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.

KEY POINTS

• PCR testing of nasopharyngeal or bronchoalveolar lavage (BAL) is recommended for the diagnosis of SARS-CoV-2 infection (COVID-19).
• Duration of shedding in transplants may be prolonged.
• Risk of transmission is not known in transplant patients with prolonged shedding.
• Serology is helpful for assessment of seroprevalence but not for diagnosis or donor screening.

As clinical presentation of COVID-19 is varied, including diarrhea as a common early symptom, clinicians should have a low threshold for diagnostic testing.

Polymerase Chain Reaction (PCR)
While the literature on COVID-19 in SOT is expanding, all have depended upon PCR to confirm the diagnosis. While testing is generally applied to nasopharyngeal swabs, collection of sputum, nasal and throat swab and saliva have also been used.1, 2, 3, 4  PCR of nasopharyneal or BAL specimens are considered the gold standard for diagnosis.  Of note, the oropharyngeal swab requires almost no training, whereas the nasopharyngeal swab does require some training.7

While PCR has the benefit of rapid turn-around-time and scalability, they may not be available in all parts of the world; some countries have wider access to antigen testing which have lower sensitivity than PCR testing.  The virus may mutate over time which may require continuous updating of primers/probes over time.5

Although PCR seems to be the gold standard, questions remain regarding the sample that will give the best yield, the number of samples that gives the best sensitivity, and the timing of sampling in relation to symptoms.

In an early guidance document released on 17 January 2020, the World Health Organization (WHO) recommended using “nasopharyngeal and oropharyngeal swab in ambulatory patients and sputum (if produced) and/or endotracheal aspirate or bronchoalveolar lavage in patients with more severe respiratory disease”.6 The document emphasized that the recommendation may change if data were to emerge indicating upper or lower respiratory tract specimens as being more appropriate. 

In a systematic review of the literature on this question, the Centre for Evidence-Based Medicine (Oxford) found only 2 low quality, non-peer-reviewed preprints, which, in their opinion, should be “viewed with caution”.7 They concluded, in very tentative fashion, that possibly nasopharyngeal swabs had a slight advantage over oropharyngeal swabs, especially from day 8 of illness onwards.

A multitude of articles describe positive results for SARS-CoV-2 PCR from multiple sources - nasal swabs, saliva, faeces.8, 9 Further, viral changes have been noted either pathologically or physiologically with multiple end organs, including the heart, kidney, liver and GI tract.  The importance of these for donors or recipients require further study.

For how long an immunocompromised person sheds infectious virus and what the determinants are of viral shedding are not yet known. In theory, SOT patients may shed greater amounts of virus for longer periods and therefore they may remain infectious for longer. Information on longitudinal follow-up of viral shedding in SOT patients is scarce, but it is possible that they may behave like critically ill patients or may show a fluctuating pattern. 14, 15, 17, 18

In summary, upper respiratory samples for PCR are currently the most common means of establishing the diagnosis of COVID-19 and are the diagnostic method of choice in transplant recipients. Physicians may choose to combine these specimens with other sources (eg, a nasal swab) to optimize the yield. 

The single biggest concern for frontline doctors is the false-negative PCR result. Although viral load is highest in the first few days of symptoms,10 occasional reports of initial negative PCRs have led to worries of how best to effectively rule out COVID-19.11 This is of relevance in donor screening and will be dealt with in a separate post. 

Serologic Testing
Alternatives to the PCR as a means of diagnosing COVID-19 include serology and cultures. The problems associated with these alternative tests are many. Serological assays, as might be expected, take several days to become positive. A review of 23 published studies found that ELISA-based assays detecting IgG to nucleoprotein became positive at a mean of 13.3 days post symptoms, and that ELISA-based assays detecting IgM to spike protein became positive at a mean of 12.6 days post symptoms.12  The time to seroconversion is not markedly different for papers reporting serology results using magnetic chemiluminescence assays.12 There are individuals who mount an antibody response within the first week of symptoms, but these tend to be in the minority.13  Despite poor overall performance of serological assays, recent studies suggest that SOT patients probably can mount an antibody response to SARS-CoV-2. However, further investigation into the dynamics of serologic response is required.14, 15  The primary role of antibody testing would, at the moment, be for seroepidemiological studies.16  

Serology is not routinely recommended for diagnosis in transplant patients.  The presence of antibodies in transplant recipients likely suggest some degree of protection of infection, although what titers are needed to prevent infection are not well studied yet.  Further, the duration of serologic protection is not yet defined, particularly in the transplant population.

Cultures are a difficult undertaking for most routine laboratories, with SARS-CoV-2 requiring Biosafety Level 3 facilities.

 

TID COVID-19 Guidance Focused Review:
Diagnostic Testing – PCR and Serology
Date of Update:  14 July 2020

KEY POINTS

1. Fernández-Ruiz M  et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain.  Am J Transplant. 2020 Apr 16. doi: 10.1111/ajt.15929.
2. Zhong Z et al. Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients. Am J Transpl 2020 DOI: 10.1111/ajt.15928
3. Hoek RAS et al. Covid-19 in solid organ transplant recipients: A single center experience. Transpl Int. 2020 May 27:10.1111/tri.13662.
4. Zhu L et a. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am J Transplant 2020; DOI: 10.1111/ajt.15869.
5. 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
6. WHO. Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases. Interim guidance. 17 January 2020.
7. Carver C et al. Comparative accuracy of oropharyngeal and nasopharyngeal swabs for diagnosis of COVID-19. From:  https://www.cebm.net/covid-19/comparative-accuracy-of-oropharyngeal-and-nasopharyngeal-swabs-for-diagnosis-of-covid-19/  accessed@2155hrs on 26052020.
8. Xie C et al. False Negative rate of COVID-19 is eliminated by using nasal swab test. Travel Med Infect Dis 2020 Apr 11;101668. doi: 10.1016/j.tmaid.2020.101668.
9. Chen Y et al. The presence of SARS‐CoV‐2 RNA in the feces of COVID‐19 Patients. J Med Virol 2020; DOI: 10.1002/jmv.25825.
10. Zou L et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179.
11. Tay J-Y et al. De-isolating COVID-19 suspect cases: a continuing challenge. Clin Infect Dis 2020 doi: 10.1093/cid/ciaa179.
12. Benny B et al. Quantifying antibody kinetics and RNA shedding during early-phase SARS-CoV-2 infection. medRxiv preprint doi: https://doi.org/10.1101/2020.05.15.20103275
13. Zhang Y et al. Different longitudinal patterns of nucleic acid and serology testing results based on disease severity of COVID-19 patients. Emerging Microbes & Infections, 9:1,833-836.
14. Fung, M et al. Clinical outcomes and serologic response in solid organ transplant recipients with COVID-19; a case series from the United States doi:10.1111/AJT.16079
15. Zhang Man et al Viral Shedding Prolongation in a Kidney Transplant Patient with COVID-19 Pneumonia. doi: 10.1111/AJT.15996
16. Cheng MP et al. Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus-2: a narrative review.  Ann Intern Med 2020;M20-2854. doi: 10.7326/M20-2854.
17. Lan Zhu et al Coronavirus Disease 2019 pneumonia in immunosuppressed renal transplant recipients: a summary of 10 confirmed cases in Wuhan, China. https://doi.org/10.1016/j.eururo.2020.03.039
18. Decker A et al Prolonged SARS-CoV-2 shedding and mild course of COVID-19 in a patient after recent heart transplantation doi:10.1111/AJT.16133.

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:  14 July 2020

KEY POINTS

• There is limited data for specific therapies in transplant patients. 
• Where available, remdesivir should be considered for at least 5 days for patients requiring oxygen or with room air SpO2 ≤94% and for 10 days in patients requiring mechanical ventilation or ECMO.
• Dexamethasone 6mg QD for up to 10 days can be considered in patients who require supplemental oxygen or are mechanically ventilated. 
• Hydroxychloroquine should not be used to prevent or treat COVID-19.

Overview
There is limited data on the specific role of any therapy for the treatment of COVID-19 in transplant patients.  As such, recommendations are based on data in the general population.  Attention should be paid to the potential drug interactions with current immunosuppression and the potential for increased risk of infectious complications with immunomodulatory agents are added to existing immunosuppressive therapy.  A summary of the current evidence review for most of the agents listed below with links to key data are found in Table 1.

Antiviral Agents
Remdesivir
While well-established therapeutic options are limited, remdesivir, an investigational antiviral, has demonstrated the strongest evidence as a potential treatment against COVID-19. With known activity against Ebola, MERS, SARS-CoV-1, and SARS-CoV-2, remdesivir has shown to be clinically efficacious compared to the standard of care in patients with severe COVID-19, requiring hospitalization and supplemental oxygenation, including mechanical ventilation. Preliminary results from the double-blind, randomized, controlled NIAID ACTT-1 trial found that among 1063 patients, remdesivir (n=538) compared to placebo (n=521) resulted in a shortened median time to recovery (11 days v 15 days), a higher rate of clinical status improvement, measured by an 8-point ordinal scale (59.2% v 49.5%, OR 1.5), and a numerically lower rate of 14-day mortality (7.1% v 11.9%).(1) Analysis and publication of full ACTT-1 and follow-up ACTT-2 (remdesivir + baricitinib v remdesivir alone) trials are pending. Regarding the duration of remdesivir therapy, a randomized, open-label, phase 3 trial of 397 hospitalized patients with COVID-19 demonstrated similar efficacy and safety with 5 days of treatment compared to 10 days. Among patients receiving supplemental oxygen not on mechanical ventilation, 5 days of remdesivir compared to 10 days of therapy resulted in similar rates of clinical improvement, measured by 2 points on a 7-point ordinal scale (64% v 54%) and duration of hospitalization (7 days v 8 days).(2) Reported adverse events include hepatic transaminase elevations, reduced eGFR or CrCl, nausea, constipation, and hyperglycemia.

Hydroxychloroquine
Due to lack of definitive evidence supporting efficacy of hydroxychloroquine and reports of increased risk of adverse events including QT prolongation and cardiac arrhythmias, particularly among those receiving concurrent azithromycin, hydroxychloroquine is not recommended for treatment nor prophylaxis of COVID-19. (3-9)

Lopinavir/ritonavir
Despite in vitro inhibition of the 3CL protease enzyme responsible for viral replication of SARS-CoV-2, lopinavir/ritonavir has not demonstrated efficacy against COVID-19 in randomized, controlled trials compared to standard of care. (10, 11)

Favipravir
An investigational antiviral agent with in vitro activity against SARS-CoV-2 is currently undergoing evaluation for treatment of COVID-19 following reports of limited evidence demonstrating benefit with favipravir compared to other investigational agents.(12-14) Data from randomized, controlled trials are pending trial completion.

Management of Cytokine Release Syndrome
In severe COVID-19, the cytokine release syndrome (CRS) in response to SARS-COV2 can result in lung injury and multi system organ dysfunction. The use of anti-inflammatory agent such as corticosteroids and immunomodulators may have a role in mitigating the effect of CRS. Initial retrospective cohort or case series study have reported conflicting results on benefit of using corticosteroids in novel coronaviruses (15-19). However,  a  recent preliminary unpublished analysis from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) study, a multi-center, open label trial study in the United Kingdom, has shown benefit of dexamethasone in patients with severe COVID-19 (i.e., requiring supplemental O2)  and greatest amongst those requiring mechanical ventilation at time of enrollment (20). The IDSA and NIH have recommended in their respective guidelines the utility of corticosteroids (21, 22) . The applicability of this result to transplant recipients are yet to be answered by future studies. Similarly, use of immunomodulators, such as IL-1 or IL-6 inhibitor, is not well studied in transplant recipients and should be only used in the setting of clinical trials.

Drug-Drug Interaction
Potential agents in COVID-19 may have drug-drug interactions that can increase risk for adverse events. Use of chloroquine and hydroxychloroquine with tacrolimus may increase risk for QTc prolongation. HCQ can also potentially decrease therapeutic drug level of remdesivir. Recently, the FDA has issued a warning about the concurrent use of these drugs (23). The use of protease inhibitor such as lopinavir-ritonavir, a CYP34A inhibitor, can result to marked elevation of calcineurin inhibitor and mTOR inhibitor levels. The use of this lopinavir-ritonavir, in addition to drug-drug interaction, is not recommended due to its lack of clinical efficacy(10). 

A useful resource for drug-drug interactions can be found online at: https://www.covid19-druginteractions.org. This website includes an interaction checker to reliably detect interactions.

References

1. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020.
2. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020.
3. Mahevas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844.
4. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020:2020.03.22.20040758.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Statement from chief investigators of the randomized evaluation of COVID-19 therapy (RECOVERY) trial on lopinavir-ritonavir [press release]. 29 June 2020 2020.
12. Coomes EA, Haghbayan H. Favipiravir, an antiviral for COVID-19? J Antimicrob Chemother. 2020;75(7):2013-4.
13. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020.
14. Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, et al. Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection. J Infect Dis. 2020;221(10):1688-98.
15. Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, Chiu RW, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31(4):304-9.
16. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343.
17. Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67.
18. WHO. Country & Technical Guidance - Coronavirus disease (COVID-19). 2020.
19. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020.
20. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. 2020:2020.06.22.20137273.
21. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19  [Available from: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/.
22. NIH COVID-19 Treatment Guidelines  [June 25,2020:[Available from: https://www.covid19treatmentguidelines.nih.gov/whats-new/.
23. FDA. Remdesivir by Gilead Sciences: FDA Warns of Newly Discovered Potential Drug Interaction That May Reduce Effectiveness of Treatment FDA.gov [Available from: https://www.fda.gov/safety/medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-interaction-may-reduce.

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: 5 January 2021

KEY POINTS

• Transplant recipients may be vaccinated with any of the COVID-19 vaccines (except LAV and VVr vaccines), as soon as they become approved and available.
• All transplant recipients should receive the vaccine, irrespective of past COVID-19 infection or positive SARS CoV-2 antibodies. Case reports of reinfection in immunocompromised patients suggest that protection after a first infection is inadequate or wanes over time.
• For SOT recipients, the ideal timing of vaccination is uncertain in the post-transplantation setting. Vaccination should be delayed at least one month from transplant surgery. A risk-benefit assessment should weigh the community transmission risks against the likelihood of side effects.
• 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.
• SOT and HSCT candidates should also receive the COVID-19 vaccine. The concomitant administration of COVID-19 vaccines with other vaccines has not been studied. A few national guidelines advise separating them from other vaccines by at least 2 weeks.  It is not yet known if antibodies persist post-transplant or if revaccination is required.  
• Transplant recipients are at risk of poor outcomes with COVID-19. Ideally, they should be prioritized for early vaccination, as allowable by local health authorities.
• Consider prioritizing household contacts of transplant recipients with recipients as transmission rates within households have been shown to be high.
• Note: The response to most vaccines are less robust in transplant recipients, compared with healthy persons. Recent use of T- and B-cell-depleting agents have also been associated with muted immune responses to vaccination. 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

According to the WHO update of Dec 22, 2020 on the development of COVID-19 vaccines, there are 172 vaccine candidates in pre-clinical development and 61 vaccines in clinical studies (1).

So far, 10 different platforms have been used in the development of these vaccines: 1) protein subunit (PS); 2) inactivated virus (IV); 3) non-replicating viral vector (VVnr); 4) RNA; 5) DNA; 6) virus-like particle (VLP); 7) replicating viral vector (VVr); 8) live attenuated virus (LAV); 9) VVnr + antigen-presenting cell (APC); and 10) VVr + APC. The first 5 platforms represent 84% of the vaccine candidates in clinical phase of development (1). Currently, 14 developers have COVID-19 vaccines in phase 3 studies, as shown in Table 1.

Among the vaccines in phase 3 studies, 6 have been authorized in several countries for emergency use (Pfizer/ BioNTech, Moderna, Gamaleya, Sinovac, Sinopharm, AstraZeneca/Oxford) and have started to be administered to health professionals and the elderly in Europe, the Americas, the Eastern Mediterranean region and Singapore. In the healthy population, projected clinical efficacy based on phase 2 and phase 3 studies varies from more than 50% to 95% (2-5).

Despite the achievements in such a short time, many questions remain unanswered, such as the titers of neutralizing antibodies for a COVID-19 vaccine to protect humans, the duration of vaccine-induced immunity, the possibility of occurrence of antibody-dependent enhancement (ADE) phenomenon, antibody responses in transplant recipients, among others. These and other queries that may arise with the expanded use of the COVID-19 vaccines will likely be clarified over time.

Table 1. Summary of phase 3 COVID-19 vaccines’ information.

Developers	Vaccine platform/type	No. of doses	Schedule days	Route
Sinovac	Inactivated	2	0, 14	IM
Wuhan Institute of Biological Products/ Sinopharm	Inactivated	2	0, 21	IM
Beijing Institute of Biological Products/ Sinopharm	Inactivated	2	0, 21	IM
Bharat Biotech	Inactivated	2	0, 28	IM
Institute of Medical Biology and Chinese Academy of Medical Sciences	Inactivated	2	0, 28	IM
University of Oxford/ AstraZeneca	VVnr/ChAdOx1-S	2	0, 28	IM
CanSino Biological Inc/Beijing Institute of Biotechnology	VVnr/Ad type 5	1	-	IM
Gamaleya Research Institute	VVnr/rAd26-S + rAd5-S	2	0, 21	IM
Janssen Pharmaceutical Companies	VVnr/Ad type 26	2	0, 56	IM
Moderna/NIAID	RNA/LNP encapsulated mRNA	2	0, 28	IM
BioNTech/Fosun Pharma/Pfizer	RNA/LNP encapsulated mRNA	2	0, 28	IM
CureVac AG	RNA/CVnCoV Vaccine	2	0, 28	IM
Novavax	Protein subunit/SARS CoV-2 rS – Matrix M1 adjuvant	2	0, 21	IM
Anhui Zhifei Longcom Biopharmaceutica, Chinese Academy of Sciences	Protein subunit/ recombinant SARS CoV-2 vaccine (CHO cells)	3	0, 28, 56	IM

COVID-19 vaccines in transplant recipients

While prioritization of vaccine is generally determined by the federal, state and local health authorities, transplant recipients should be included in groups for earlier vaccination due to the risk for severe COVID-19. Immunocompromised patients, including transplant recipients, have not been included in studies performed to date.  As such, transplant recipients should be counseled that the effectiveness and safety profile of these vaccines for them are not currently known. As these are not live virus vaccines, it is unlikely that these vaccines would pose additional risks, Transplant recipients may have decreased vaccine responses compared to the general population, and thus should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination, including continuing to use masks, focus on hand hygiene and social distancing. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when available to them to protect the patient.

Inactivated vaccines, protein subunit recombinant or virus-like vaccines are considered safe to be administered to transplant populations. Particle vaccines have been used for decades in transplant vaccination programs (e.g., influenza, hepatitis B and HPV vaccines). RNA vaccines (BioNTech/Pfizer, Moderna) and non-replicating viral vector vaccines (Oxford/AstraZeneca, Gamaleya) are also considered safe vaccines, but have never been used in the transplant scenario. Vigilance will be necessary to determine if the induced protective immunity is not associated with an increased risk for rejection episodes or the development of graft versus host disease (GVHD).

Live attenuated vaccines are generally contraindicated in SOT recipients and may be used with restrictions in HSCT recipients. Replicating viral vector vaccines are not recommended in transplant populations at this moment.

References:

1. Organization WH. Draft landscape of COVID-19 candidate vaccines.  2020; Available from: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
2. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2020.
3. Logunov DY, Dolzhikova IV, Zubkova OV, Tukhvatullin AI, Shcheblyakov DV, Dzharullaeva AS 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.
4. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK 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 2020.
5. Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K 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.

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