaccine doses has recently provided early insight into the safety and efficacy of the mRNA vaccine in this population.9 Equal numbers of recipients received the Pfizer and Moderna vaccines and had low rates of local (84% after dose 1 and 77% after dose 2and systemic (overall: 49% after dose 1 and 69% after dose 2; fatigue 36% after dose 1 and 56% after dose 2; headache 28% after dose 1 and 42% after dose 2) reactions. Only 1 patient developed acute rejection following the second dose of vaccine.10,11 To date, there are far fewer data on the safety and efficacy of non-mRNA vaccines in SOT recipients.10
Unlike live virus vaccines, Adenovirus-vector vaccines have been genetically engineered to not replicate, and therefore cannot cause Adenovirus infection in the recipient. Based on the mechanism of action, expert opinion is that this vaccine is unlikely to trigger rejection episodes or have a novel or more severe side effects in transplant recipients, but more data are needed.
Several early studies have looked at the serologic response to the mRNA vaccines in SOT recipients. Detectable antibodies have been demonstrated to be relatively infrequent after the first dose but detectable in up to 54% of patients after both doses of the vaccine. When quantitative titers were available, they were frequently below the median titer in immunocompetent patients. However, the level of protective antibodies has not yet been defined. Furthermore, the protective components of both cellular (T and NK T cells) and humoral responses (IgG/IgM or IgA) may not be linked in individual SOT recipients, and it is possible to still have an active acquired immune response in the absence of antibody and vice versa.12 In fact, 46% of patients with a negative anti-RBD can have a positive CD4+ T cell response.13 Hence, the rate of breakthrough and severity of breakthrough infections based on antibody or cellular response has not been fully studied to inform the clinical efficacy of the vaccine in the transplant population.10, 14-18
While there have been some observational cohort studies of transplant patients who have received a third dose of vaccine, either through government-approved channels or through other unapproved pathways, only one study to date has been a prospective, placebo-controlled study.13 In this trial, a third dose of vaccine was associated with a higher rate of patients having a pre-defined anti-RBD antibody level of at least 100 U per milliliter (33/60, 55% mRNA-1273 group vs. 10/57, 18% placebo), higher rate of neutralizing antibody titer and greater frequency of SARS-CoV-2 specific CD4+ T cell counts (432 vs. 67 cells per 106). Looking at specific neutralizing titers to specific variants, a third dose of mRNA vaccine improved the proportion of patients with neutralizing titers from 18% after 2 doses to 55% after 3 doses.19 A number of observational studies of a supplemental dose of vaccine have been published and demonstrate improvement in humoral responses in many but far from all patients.11,18 Without boosting, about a quarter of patients have undetectable antibodies and a further quarter have low antibody titers.20
A number of factors have been associated with reduced vaccine efficacy among transplant patients. The most deficient responses are among patients receiving B-cell active therapy, including rituximab, and belatacept. Further, patients on higher doses of combination immunosuppression, particularly those containing mycofenolate, also have worse responses. Pre-transplant vaccination appears to result in persistent immunity post-transplant, favoring the vaccination of patients pre-transplant.20a
There is no data yet on the impact of a third dose of vaccine on important clinical measures, including frequency and severity of COVID-19 of breakthrough infections. Likewise, it is important to note that 45% of patients failed to have a relevant antibody response even after 3 doses. Since seroprotective titers have yet to be established this may be an underestimate of the population still at risk for breakthrough infections. While the larger studies suggest have demonstrated the safety of boosting with the same vaccine as the initial series, a recent study showed that BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S (transplant recipients were not included), induced a robust immune response with an acceptable and manageable reactogenicity profile.21 A more recent studies has shown, in immunocompetent patients, giving an mRNA booster in patients with prior Janssen Ad26.COV2.S resulted in ten-fold higher antibody titers compared to a second Janssen Ad26.COV2.S.22,23 Based on this data, most experts advise for patients who have received adenoviral-vectored vaccine select an mRNA vaccine, if available, for a supplemental dose.
Since humoral and cellular responses to vaccine, even with 3 doses, are reduced in immunocompromised patients, additional mitigation strategies should be continued post-vaccine and additional studies of alternative protective approaches are needed.
There is emerging data on the benefit of the vaccine on transplant patients. The best data to date comes from the UK NHS Blood & Transplant group. In their retrospective review of registry data, 82% of English transplant recipients were fully vaccinated by July 9, 2021. Unadjusted data demonstrated a reduction in the frequency of breakthrough infections (3,473 in the unvaccinated vs. 143 in fully vaccinated) and case-fatality (438 deaths (12.6%) vs. 11 deaths (7.7%)) were lower in the vaccinated population.24
There are still limited studies on the efficacy of vaccines against SARS-CoV-2 in HSCT. A recent study of 857 patients with hematological malignancies showed a lower median anti-S1 IgG antibody responses after two BNT162b2 vaccine doses in these patients than in healthcare workers of the same age group. Patients who are actively treated with BTKIs, ruxolitinib, venetoclax, or anti-CD20 antibody therapies seem to be the most negatively affected and might be left unprotected from SARS-CoV-2 infection. Surprisingly, patients who received autologous HSCT or allogeneic HSCT were among the subgroups with the highest responses to the SARS-CoV-2 vaccine, in comparison with other hematological patients.25
Given the existing data, it is essential that transplant programs provide education about the benefits and safety of the vaccine in transplant patients and strongly encourage vaccination. They should also remind patients that, given the limitations of vaccines in this population, even among patients who receive a third dose, they should continue to maintain the use of masks in public indoor spaces, maintain social distancing, and avoid high-risk exposures. Further, vaccination of close contact of our immunocompromised patients will reduce the risk of transmission of COVID-19 within a household.26
Options for Those with Expected Poor Vaccine Responses
When vaccine is known or suspected to have a poor response, protection against infections can be accomplished via delivery of monoclonal antibodies. These are discussed in greater detail in the therapy section. If patients develop infection despite vaccine, antiviral or antibody-based therapy should be started as soon as possible.
Vaccine mandates have been used to achieve herd immunity both in the general population and among healthcare worker (HCW).27 COVID -19 vaccine mandates have been proposed for transplant center staff and transplant candidates because the risk of transmission of infection and severity of disease are higher among this vulnerable population.28 HCWs have a special professional responsability for their patient care and are obligated to follow all reasonable, evidence-based, best practices to ensure patients’ safety and to prevent harm to their patient.28,29
Health professionals can be exposed to COVID-19 as part of their work and can also act as a source of nosocomial infection for patients, resulting in patient illness or death.29,30 Vaccine requirement for HCW vary widely among countries.
The available evidence to inform an ethical analysis of the harms, benefits, and individual and societal impact of mandatory vaccination has been recently summarized in the novel context of COVID-19 vaccination.28 The individual and societal benefit, coupled with the safety of SARS-CoV-2 vaccination, makes vaccine requirement for transplant professionals and all healthcare workers (HCWs), transplant candidates (TCs) and transplant recipients (TRs) ethically justified.28 Logistics of implementation are more challenging and require careful consideration using local legal and ethical frameworks.
Vaccines given pre-transplant provide persistent protection post-transplant.20a Key considerations for requiring vaccine prior to transplant include the higher rates of seroconversion compared to transplant recipients (TR), waitlist inactivation in case of infection and the higher rates of SARS-CoV-2 hospitalization rates and death of transplant recipients. Even if vaccine mandate might result in removal from the waiting list, vaccination mandate could increase the net utility of transplantation, stewardship and beneficience. Arguments opposing such a policy emphasize justice and respect for persons and seek to avoid worsening inequities or medical coercion.31 For this reason implementation of COVID-19 vaccination requirement for transplant listing should be coupled with enhanced information of patients and should allow sufficient time to consider vaccination in order to guarantee transplant equity.
Finally, it is essential to implement strategies to mitigate the refusal of vaccination and concerns about respect of autonomy for HCWs, TCs and TRs such as addressing informational needs and allowing enough time to contemplate a vaccination decision or reconsider the refusal.
Since our initial guideline, COVID-19 has been declared a “public health emergency of international concern” and a pandemic by WHO. Further, the disease has been given the name Coronavirus Disease 2019 (COVID-19) and is caused by the virus named SARS CoV-2. As of 13 July 2020, there are 12,768,307 confirmed cases and 566,654 deaths globally (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/). Ongoing community transmission has been noted on all continents except Antarctica.
As this is an emerging infection, we advise that, for decision making, careful attention to reports from local health authorities as well as review of updated data is essential.
Initially limited to Wuhan, infection with COVID-19 is now a pandemic. As local community spread can now occur nearly in any country, centers should consult with local health authorities to identify specific rates in your area. Useful global resources include:
NY Times COVID Maps: https://www.nytimes.com/interactive/2020/world/coronavirus-maps.html
Please refer to the “Update on Epidemiology” for updated details.
A number of case series of transplant patients have recently been published and provide some insight into the clinical presentation and course of SARS-CoV-2 infection in transplant patients.1-21 Imaging demonstrates pneumonia in the majority of patients that are hospitalized (75-100%). Patients with less severe infections may have lower rates of abnormalities. Mortality appears to be age dependent, with the highest rates among older adults (Age 50-59: 1.3%, 60-69: 3.6%, 70-79: 8%, 80+: 14.8%).22 Mortality appears to be highest in lung transplant recipients and lowest in the liver and heart transplant populations. There is a paucity of data on mild and asymptomatic infections which will alter these estimates.
Although many patients had co-morbidities in the reported series, data on transplant patients is limited; patients with cancer are more likely to have more severe disease (HR 3.56, 95% CI 1.65-7.69).23 Hence a description of the disease in transplant recipients is still not available. Nevertheless the lymphocyte count was lower in those who required ICU care, and in those who perished.1 It is not possible to tell if lymphopenia was a manifestation of a more severe form of disease, or if it predisposed to severe disease. Many transplant recipients have medication-induced lymphopenia. Particularly close attention should be paid to transplant patients with suspected or confirmed COVID-19 infection who are lymphopenic. Such attention may include admission (rather than care at home) and paying careful heed to oxygen saturation.
Patient-to-patient, and patient-to-healthcare worker infection were described and human-to-human transmission has been confirmed.1,24 As such, strict infection prevention practices are essential.25
The mainstay of diagnostic testing is the use of PCR to detect presence of virus in samples collected from the respiratory tract of persons under investigation. Negative testing may occur early when patients are asymptomatic.26
Please refer to the “Update on SARS-CoV-2 and Organ Donation” for updated details.
Persons who have been exposed to a patient with confirmed or suspected COVID-19 within 14 days should not be accepted as a donor. Likewise donors with unexplained respiratory failure leading to death should be excluded. Donors with positive PCR testing for COVID-19 should not be utilized.
In a country with widespread community transmission, temporary suspension of the deceased donor program should be considered, especially when resources at the transplant center may be constrained.
A tiered suspension may also be considered (i.e. deferral of more elective transplants, i.e. kidney, pancreas and heart transplantation for patients with VADs).This was the approach in Toronto during the SARS outbreak in 2003.27
In countries where the chains of transmission can be defined, eg, because of excellent contact tracing and transparent public reporting of clusters, transplantation may be considered. Small countries with limited, identifiable chains of transmission may have an advantage in this respect.28 Beyond donor suitability, considerations such as availability of ICU beds and transplant surgeons in the recipient hospital are also critical.
There is no clear reason to suspend deceased donor transplants in countries only experiencing sporadic cases of COVID-19 cases.
Living donation should not be performed on either a donor or recipient who has been exposed to a patient with confirmed or suspected COVID-19 within 14 days. Donors should not be utilized if they have fever and/or respiratory symptoms unless SARS-CoV-2 is excluded. Donors with positive SARS-CoV-2 PCR testing should not be utilized.
In countries with widespread community transmission, temporary suspension of the living-donor kidney and liver transplant programs should be considered when donation can safely be deferred to a later date.
If a transplant candidate is sick and found to be infected with COVID-19, transplant should be deferred until clinically improved with no detectable virus. Prolonged viral shedding has been described.29,30 Documentation of negative PCR testing at least 24 hours apart is recommended before a candidate should be cleared for transplant unless the need for transplant is urgent.
There are few data on how long a patient with COVID-19 remains infectious and most published studies are from otherwise immunocompetent patients. In one study, investigators have not been able to culture virus after Day 8 of illness, although the viral load was 106 for culturable virus which is much higher than most other respiratory viruses.31 Ideally, patients should be tested 10-14 days after symptom onset and only once symptoms have resolved. Patients should have 2 negative PCR tests done at least 24 hours apart.32
Like all persons, transplant recipients should adhere to travel advisories issued by their respective health authorities/government bodies. This may necessitate postponing travel to a country with >10 cases of COVID-19.
Transplant recipients should avoid all cruise ship travel.
Please refer to the “Prevention and Management of COVID-19 in HSCT Recipients” for updated details.
Treatment of Cases
Please refer to the “Update on Treatment for COVID19” and our updated “Evidence Review for Treatment” for updated details.
All transplant-related teams should develop plans to address the following key issues to reduce burden on the healthcare system and mitigate against interruption in care of transplant patients:
Transplant Infectious Disease
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