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
KEY POINTS
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:
References
TID COVID-19 Guidance Focused Review:
Update on SOT Recipient Advice to Prevent COVID-19
Date of Update: 30 June 2020
KEY POINTS
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:
References
KEY POINTS
As clinical presentation of COVID-19 is varied, including diarrhea as a common early symptom, clinicians should have a low threshold for diagnostic testing.
Polymerase Chain Reaction (PCR)
While the literature on COVID-19 in SOT is expanding, all have depended upon PCR to confirm the diagnosis. While testing is generally applied to nasopharyngeal swabs, collection of sputum, nasal and throat swab and saliva have also been used.1, 2, 3, 4 PCR of nasopharyneal or BAL specimens are considered the gold standard for diagnosis. Of note, the oropharyngeal swab requires almost no training, whereas the nasopharyngeal swab does require some training.7
While PCR has the benefit of rapid turn-around-time and scalability, they may not be available in all parts of the world; some countries have wider access to antigen testing which have lower sensitivity than PCR testing. The virus may mutate over time which may require continuous updating of primers/probes over time.5
Although PCR seems to be the gold standard, questions remain regarding the sample that will give the best yield, the number of samples that gives the best sensitivity, and the timing of sampling in relation to symptoms.
In an early guidance document released on 17 January 2020, the World Health Organization (WHO) recommended using “nasopharyngeal and oropharyngeal swab in ambulatory patients and sputum (if produced) and/or endotracheal aspirate or bronchoalveolar lavage in patients with more severe respiratory disease”.6 The document emphasized that the recommendation may change if data were to emerge indicating upper or lower respiratory tract specimens as being more appropriate.
In a systematic review of the literature on this question, the Centre for Evidence-Based Medicine (Oxford) found only 2 low quality, non-peer-reviewed preprints, which, in their opinion, should be “viewed with caution”.7 They concluded, in very tentative fashion, that possibly nasopharyngeal swabs had a slight advantage over oropharyngeal swabs, especially from day 8 of illness onwards.
A multitude of articles describe positive results for SARS-CoV-2 PCR from multiple sources - nasal swabs, saliva, faeces.8, 9 Further, 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 or recipients require further study.
For how long an immunocompromised person sheds infectious virus and what the determinants are of viral shedding are not yet known. In theory, SOT patients may shed greater amounts of virus for longer periods and therefore they may remain infectious for longer. Information on longitudinal follow-up of viral shedding in SOT patients is scarce, but it is possible that they may behave like critically ill patients or may show a fluctuating pattern. 14, 15, 17, 18
In summary, upper respiratory samples for PCR are currently the most common means of establishing the diagnosis of COVID-19 and are the diagnostic method of choice in transplant recipients. Physicians may choose to combine these specimens with other sources (eg, a nasal swab) to optimize the yield.
The single biggest concern for frontline doctors is the false-negative PCR result. Although viral load is highest in the first few days of symptoms,10 occasional reports of initial negative PCRs have led to worries of how best to effectively rule out COVID-19.11 This is of relevance in donor screening and will be dealt with in a separate post.
Serologic Testing
Alternatives to the PCR as a means of diagnosing COVID-19 include serology and cultures. The problems associated with these alternative tests are many. 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.12 The time to seroconversion is not markedly different for papers reporting serology results using magnetic chemiluminescence assays.12 There are individuals who mount an antibody response within the first week of symptoms, but these tend to be in the minority.13 Despite poor overall performance of serological assays, recent studies suggest that SOT patients probably can mount an antibody response to SARS-CoV-2. However, further investigation into the dynamics of serologic response is required.14, 15 The primary role of antibody testing would, at the moment, be for seroepidemiological studies.16
Serology is not routinely recommended for diagnosis in transplant patients. The presence of antibodies in transplant recipients likely suggest some degree of protection of infection, although what titers are needed to prevent infection are not well studied yet. Further, the duration of serologic protection is not yet defined, particularly in the transplant population.
Cultures are a difficult undertaking for most routine laboratories, with SARS-CoV-2 requiring Biosafety Level 3 facilities.
TID COVID-19 Guidance Focused Review:
Diagnostic Testing – PCR and Serology
Date of Update: 14 July 2020
KEY POINTS
TID COVID-19 Guidance Focused Review:
Update on SARS-CoV-2 and Organ Donation
Date of Update: 30 June 2020
KEY POINTS
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.
References
TID COVID-19 Guidance Focused Review:
Update on Therapeutic Agents for COVID-19
Date of Update: 14 July 2020
KEY POINTS
Overview
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 with 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.
Antiviral Agents
Remdesivir
While well-established therapeutic options are limited, remdesivir, an investigational antiviral, has demonstrated the strongest evidence as a potential treatment against COVID-19. With known activity against Ebola, MERS, SARS-CoV-1, and SARS-CoV-2, remdesivir has 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. Preliminary results from the double-blind, randomized, controlled NIAID ACTT-1 trial found that among 1063 patients, remdesivir (n=538) compared to placebo (n=521) resulted in a shortened median time to recovery (11 days v 15 days), a higher rate of clinical status improvement, measured by an 8-point ordinal scale (59.2% v 49.5%, OR 1.5), and a numerically lower rate of 14-day mortality (7.1% v 11.9%).(1) Analysis and publication of full ACTT-1 and follow-up ACTT-2 (remdesivir + baricitinib v remdesivir alone) trials are pending. Regarding the duration of remdesivir therapy, a randomized, open-label, phase 3 trial of 397 hospitalized patients with COVID-19 demonstrated similar efficacy and safety with 5 days of treatment compared to 10 days. 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% v 54%) and duration of hospitalization (7 days v 8 days).(2) Reported adverse events include hepatic transaminase elevations, reduced eGFR or CrCl, nausea, constipation, and hyperglycemia.
Hydroxychloroquine
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. (3-9)
Lopinavir/ritonavir
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. (10, 11)
Favipravir
An investigational antiviral agent with in vitro activity against SARS-CoV-2 is currently undergoing evaluation for treatment of COVID-19 following reports of limited evidence demonstrating benefit with favipravir compared to other investigational agents.(12-14) Data from randomized, controlled trials are pending trial completion.
Management of Cytokine Release Syndrome
In severe COVID-19, the cytokine release syndrome (CRS) in response to SARS-COV2 can result in lung injury and multi system organ dysfunction. The use of anti-inflammatory agent such as corticosteroids and immunomodulators may have a role in mitigating the effect of CRS. Initial retrospective cohort or case series study have reported conflicting results on benefit of using corticosteroids in novel coronaviruses (15-19). However, a recent preliminary unpublished analysis from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) study, a multi-center, open label trial study in the United Kingdom, has shown benefit of dexamethasone in patients with severe COVID-19 (i.e., requiring supplemental O2) and greatest amongst those requiring mechanical ventilation at time of enrollment (20). The IDSA and NIH have recommended in their respective guidelines the utility of corticosteroids (21, 22) . The applicability of this result to transplant recipients are yet to be answered by future studies. Similarly, use of immunomodulators, such as IL-1 or IL-6 inhibitor, is not well studied in transplant recipients and should be only used in the setting of clinical trials.
Drug-Drug Interaction
Potential agents in COVID-19 may have drug-drug interactions that can increase risk for adverse events. Use of chloroquine and hydroxychloroquine with tacrolimus may increase risk for QTc prolongation. HCQ can also potentially decrease therapeutic drug level of remdesivir. Recently, the FDA has issued a warning about the concurrent use of these drugs (23). The use of protease inhibitor such as lopinavir-ritonavir, a CYP34A inhibitor, can result to marked elevation of calcineurin inhibitor and mTOR inhibitor levels. The use of this lopinavir-ritonavir, in addition to drug-drug interaction, is not recommended due to its lack of clinical efficacy(10).
A useful resource for drug-drug interactions can be found online at: https://www.covid19-druginteractions.org. This website includes an interaction checker to reliably detect interactions.
References
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.
Click here to download as a PDF
Remdesivir (GS-5734) |
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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 |
Investigational agent Emergency Use Authorization (EUA) available in US with limited supply. Expanded Access via Gilead: Critically-ill patients with severe COVID-19, requiring mechanical ventilation, not on vasopressors at time of initiation |
Avoid co-administration with:
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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 cyclodextrin FDA MedWatch Adverse Event Reporting for patients receiving EUA remdesivir |
Evidence
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Clinical Trials
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References |
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Hydroxychloroquine (HCQ) |
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AGENTS | PLACE IN THERAPY | DRUG INTERACTIONS | CONTRAINDICATIONS/ADVERSE EVENTS |
Antimalarial 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 efficacy FDA 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:
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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 |
Evidence
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References
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Lopinavir/Ritonavir (Kaletra®) |
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AGENTS | PLACE IN THERAPY | DRUG INTERACTIONS | CONTRAINDICATIONS/ADVERSE EVENTS |
Antiretroviral HIV 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:
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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 |
Evidence
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References |
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Favipravir (T-705, Avigan®) |
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AGENTS | PLACE IN THERAPY | DRUG INTERACTIONS | CONTRAINDICATIONS/ADVERSE EVENTS |
Antiviral 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, neutropenia Contraindications/Precautions: teratogenic, avoid use in pregnancy |
Evidence
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Clinical Trials
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References |
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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).
Current recommendations
HSCT centers
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).
Transplant candidates
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.
Donors
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
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.
References
Date of Update: 5 January 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. The first 5 platforms represent 84% of the vaccine candidates in clinical phase of development (1). Currently, 14 developers have COVID-19 vaccines in phase 3 studies, as shown in Table 1.
Among the vaccines in phase 3 studies, 6 have been authorized in several countries for emergency use (Pfizer/ BioNTech, Moderna, Gamaleya, Sinovac, Sinopharm, AstraZeneca/Oxford) and have started to be administered to health professionals and the elderly in Europe, the Americas, the Eastern Mediterranean region and Singapore. In the healthy population, projected clinical efficacy based on phase 2 and phase 3 studies varies from more than 50% to 95% (2-5).
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, the possibility of occurrence of antibody-dependent enhancement (ADE) phenomenon, antibody responses in transplant recipients, among others. These and other queries that may arise with the expanded use of the COVID-19 vaccines will likely be clarified over time.
Table 1. Summary of phase 3 COVID-19 vaccines’ information.
Developers |
Vaccine platform/type |
No. of doses |
Schedule days |
Route |
Sinovac |
Inactivated |
2 |
0, 14 |
IM |
Wuhan Institute of Biological Products/ Sinopharm |
Inactivated |
2 |
0, 21 |
IM |
Beijing Institute of Biological Products/ Sinopharm |
Inactivated |
2 |
0, 21 |
IM |
Bharat Biotech |
Inactivated |
2 |
0, 28 |
IM |
Institute of Medical Biology and Chinese Academy of Medical Sciences |
Inactivated |
2 |
0, 28 |
IM |
University of Oxford/ AstraZeneca |
VVnr/ChAdOx1-S |
2 |
0, 28 |
IM |
CanSino Biological Inc/Beijing Institute of Biotechnology |
VVnr/Ad type 5 |
1 |
- |
IM |
Gamaleya Research Institute |
VVnr/rAd26-S + rAd5-S |
2 |
0, 21 |
IM |
Janssen Pharmaceutical Companies |
VVnr/Ad type 26 |
2 |
0, 56 |
IM |
Moderna/NIAID |
RNA/LNP encapsulated mRNA |
2 |
0, 28 |
IM |
BioNTech/Fosun Pharma/Pfizer |
RNA/LNP encapsulated mRNA |
2 |
0, 28 |
IM |
CureVac AG |
RNA/CVnCoV Vaccine |
2 |
0, 28 |
IM |
Novavax |
Protein subunit/SARS CoV-2 rS – Matrix M1 adjuvant |
2 |
0, 21 |
IM |
Anhui Zhifei Longcom Biopharmaceutica, Chinese Academy of Sciences |
Protein subunit/ recombinant SARS CoV-2 vaccine (CHO cells) |
3 |
0, 28, 56 |
IM |
While prioritization of vaccine 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 such, transplant recipients should be counseled that the effectiveness and safety profile of these vaccines for them are not currently known. As these are not live virus vaccines, it is unlikely that these vaccines would pose additional risks, Transplant recipients may 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, Gamaleya) are also considered safe vaccines, but have never been used in the transplant scenario. Vigilance will be necessary to determine if the induced protective immunity is not associated with an increased risk for rejection episodes or the development of graft versus host disease (GVHD).
Live attenuated vaccines are generally contraindicated in SOT recipients and may be used with restrictions in HSCT recipients. Replicating viral vector vaccines are not recommended in transplant populations at this moment.
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.
HSCT Guidance
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
International Headquarters
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