TID COVID-19 Guidance Focused Review:
Update on Epidemiology of COVID-19 in Transplant Patients
Date of Update:  30 June 2020

KEY POINTS 

• Transplant patients with COVID-19 are frequently hospitalized, and the majority have moderate to severe disease
• Common symptoms include, fever, dyspnea, cough and diarrhea.
• Immunosuppression reduction is frequent upon diagnosis of COVID-19, but impact on outcomes is not well defined at this time.
• Lung transplant patients may develop infection earlier post-transplant and are associated with more severe outcomes.
• Mortality appears to be increased compared with contemporary non-transplant international cohorts, and is higher in older recipients.

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:

• Pereira and colleagues investigated a cohort of 90 transplant patients with COVID-19 from two large transplant centers in New York City4. Most patients (46/90) were kidney transplant recipients, followed by lung (17), liver (13), heart (9) and (5) dual organs. Common presenting symptoms were fever (70%), cough (59%), dyspnea (43%) and diarrhea (31%). Sixty-eight (76%) patients were hospitalized and approximately one-third of patients had severe disease. It was common practice to reduce immunosuppression, where 88% of patients had antimetabolites decreased or held. Sixteen (18%) patients died due to complications of COVID-19, including 12 (52%) of 23 ICU patients.

• Akalin and colleagues described 36 consecutive kidney transplant patients who tested positive for COVID-19 at Montefiore Medical Center in New York5.  Common underlying diseases in patients were hypertension and diabetes. Fever was present in 58% of patients and diarrhea in 22%. Twenty-eight (78%) patients were admitted to the hospital, and 97% had radiographic findings consistent with viral pneumonia. Immunosuppression reduction by withdrawal of antimetabolites occurred on 86% of patients. Eleven (39%) patients required mechanical ventilation. Ten (28%) of 36 patients died, including 64% who died after intubation.

• The European Liver Transplant Registry, representing 30 European countries, recently reported data in liver transplant patients with COVID-196. Of 103 patients, median age was 65 years. Approximately 80% were admitted to the hospital, with 15% requiring intensive care unit admission. Common presenting symptoms were fever (70%), cough (59%), dyspnea (34%) and diarrhea (24%).  Sixty-four (66%) patients had radiographic evidence of viral pneumonia. Mechanical ventilation was required in 10 (15%) patients. At a median follow-up of 16 days, 16 (16%) patients had died. Mortality was 44% among patients on mechanical ventilation. Mortality was observed only in patients 60 years of age or older and was higher among males when compared to females (18% vs 7%).

• Ketcham and colleagues described a case series of 13 heart transplant patients hospitalized with COVID-19 from two hospitals in Michigan, USA7. Co-morbid conditions such as hypertension, kidney disease and diabetes were prevalent. The mean time to presentation from transplant was 9.6 years. Common symptoms included fever, dyspnea, and cough. Diarrhea occurred in 46% of patients. Lymphopenia occurred in all patients, and 62% had thrombocytopenia. Of 13 admitted patients, 2(15%) had died at time of publication, and 2 remained hospitalized.

• Myers and colleagues reported 8 lung transplant patients with COVID-19, five of whom had been transplanted in the past year8. Common symptoms included dyspnea, cough, fever and gastrointestinal symptoms. All patients had pneumonia, and ground glass opacities on imaging were present in all patients. Five (62.5%) had severe disease. Two patients developed COVID-19 pneumonia within 2 weeks of transplant. Three (37.5%) patients had superimposed bacterial infections. With a mean follow-up of 24 days, 2 (25%) patients died. Both patients who died received transplants within two weeks prior to diagnosis. Recovered patients seemed to have preserved lung function.
  

References

1. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy. Lancet Gastroenterol Hepatol 2020;5:532-3.
2. Fernández-Ruiz M, Andrés A, Loinaz C, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant 2020.
3. Kates OS, Fisher CE, Stankiewicz-Karita HC, et al. Earliest cases of coronavirus disease 2019 (COVID-19) identified in solid organ transplant recipients in the United States. Am J Transplant 2020.
4. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant 2020.
5. Akalin E, Azzi Y, Bartash R, Seethamraju H, Parides M, Hemmige V, Ross M, Forest S, Goldstein YD, Ajaimy M, Liriano-Ward L, Pynadath C, Loarte-Campos P, Nandigam PB, Graham J, Le M, Rocca J, Kinkhabwala M. Akalin Covid-19 and Kidney Transplantation.  N Engl J Med. 2020 Apr 24: Online ahead of print. PMID: 32329975.
6. Belli LS, Duvoux C, Karam V, Adam R, Cuervas-Mons V, Pasulo L, Loinaz C, Invernizzi F, Patrono D, Bhoori S, Ciccarelli O, Morelli MC, Castells L, Lopez-Lopez V, Conti S, Fondevila C, Polak W. COVID-19 in liver transplant recipients: preliminary data from the ELITA/ELTR registry. Lancet Gastroenterol Hepatol. 2020 Jun 4:S2468-1253(20)30183-7. Online ahead of print. PMID: 32505228.
7. Ketcham SW, Adie SK, Malliett A, Abdul-Aziz AA, Bitar A, Grafton G, Konerman MC. Coronavirus Disease-2019 in Heart Transplant Recipients in Southeastern Michigan: A Case Series. J Card Fail. 2020 May 14:S1071-9164(20)30415-2. Online ahead of print. PMID: 32417380.
8. Myers CN, Scott JH, Criner GJ, Cordova FC, Mamary AJ, Marchetti N, Shenoy KV, Galli JA, Mulhall PD, Brown JC, Shigemura N, Sehgal S; Temple University COVID-19 Research Group. COVID-19 in Lung Transplant Recipients. Transpl Infect Dis. 2020 Jun 10:e13364. PMID: 32521074

TID COVID-19 Guidance Focused Review:
Update on SOT Recipient Advice to Prevent COVID-19
Date of Update:  30 June 2020
KEY POINTS

• Wear a face covering/mask at all times
• Wash your hands regularly with soap and water or alcohol-based hand rubs
• Call the transplant team if you have any common COVID-19 symptoms

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:

• Stay home and safe as long as you can. If you have to go anywhere, focus on 3 key goals(1):
• Keep a physical distancing of at least 1 meter (better 2m)
• Wear a face mask (cloth or surgical) at all times
• Wash your hands regularly with soap and water or alcohol-based hand rubs
• Avoid touching your face with unwashed hands
• Eye protection (common glasses) may also decrease risk of infection
• Avoid non-essential travel, home visitors and public transport when possible (https://www.cdc.gov/coronavirus/2019-ncov/travelers/index.html),
• Monitor for symptoms of COVID-19 (fever, dyspnea, cough, loss of smell or taste and diarrhea) and seek medical attention if you have any new symptom.
• Reduce healthcare facilities visits, if possible.
• Utilize telemedicine services if available at your transplant center
• Minimize routine blood tests samples and attempt to collect these tests as close to or at home, if possible.
• For lung transplant patients, the use of home spirometry is recommended, when available, for routine monitoring of lung function; notify your transplant team if there is a decline in the forced expiratory volume in 1 second (FEV1) of 10% over several readings.(2)
• Take medications (disease specific or immunosuppression), including corticosteroids, angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), as instructed by your transplant team.(3)
• Don’t forget to take care of your mental health: Try to be kind to yourself, cherish your family and friends; breath fresh air, engage in physical exercise, yoga, meditation and creative activities. Rest, sleep, and healthy eating are important. Avoid excessive exposure to the news; the best sources of safe information online can be found on official websites provided by medical centers, transplant societies and governments. Trust your transplant team, they are there to support you.(4)

References

1. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schunemann HJ et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet 2020;395(10242):1973-1987.
2. Aslam S, Danziger-Isakov D, Luong ML, Husain S, Silveira F, Grossi P et al. 1)        Guidance from the International Society of Heart and Lung Transplantation regarding the SARS CoV-2 pandemic.  2020  June 29, 2020]; Available from: https://ishlt.org/ishlt/media/documents/SARS-CoV-2_-Guidance-for-Cardiothoracic-Transplant-and-VAD-centers.pdf
3. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 2020;382(17):1653-1659.
4. Mauri D, Kamposioras K, Tolia M, Alongi F, Tzachanis D, International Oncology P et al. Summary of international recommendations in 23 languages for patients with cancer during the COVID-19 pandemic. Lancet Oncol 2020;21(6):759-760.

Summary - General

1. Nucleic acid testing (NAT) of respiratory tract specimens is recommended for the diagnosis of SARS-CoV-2 infection.
2. New variants may contain mutations that affect the sensitivity of existing NAT kits. Check with your lab to determine its kit’s performance with new variants.

Summary - Recipients

1. Duration of PCR shedding in transplant recipients may be prolonged.
   1. Risk of transmission is not known in transplant recipients with prolonged shedding, although the likelihood of transmission may be inferred from the cycle threshold (Ct) value.
2. Not all transplant recipients mount detectable antibody response to natural infection, nor to vaccination. However, some transplant recipients who are seronegative after vaccination demonstrate positive T-cell responses to the virus.
3. Transplant recipients who test positive at home via a rapid antigen kit should present early to a transplant centre.

Summary - Donors

Serology is helpful for assessment of seroprevalence but not for diagnosis or donor screening.

Rapid antigen tests (RATs) are not recommended for use in donor screening.

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.

Sample
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⁾

References (NAT)

1. CDC Overview of Testing for SARS-CoV-2 (COVID-19). Updated Oct. 22, 2021.
2. Coll E et al. COVID-19 in transplant recipients: The Spanish experience. Am J Transplant 2021;21:1825.
3. Nair V et al. COVID-19 in kidney transplant recipients. >Am J Transplant. 2020;20:1819.
4. Zhong Z et al. Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients. Am J Transpl 2020;20:1916.
5. Hoek RAS et al. Covid-19 in solid organ transplant recipients: A single center experience. Transpl Int. 2020;33:1099.
6. Zhu L et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am J Transplant 2020;20:1859.
7. Marais G et al. Saliva swabs are the preferred sample for omicron detection. medRxiv preprint doi: https://doi.org/10.1101/2021.12.22.21268246 .
8. Organ Procurement and Transplant Network. Summary of Current Evidence and Information – Donor SARS-CoV-2 Testing & Organ Recovery from Donors with a History of COVID-19. https://optn.transplant.hrsa.gov/media/kkhnlwah/sars-cov-2-summary-of-evidence.pdf.
9. Kute VB et al. Use of organs from SARS-CoV-2 infected donors: is it safe? A contemporary review. Curr Transplant Rep 2021; DOI: 10.1007/s40472-021-00343-0.
10. Neidlinger NA et al. Organ recovery from deceased donors with prior COVID-19: A case series. Transpl Infect Dis 2021 Apr;23(2):e13503. DOI: 10.1111/tid.13503.
11. Cao G et al. The potential transmission of SARS-CoV-2 from patients with negative RT-PCR swab tests to others: two related clusters of COVID-19 outbreak. Jpn J Infect Dis 2020;73:399.
12. Kinloch NN et al. Suboptimal biological sampling as a probable cause of false-negative COVID-19 diagnostic results. J Infect Dis 2020;222:899.
13. Pan Y et al. Potential false-negative nucleic acid testing results for severe acute respiratory syndrome coronavirus 2 from thermal inactivation of samples with low viral loads. Clin Chem 2020;66:794.
14. Tay J-Y et al. De-isolating COVID-19 suspect cases: a continuing challenge. Clin Infect Dis 2020;71:883.
15. Khan KA et al. Presence of mismatches between diagnostic PCR assays and coronavirus SARS-CoV-2 genome. Royal Society Open Science 2020; https://doi.org/10.1098/rsos.200636.
16. Ferre VM et al. Omicron variant SARS-CoV-2 variant: what we know and what we don’t. Anaesth Crit Care Pain Med 2021 Dec 10;41(1):100998.
17. European Centre for Disease Prevention and Control. Implications of the emergence and spread of the SARSCoV-2 B.1.1. 529 variant of concern (Omicron), for the EU/EEA. 26 November 2021. ECDC: Stockholm; 2021.
18. Karim SSA & Karim QA. The Lancet, 2021. Omicron SARS-CoV-2 variant: a new chapter in the COVID-19 pandemic. https://doi.org/10.1016/S0140-6736(21)02758-6.
19. Volz, E. et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature 2021;593:266.
20. Surkova E et al. False-positive COVID-19 results: hidden problems and costs. Lancet Resp Med 2020;8:1167.
21. Chen Y et al. The presence of SARS‐CoV‐2 RNA in the feces of COVID‐19 patients. J Med Virol 2020;92:833.
22. Henderson DK et al. The perplexing problem of persistently PCR-positive personnel. Infect Control Hosp Epidemiol 2021;42:203.
23. Kilic T et al. Molecular and immunological diagnostic tests of COVID-19: Current Status and Challenges. iScience 2020;23:101406.
24. Perera RAPM et al. SARS-CoV-2 virus culture and subgenomic RNA for respiratory specimens from patients with mild Coronavirus disease. Emerg Infect Dis 2020;26:2701.
25. Wolfel R et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020;581:465.
26. Bullard J et al. Predicting infectious Severe Acute Respiratory Syndrome Coronavirus 2 from diagnostic samples. Clin Infect Dis 2020;71:2663.
27. Singanayagam A et al. Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020. Eurosurv 2020;32:2.
28. An overview of cycle threshold values and their role in SARS-CoV-2 real-time PCR test interpretation. From: www.publichelathontario.ca
29. CDC Overview of Testing for SARS-CoV-2 (COVID-19). Updated Oct. 22, 2021.
30. Wolters F et al. Multi-center evaluation of cepheid xpert® xpress SARS-CoV-2 point-of-care test during the SARS-CoV-2 pandemic. J Clin Virol 2020; 128:104426.
31. Chung SJ et al. Practical considerations for solid organ transplantation during the COVID-19 global outbreak: the experience from Singapore. Transpl Direct 2020;6:e554.

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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.

References (Antibody)

1. Tan CW, et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol 2020;38:1073-1078.
2. Borremans B, et al. Quantifying antibody kinetics and RNA detection during early-phase SARS-CoV-2 infection by time since symptom onset. Elife. 2020 Sep 7;9:e60122.
3. Zhang Y et al. Different longitudinal patterns of nucleic acid and serology testing results based on disease severity of COVID-19 patients. Emerg Microbes Infect, 9:1,833.
4. Burack D et al. Prevalence and predictors of SARS-CoV-2 antibodies among solid organ transplant recipients with confirmed infection. Am J Transplant 2121;21:2254.
5. Interim guidelines for COVID-19 antibody testing. Updated September 2021. From: www.cdc.gov/coronavirus/2019-nCov/lab/resources/antibody-tests-guidelines.html. Interim Guidelines for COVID-19 Antibody Testing | CDC

Antigen Testing
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)

1. Nagura-Ikeda M et al. Clinical evaluation of self-collected saliva by quantitative reverse transcription-PCR (RT-qPCR), direct RT-qPCR, Reverse transcription–loop-mediated isothermal amplification, and a rapid antigen test to diagnose COVID-19. J Clin Microbiol 2020; 58:e01438.
2. Schuit E et al. Diagnostic accuracy of rapid antigen tests in asymptomatic and presymptomatic close contacts of individuals with confirmed SARS-CoV-2 infection: cross sectional study. BMJ 2021;374:n1676.
3. McKay SL et al. Performance evaluation of serial SARS-CoV-2 rapid antigen testing during a nursing home outbreak. Ann Intern Med 2021;174:945.
4. Scohy A et al. Low performance of rapid antigen detection test as frontline testing for COVID-19 diagnosis. J Clin Virol 2020;129:104455.
5. Surasi K et al. Effectiveness of Abbott BinaxNOW rapid antigen test for detection of SARS-CoV-2 infections in outbreak among horse racetrack workers, California, USA. Emerg Infect Dis2021;27:2061.
6. Pekosz A et al. Antigen-based testing but not real-time polymerase chain reaction correlates with Severe Acute Respiratory Syndrome Coronavirus 2 viral culture. Clin Infect Dis 2021; DOI: 10.1093/cid/ciaa1706.
7. Drain PK. Rapid diagnostic testing for SARS-CoV-2.NEJM 2022; DOI: 10.1056/NEJMcp2117115

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

KEY POINTS

• Regardless of donor screening, the center should have a discussion of risk-benefit with the recipient regarding transplantation during the ongoing pandemic.
• All donors should be screened by history of exposure to or clinical signs of COVID-19.
• All donors should undergo SARS-CoV-2 PCR/NAT screening.
• Donors known to be infected with SARS-CoV-2 should not be used as organ donors.
• In general, those who have recovered from COVID-19 should be cleared by clinical and ideally SARS-CoV-2 PCR prior to organ donation.

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

1. Galvan NTN, Moreno NF, Garza JE, Bourgeois S, Hemmersbach-Miller M, Murthy B et al. Donor and Transplant Candidate Selection for Solid Organ Transplantation during the COVID-19 Pandemic. Am J Transplant 2020.
2. Loupy A, Aubert O, Reese PP, Bastien O, Bayer F, Jacquelinet C. Organ procurement and transplantation during the COVID-19 pandemic. Lancet 2020;395(10237):e95-e96.
3. Kumar D, Manuel O, Natori Y, Egawa H, Grossi P, Han SH et al. COVID-19: A global transplant perspective on successfully navigating a pandemic. Am J Transplant 2020.
4. Shah MB, Lynch RJ, El-Haddad H, Doby B, Brockmeier D, Goldberg DS. Utilization of deceased donors during a pandemic: argument against using SARS-CoV-2-positive donors. Am J Transplant 2020.
5. Kates OS, Fisher CE, Rakita RM, Reyes JD, Limaye AP. Emerging evidence to support not always "just saying no" to SARS-CoV-2 positive donors. Am J Transplant 2020.
6. Bullard J, Dust K, Funk D, Strong JE, Alexander D, Garnett L et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis 2020.
7. Folgueira MD, Luczkowiak J, Lasala F, Perez-Rivilla A, Delgado R. Persistent SARS-CoV-2 replication in severe COVID-19. medRxiv 2020:doi.org/10.1101/2020.1106.1110.20127837.

TID COVID-19 Guidance Focused Review:
Update on Therapeutic Agents for COVID-19
Date of Update: February 10, 2022

KEY POINTS

• There is limited data for specific therapies in transplant patients.
• Monoclonal antibodies against SARS-CoV-2 spike protein should be considered for treatment of mild-to-moderate COVID-19 infection in the outpatient setting to prevent disease progression.
• Early initiation of antivirals against SARS-CoV-2 may reduce risk of hospitalization or death in patients with mild to moderate COVID-19 disease. Careful attention to drug interactions should be considered if used.
• Where available, remdesivir should be considered for at least 5 days for hospitalized patients requiring oxygen or with room air SpO2 ≤94% and for 10 days in hospitalized patients requiring mechanical ventilation or ECMO.
• Dexamethasone 6mg daily for up to 10 days can be considered in hospitalized patients who require supplemental oxygen or are mechanically ventilated.
• Tocilizumab or baricitinib, in addition to steroids, can be used among hospitalized patients with progressive severe COVID-19 with elevated inflammatory markers. There is limited safety data in immunocompromised patients.

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 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

Remdesivir
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⁾

Corticosteroids
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)}

Tocilizumab
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).

Baricitinib
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.

Remdesivir
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.

Molnupiravir
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⁾

Nirmatrelivir/ritonavir
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⁾

Prophylaxis
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.

Drug-Drug Interaction
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

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.^(40-48)

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, and is no longer recommended for treatment of COVID-19.^{(47, 49, 50)}

Ivermectin
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⁾

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41. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020.
42. Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv. 2020.
43. Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment. Circulation. 2020;141(24):e906-e7.
44. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.
45. Chorin E, Dai M, Shulman E, Wadhwani L, Bar-Cohen R, Barbhaiya C, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med. 2020;26(6):808-9.
46. Consortium WHOST, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.
47. Group RC, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020;383(21):2030-40.
48. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-99.
49. Statement from chief investigators of the randomized evaluation of COVID-19 therapy (RECOVERY) trial on lopinavir-ritonavir [press release]. 29 June 2020 2020.
50. Lopez-Medina E, Lopez P, Hurtado IC, Davalos DM, Ramirez O, Martinez E, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(14):1426-35.

TID Evidence Review for Inpatient Treatment Options for COVID-19

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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Remdesivir (GS-5734)
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. FDA EUA Fact Sheet for Providers 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: Hydroxychloroquine – potential for reduced antiviral activity of remdesivir	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 Preliminary results from double-blind RCT comparing remdesivir (n=538) versus placebo (n=521) in hospitalized patients with COVID-19 and at least one of the following criteria: infiltrates on chest imaging, SpO2 <94% on room air, or supplemental oxygen requirement including mechanical ventilation. Pts were excluded if eGFR < 30ml/min, LFTs > 5x ULN, pregnant, or breastfeeding. Among 1063 patients, those treated with remdesivir had a shortened median time to recovery (11d v 15d) compared with placebo. Significant clinical status improvement, measured by 8-point ordinal scale, was seen with remdesivir compared to placebo (59.2% v 49.5%, OR 1.5). No significant difference was found for mortality at 14 days although it was numerically lower with remdesivir (7.1% v 11.9%). Serious adverse events were experienced in 21.1% of patients receiving remdesivir compared to 27.0% in those receiving placebo. Common adverse events in remdesivir treated patients were anemia or decreased hemoglobin (7.9%), AKI, reduced eGFR or CrCl (7.4%), pyrexia (3.3%), hyperglycemia (4.1%), and LFT increases (4.1%). Full data analysis pending further enrollment. (Beigel) Randomized open-label, phase 3 trial of 397 hospitalized patients with COVID-19 who received remdesivir for a duration of 5 days v 10 days in 55 hospitals across US, Europe, and Asia. Patients had SpO2 <94% on room air,  infiltrates on chest imaging, and a positive SARS-CoV-2 PCR within 4 days of enrollment. Patients on mechanical ventilation were excluded. Supportive care was also administered. At baseline patients in 10-day group had significantly worse clinical status (p=0.02) compared to 5-day group. Patients were treated for a median duration of 5 days and 9 days in each group. At day 14, clinical improvement by 2 points, based on 7-point ordinal scale, occurred in 64% of patients treated for 5 days and 54% in those who received 10 days of remdesivir. Median duration of hospitalization among those discharged on or before day 14 was shorter in 5 day group compared to 10 day group (7d v 8d) with more patients being discharged in 5 day group (60% v 52%). Mortality was numerically lower in 5 day group (8% v 11%). Common adverse events were nausea (9%), worsening respiratory failure (8%), elevated ALT (7%), and constipation (7%). (Goldman) RCT of 237 hospitalized patients in Hubei, China with severe COVID-19 randomized 2:1 to remdesivir v placebo for up to 10 days. Study was underpowered but found no statistically significant difference in time to clinical improvement with remdesivir (21d) v placebo (23d) nor difference in duration of oxygen support, length of hospitalization, rate of discharge, nor death. No major difference in adverse reactions among groups. (Wang)
Clinical Trials Expanded Access: Remdesivir (RDV; GS-5734) for the Treatment of SARS-CoV2 (CoV) Infection (US). NCT04323761 Adaptive COVID-19 Treatment Trial (US). NCT04280705 Expanded Access Remdesivir (RDV; GS-5734™). NCT04302766  Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment (US). NCT04292730   Study to Evaluate the Safety and Antiviral Activity of Remdesivir in Participants with Severe Coronavirus Disease (COVID-19) (US). NCT04292899
References Beigel JH et al. NEJM. 22 May 2020. DOI: 10.1056/NEJMoa2007764 Goldman JD et al. NEJM. 27 May 2020. DOI: 10.1056/NEJMoa2015301 Wang Y et al. Lancet. 29 April 2020. DOI: 10.1016/ S0140-6736(20)31022-9

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Hydroxychloroquine (HCQ)
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: Remdesivir – potential to reduce antiviral activity of remdesivir Caution used for co-administration with: Tacrolimus & Sirolimus – potential to increase tacrolimus & sirolimus plasma conc due to moderate P-gp inhibition; potential risk for QT prolongation Cyclosporine – potential to increase cyclosporine plasma conc Posaconazole & Voriconazole – potential to increase HCQ plasma conc & increase risk of QT prolongation due to CYP3A4 inhibition Trimethoprim/sulfamethoxazole – potential for increased HCQ plasma conc similar to effect of chloroquine due to MATE1 inhibition & potential for enhanced hypoglycemic effect Lopinavir/ritonavir – potential to increase HCQ plasma conc & risk of QT prolongation	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. Maintain electrolytes (K>4mEq/L, Mg>2mg/dl) while on therapy (Roden) 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                                                        Randomized, double-blind, placebo-controlled trial of hydroxychloroquine post-exposure prophylaxis among 821 asymptomatic patients who were not hospitalized and reported to be at high-risk exposure to a confirmed COVID-19 contact. Pts were enrolled within 4 days following potential exposure and received HCQ 800mg once followed by 600mg once 6-8 hours later, then 600mg daily for 4 additional days or placebo. Primary outcome of incidence of lab-confirmed COVID-19 or clinically-suspected COVID-19 within 14 days did not differ significantly among those receiving HCQ v placebo (11.8% v 14.3%). Side effects were more common with HCQ than placebo (40.1% v 16.8%) without any reports of serious adverse events. (Boulware) Randomized, parallel-group trial to evaluate the efficacy of HCQ (400mg/day; 200mg BID x 5 days) v standard treatment (supportive care=control) in 31/62 patients with mild COVID-19 illness (excluded severe/critically ill) in Wuhan. Time to clinical recovery (TTCR) in days, clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment. Fever recovery time (3.2d vs. 2.2d, p=0.0008) and duration of cough (3.1d vs. 2d, p=0.0016) significantly shortened in HCQ versus control group, respectively; per chest CT, pneumonia improved 25/31 (80.6%) in HCQ vs. 17/31 (54.8%) in control group, p=0.047. Severe illness progressed in 4 of 62 patients (all controls). Mild adverse reactions (HCQ): rash, headache. (Chen Z) Pre-print information: Non-randomized propensity-matched comparative study of pts receiving HCQ 600mg daily within 48hrs of hosp (n=84) v those who did not (control, n=97) combined with standard of care. Among 181 pts, all of whom had bilateral PNA and required supplemental oxygen, no difference found in the composite outcome of transfer to ICU within 7 days or all-cause mortality (HCQ 20.2% v control 22.1%). ARDS developed within 7 days in 27.7% of pts treated with HCQ v 24.1% in controls. 9.5% of pts in HCQ group experienced EKG changes requiring therapy discontinuation, with a median d/c time of 4 days. Authors stated findings do not support use of HCQ in COVID PNA. (Mahévas) Pre-print information: Multicenter, open-label RCT of 150 pts hospitalized with COVID-19 who received HCQ 1,200mg daily x 3 days followed by 800mg daily + SOC (n=75) v SOC alone (control, n=75). 28-day negative conversion rates of SARS-CoV-2 was not different between HCQ + SOC v controls (85.4% v 81.3%, median time to negative conversion 8 v 7 days) nor were differences in negative conversion rates at days 4, 7, 10, 14, 21, including in a sub-analysis of pts who received HCQ within 7 days of symptom onset v those with initiation beyond 7 days. No difference in 28-day symptom alleviation (59.9% v 66.6%), however in a post-hoc analysis in which confounding use of other antiviral agents were removed, HCQ was associated with an improved rate of symptom alleviation, more rapid normalization of CRP, and a trend towards more rapid recovery of lymphopenia. AE rate of 30% in HCQ (10% diarrhea) v 8.8% in controls. (Tang) Pre-print information: Retrospective review of 84 adult pts with COVID-19 in US treated with HCQ and azithro combination therapy, which found a significant association with QTc prolongation (30% of pts with increase >40ms, 11% of pts with increase to >500ms), placing these pts at higher risk for arrhythmias, although no cases of torsades reported. Maximal QTc increase was noted on treatment days 3-4. Acute renal failure was noted to be a significant predictor of severe QTc prolongation, but baseline QTc and QTc >460ms did not predict QTc prolongation. Concurrent amiodarone use associated w/ risk. Authors recommend repeat monitoring of QTc for pts receiving HCQ/Azithro combo. (Chorin) Pre-print information: Retrospective review of 368 adult pts with COVID-19 at VAMC treated with HCQ alone (n=97), HCQ+Azithro (n=113), or controls receiving no HCQ (n=158). Higher mortality reported with HCQ alone (27.8%) compared to HCQ+Azithro (22.1%) & controls (11.4%) w/ similar rates of risk of mech ventilation (adjusted HR 1.43 HCQ alone v HR 0.43 HCQ+Azithro compared to controls). Emphasize need for results from ongoing RCT prior to recommended use of HCQ. (Magagnoli)
References Boulware DR et al. NEJM. 3 June 2020. DOI: 10.1056/NEJMoa2016638. Chen Z et al. medRxIV Preprint 22 March 2020 doi 2020.03.22.20040758v1.full.pdf Magagnoli J et al. medRxiv Pre-print. April 21, 2020: https://doi.org/10.1101/2020.04.16.20065920 Roden DM et al. 2020 Apr 8 DOI: 10.1161/CIRCULATIONAHA.120.047521 Tang W et al. medRxiv Preprint 10 April 2020. doi: https://doi.org/10.1101/2020.04.10.20060558

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Lopinavir/Ritonavir (Kaletra®)
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: Sirolimus & Everolimus – potential to increase sirolimus & everolimus plasma conc due to CYP3A & P-gp inhibition Caution used for co-administration with: Tacrolimus – potential to increase tacrolimus plasma conc due to CYP & P-gp induction Cyclosporine – potential to increase cyclosporine plasma conc due to CYP3A4 inhibition Mycophenolate – potential to alter mycophenolate plasma conc due to interference with glucoronidation Voriconazole – potential to decrease voriconazole plasma conc due to CYP induction Posaconazole – potential to increase ritonavir plasma conc due to CYP3A inhibition Methylprednisolone & prednisone– potential to increase methylprednisolone & prednisone plasma conc due to CYP3A4 inhibition Atovaquone – potential to decrease atovaquone plasma conc due to glucoronidation induction Hydroxychloroquine – potential to increase HCQ plasma conc & risk of QT prolongation	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 Press Release – RECOVERY: Randomized, controlled trial of 1596 hospitalized patients who received lopinavir-ritonavir compared with 3376 patients who received usual care alone demonstrated no significant difference in the primary end point of 28-day mortality (22.1% with lopinavir-ritonavir v 21.3% usual care, RR 1.04, p=0.58). 70% of patients required supplemental oxygen, 4% required mechanical ventilation, however mortality was similar among subgroups, and no evidence to support benefit on the risk of progression to mechanical ventilation or length of hospitalization. (RECOVERY) Randomized, controlled, open-label trial of 199 severely-ill hospitalized patients with confirmed SARS-CoV-2 comparing lopinavir/ritonavir with standard of care (n=99) versus SOC alone (n=100) for 14 days, with a 13 day median time between symptom onset and randomization. Primary endpoint of time to clinical improvement or live hospital discharge was not significantly different (16d v 16d), although lopinavir/ritonavir led to a median time to clinical improvement 1 day shorter than SOC (15d v 16d) in mITT group, however treatment within 12 days was not found to be associated with a shorter time to clinical improvement. 28-day mortality in lopinavir/ritonavir treated patients was numerically lower (19.2% v 25.0%) in mITT analysis, with shorter ICU stay (6d v 11d), and fewer instances of mechanical ventilation. Percentage of patients with clinical improvement at day 14 was higher in lopinavir/ritonavir treated group (45.5% v 30.0%), but had similar percentage of patients with detectable viral RNA to SOC group. Lopinavir/ritonavir was more frequently associated with GI-related AE, and was stopped early in 13 pts due to adverse events. Systemic steroids were given in both groups (33.0% v 35.7%). (Cao) Retrospective, multicenter cohort study of 191 COVID-19 confirmed patients in Wuhan, China, with 41 (21%) patients receiving lopinavir/ritonavir. 29 of these patients were discharged and found to have a median duration of viral shedding of 22 days with no observable difference in duration of viral shedding among survivors who did and did not receive lopinavir/ritonavir. Receipt of lopinavir/ritonavir was not significantly different amongst survivors and non-survivors (22% v 21%). (Zhou)
References Press Release – Statement from chief investigators of the randomized evaluation of COVID-19 therapy (RECOVERY) trial on lopinavir-ritonavir. Univ of Oxford. 29 June 2020.

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Favipravir (T-705, Avigan®)
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 Randomized, open-label, clinical trial of 240 patients to evaluate favipiravir versus umifenovir (Arbidol) in COVID-19 patients at 3 hospitals in Wuhan, China. The primary outcome was clinical recovery on day 7, and the secondary outcomes were duration of fever, cough relief time, oxygen therapy, and MV rate. 116 patients were assigned to favipiravir (1600 mg BID on day1, followed by 600 mg BID), and 120 patients to umifenovir (200 mg TID). The rate of clinical recovery on day 7 was 61.21% (71/116) in the favipiravir group and 51.67% (62/120) in the umifenovir group (P=0.0199). The duration of fever and time to cough relief was significantly shorter in the favipiravir group (both p<0.001). However, there was no difference in supplemental oxygen therapy use and MV rate. GI symptoms, and elevated uric acid was more common with favipiravir. (Chang Chen) Open-label, controlled study of 80 COVID-19 patients to compare favipiravir (Day 1: 1600 mg BID; Days 2–14: 600 mg BID) with lopinavir/ritonavir (Days 1–14: 400 mg/100 mg BID). Patients had mild to moderate COVID-19 and were enrolled within 7 days from disease onset. Both groups were treated with added interferon-α by aerosol inhalation (5 million units twice daily). Outcomes were changes in CT, viral clearance, and drug safety. There were 35 patients in the favipiravir arm and 45 patients in the lopinavir/ritonavir arm. Time to viral clearance was shorter in the favipiravir group (4 days v 11 days, P<0.001), and CT imaging showed significant improvement with favipiravir (91.4% v 62.2%, P=0.004). Adverse reactions were less common in the favipiravir group compared to lopinavir/ritonavir (11.4% v 55.6%, p<0.01). (Cai)
Clinical Trials Study of the use of favipravir in hospitalized subjects with COVID-19 (US). NCT04358549 Favipravir v hydroxychloroquine, azithromycin, zinc v standard of care (PIONEER) (UK). NCT04373733 Efficacy and safety of favipravir in management of COVID-19 (Egypt). NCT04349241 Favipravir combined with tocilizumab in the treatment of COVID-19 (China). NCT04310228
References Coomes EA et al. Favipiravir, an antiviral for COVID-19?, Journal of Antimicrobial Chemotherapy, Volume 75, Issue 7, July 2020. DOI: 10.1093/jac/dkaa171. Cai Q et al. Experimental Treatment With Favipiravir For COVID-19: An Open-Label Control Study. Engineering, 2020. DOI:10.1016/j.eng.2020.03.007.

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

1. Ljungman P, Mikulska M, de la Camara R, Basak GW, Chabannon C, Corbacioglu S, et al. The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy. Bone Marrow Transplant [Internet]. 2020; Available from: http://dx.doi.org/10.1038/s41409-020-0919-0
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England). 2020;395(10229):1054–62.
3. Liu Y, Yan L, Wan L, Xiang T, Le A, Liu J, et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020 Jun;20(6):656–7.
4. The Lancet. COVID-19: protecting health-care workers. Lancet (London, England) [Internet]. 2020;395(10228):922. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32199474

TID COVID-19 Guidance Focused Review: SARS-CoV-2 Vaccines in Transplant Recipients

Date of Update: 1 December 2021

KEY POINTS

• Transplant recipients may be vaccinated with any of the authorized or approved COVID-19 vaccines.
  • Caccines containing live attenuated virus or replication competent vectors, if authorized for use in the future, will not be suitable for the immunocompromised.
• All transplant recipients should be vaccinated, irrespective of past COVID-19 infection or positive SARS CoV-2 antibodies.
• Household contacts of transplant recipients should be vaccinated to improve ring protection of the recipient and reduce the risk of transmission within the household
• Primary vaccination and booster doses schedule should follow local or national policies.
• The concomitant administration of COVID-19 vaccines with other vaccines is considered safe.
• Adjustment of immunosuppressive medications before vaccination is not recommended.
• Checking antibody responses to the vaccine is not currently recommended.
• For SOT recipients, the ideal timing of vaccination is uncertain in the post-transplantation setting and will depend on the induction therapy given, intensity of maintenance immunosuppression and treatment of rejection. It is generally accepted that vaccine immunogenicity is lowest in the first few months post -transplant or after rejection treatment.
  • All efforts should be made to vaccinate patients pre-transplantation.
  • Transplant candidates who have been recently vaccinated or are between doses 1 and 2 should generally proceed to transplant as per clinical need. They should complete the schedule as described below.
  • Vaccination should be delayed for 1 to 3 months after transplant surgery or rejection treatment.
  • Longer delays may be required for patients who have received anti-B (i.e. rituximab; 6+ mo) or anti-T cell (anti-thymocyte globulin, alemtuzumab; 3 mo).
  • A risk-benefit assessment should weigh the community transmission risks against the likelihood of side effects.
• Organ donors who have received any COVID-19 vaccine may be used irrespective of time since vaccine; no vaccine would rule out a donor.
• For HSCT, in regions with accelerated transmission rates, COVID-19 vaccination may start at the 3rd month of HSCT. In regions where the risk of community acquisition of Covid-19 is lower, it is reasonable to wait until the sixth month after HSCT when better vaccine response is expected.
• We do recommend each center to develop approaches to educate patients on the importance of vaccination and consider tracking vaccination rates.
• A third-dose of mRNA COVID-19 vaccine should be considered, where allowed by local regulatory approval. For patients who have received other vaccines, a supplemental dose of the same vaccine or an mRNA vaccine should be considered to improve humoral responses where allowed by local regulatory approval.
• Transplant recipients who have received the COVID-19 vaccine should continue to observe all current preventive measures, such as masking, hand hygiene and safe distancing.
• Transplant recipients who have received the COVID-19 vaccine should continue to observe all current preventive measures, such as masking, hand hygiene and safe distancing.

Introduction
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
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.

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References:

1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384(5): 403-416.
2. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020;396(10255): 887-897.
3. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269): 99-111.
4. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2020.
5. Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249): 479-488.
6. Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet. 2021;396(10267): 1979-1993.
7. Wu Z, Hu Y, Xu M, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021.
8. Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis. 2021;21(1): 39-51.
9. Ou MT, Boyarsky BJ, Motter JD, et al. Safety and Reactogenicity of 2 Doses of SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients. Transplantation. 2021;105(10): 2170-2174.
10. Boyarsky BJ, Chiang TP, Ou MT, et al. Antibody Response to the Janssen COVID-19 Vaccine in Solid Organ Transplant Recipients. Transplantation. 2021;105(8): e82-e83.
11. Del Bello A, Abravanel F, Marion O, et al. Efficiency of a boost with a third dose of anti-SARS-CoV-2 messenger RNA-based vaccines in solid organ transplant recipients. Am J Transplant. 2021.
12. Schmidt T, Klemis V, Schub D, et al. Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients. Am J Transplant. 2021.
13. Hall VG, Ferreira VH, Ku T, et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. N Engl J Med. 2021;385(13): 1244-1246.
14. Wadei HM, Gonwa TA, Leoni JC, Shah SZ, Aslam N, Speicher LL. COVID-19 infection in solid organ transplant recipients after SARS-CoV-2 vaccination. Am J Transplant. 2021;21(10): 3496-3499.
15. Benotmane I, Gautier G, Perrin P, et al. Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses. JAMA. 2021.
17. Rabinowich L, Grupper A, Baruch R, et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J Hepatol. 2021;75(2): 435-438.
18. Grupper A, Rabinowich L, Schwartz D, et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. 2021;21(8): 2719-2726.
19. Peled Y, Ram E, Lavee J, et al. Third dose of the BNT162b2 vaccine in heart transplant recipients: Immunogenicity and clinical experience. J Heart Lung Transplant. 2021.
20. Kumar D, Ferreira VH, Hall VG, et al. Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial. Ann Intern Med. 2021.
21. Alejo JL, Mitchell J, Chiang TP, et al. Six-month Antibody Kinetics and Durability in SARS-CoV-2 mRNA Vaccinated Solid Organ Transplant Recipients. Transplantation. 2021.
22. 20a. Grupper A et al. Kidney transplant recipients vaccinated before transplantation maintain superior humoral response to SARS-CoV-2 vaccine. Clin Transplant 2021;35:e14478.
23. Borobia AM, Carcas AJ, Perez-Olmeda M, et al. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet. 2021;398(10295): 121-130.
24. Atmar RL, Lyke KE, Deming ME, et al. Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report. medRxiv. 2021.
25. Liu X, Shaw RH, Stuart ASV, et al. Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial. Lancet. 2021;398(10303): 856-869.
26. Ravanan R, Mumford L, Ushiro-Lumb I, et al. Two Doses of SARS-CoV-2 Vaccines Reduce Risk of Death Due to COVID-19 in Solid Organ Transplant Recipients: Preliminary Outcomes From a UK Registry Linkage Analysis. Transplantation. 2021.
27. Maneikis K, Sablauskas K, Ringeleviciute U, et al. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8): e583-e592.
28. Harris RJ, Hall JA, Zaidi A, Andrews NJ, Dunbar JK, Dabrera G. Effect of Vaccination on Household Transmission of SARS-CoV-2 in England. N Engl J Med. 2021;385(8): 759-760.
29. Haviari S, Benet T, Saadatian-Elahi M, Andre P, Loulergue P, Vanhems P. Vaccination of healthcare workers: A review. Hum Vaccin Immunother. 2015;11(11): 2522-2537.
30. Kates OS, Stock PG, Ison MG, et al. Ethical review of COVID-19 vaccination requirements for transplant center staff and patients. Am J Transplant. 2021.
31. Van Hooste WLC, Bekaert M. To Be or Not to Be Vaccinated? The Ethical Aspects of Influenza Vaccination among Healthcare Workers. Int J Environ Res Public Health. 2019;16(20).
32. Cheng VC, Fung KS, Siu GK, et al. Nosocomial Outbreak of Coronavirus Disease 2019 by Possible Airborne Transmission Leading to a Superspreading Event. Clin Infect Dis. 2021;73(6): e1356-e1364.
33. Kates OS, Stohs EJ, Pergam SA, et al. The limits of refusal: An ethical review of solid organ transplantation and vaccine hesitancy. Am J Transplant. 2021;21(8): 2637-2645.

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:

• John’s Hopkins’ COVID-19 Dashboard:  https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6

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

There are a number of resources that allow for access of up-to-date guidelines for transplant donors and recipients.  These are viewable at the COVID-19 Coronavirus Dashboard.

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  

Please refer to the “Update on SOT Recipient Advice to Prevent COVID-19” for updated details.

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:

• Have a plan for physician and staff absences or furloughs due exposure to patients with or team member illness with COVID-19.
• Identify team members who may be impacted by school closures.
• Determine who can work remotely and ensure they have the resources to do so.
• Develop messaging for candidates and recipients about how and when to contact the transplant center in case of illness.
• Develop guidance for candidates and recipients about risk mitigation, including limiting exposure to large crowds, hand hygiene and avoidance of sick exposures.
• Implement procedures to screen patients coming to clinic for fever and respiratory symptoms.
• Determine approaches to minimize exposure to the healthcare setting
• Consider reduced frequencies of clinic visits and laboratory testing
• Consider deferral of elective procedures (i.e. protocol biopsies) in stable patients
• Consider delaying pre-transplant evaluations for patients who do not require immediate evaluation