COVID-19 and Liver Transplants are mutually exclusive – Fact or Fiction?
COVID-19 has fundamentally altered clinical practices and guidelines. This also applies to liver transplantation. In the UK, liver transplant activity has dramatically decreased during the early months of the pandemic. The traditional logic dictates that transplantation-related immunosuppression increases the risk of COVID-19 infection and entails sub-par clinical outcomes. However, theories remain theories without clinical evidence. This article examines whether such concerns justify reducing liver transplant activity. It first gives a global picture of liver transplantation during the pandemic. It then discusses whether COVID-19 in patients having received liver transplantation contributes to sub-par clinical outcomes in four aspects: (a) mortality rates, (b) likelihood of contracting more severe disease, (c) graft efficacy and need for re-transplantation, and (d) change in immunosuppression regimen. The article argues that preliminary data positively support up-regulating liver transplant activity to pre-pandemic levels, subjected to issues in healthcare resource allocation. It also proffers future research directions, including validation of results in non-white cohorts and correlations between COVID-19 and acute complications of liver transplantation.
It has been a challenging year. Ever since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first discovered in Wuhan, China in December 2019 , major changes have been introduced to healthcare provision, public health policies and academic medicine. Most importantly, the coronavirus disease outbreak 2019 (COVID-19) brought modifications to existing paradigms of treatment which, although logical on face, should ultimately be reviewed and reflected in light of the emergence of new clinical evidence. This cannot be more veritable in organ transplantation. Transplant services are slashed at the start of the pandemic. For instance, the Birmingham Liver Unit (UK) temporarily suspended all liver transplant (LT) activity, except for extremely urgent cases, on 27 March 2020. The criteria for emergency surgery reverted from the ‘treatment benefit’ paradigm to an individualised risk assessment approach.  Decisions can be attributed to logistical challenges and the belief that transplant recipients, owing to their immunocompromised status, are more likely to contract COVID-19. They may also experience higher risks of graft failure, re-transplantation and mortality rates. However, theories remain theories unless clinically proven. This article aims to, firstly, give a general picture of LT activity during COVID-19 so far. Secondly, it sets a number of criteria central to answering whether LT should be performed on recipients due to presumed sub-par clinical outcomes attributable to COVID-19 infection. Thirdly, it explores whether findings from current research can answer them adequately and outlines future research directions.
Figure 1: Possible indications of liver transplantation. (a) liver cirrhosis of any aetiology, including autoimmune hepatitis and drug-induced hepatotoxicity; (b) hepatocellular carcinoma (Barcelona Clinic Liver Cancer Stage A; and eligible under Milan Criteria only); (c) chronic Hepatitis B infection; (d) chronic Hepatitis C infection; (e) metabolic-associated fatty liver disease (MAFLD). (Created with Biorender.com)
PubMed and ScienceDirect (Elsevier) are searched for relevant scientific literature. Key words employed include ‘liver transplant’, ‘liver transplantation’, ‘transplantation’, ‘COVID-19’, ‘SARS-CoV-2’, ‘mortality’, ‘hospitalisation’, ‘mechanical ventilation’, ‘graft injury’ and ‘immunosuppression’. Only articles written in English or feature English abstracts are considered. The selection of references depends on their relevance to the topic. A narrative review is used in this context. Due to the lack of comparator groups and the heterogeneity of data, a meta-analysis is deemed inappropriate.
Global Transplantation Activity during COVID-19
Countries worldwide adopted different ways in response to COVID-19. This includes policies and guidelines regarding LT. In the United States, weekly rates of deceased donor and living donor LTs performed from January to March 2020 (where March marks the peak of the pandemic) decreased dramatically.  Such figures rose back to pre-pandemic levels since June. However, strict policies are in place to ensure donor and recipient safety, as well as improvement in clinical outcomes. This includes routine evaluation of donor history and rapid COVID-19 testing, accompanied by the implementation of organ refusal codes established by the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN). These codes recognise donor and recipient risk factors and the ability for medical centres to perform transplants safely. They are postulated to be the root cause of decreased transplantations during the pandemic. Transplant wait-list registrants inactivated by COVID-19 make up approximately 5% of the US waiting list.
A similar phenomenon is observed in the United Kingdom. Compared to the same period in 2019, the number of deceased donors decreased by 66%. The number of deceased donor transplants suffered a similar decrease, at 68%. The number of referrals of potential donors also decreased by 39%.  This took place despite the increased all-cause mortality rate in the UK during the height of the COVID-19 lockdown. This should be interpreted in light of that livers procured from patients having died of COVID-19 are ineligible for transplantation. Due to logistical challenges, the maximum age for donation after brain death was decreased from 85 years to 60 years at the start of lockdown. All donors are, similar to the US, required to have a negative COVID-19 test result. Due to the decrease in free ICU bedspace and available healthcare staff, transplant priority is given to those on ‘super urgent’ liver and heart transplantation lists.
The Anglo-American experience have painted a seemingly logical picture. Due to the onset of a serious infectious disease, more patients require intensive care. There would also be greater pressure exerted on the healthcare system if as many transplants as yester-year were executed due to the need to screen for COVID-19. Patients receiving LT are also more likely to have pre-operative comorbidities such as diabetes mellitus due to the presence of chronic liver conditions.  Coupled with immunosuppressive therapy, transplant recipients are expected to experience greater risk of post-operative mortality, such as via opportunistic infections. Quality of life measures might be improved by offering non-urgent patients a longer period of bridging therapy in light of transplant deferrals, such as radiofrequency ablation or the administration of hepatoprotective agents for in-Milan (the patient satisfies the requirements in the Milan Criteria for receiving a transplanted liver) patients with hepatocellular carcinoma. However, the Anglo-American model is not necessarily followed elsewhere. In Germany, despite the increase in COVID-19 cases in Europe over the same time-period, transplantation remained robust. The number of deceased donor LTs even increased from January to April.  South Korea, despite having the second-highest number of COVID-19 cases amongst member states of the Asian Society of Transplantation, kept most transplantation programmes active. 1,040 transplants were carried out in January-March 2020 (height of pandemic in Asia), comparable to 2018 pre-pandemic figures. [7, 8]
Figure 2: Causes of increased transaminase levels in patients infected with SARS-CoV-2. Such causes include hepatotoxicity resultant from the drugs used in treating COVID-19, SARS-CoV-2 hepatic invasion and direct cytopathy, systemic inflammation in severe COVID-19, and COVID-19-associated myopathy. (Created with Biorender.com)
However, due to the recent emergence of new COVID-19 variants in the UK, Brazil, and South Africa,  the entire LT scene remains uncertain. One of the major challenges is the increase in hospital admissions and severe COVID-19 cases, leading to the imposition of a strain on healthcare resource allocation. This second COVID-19 wave has prompted the transfer of intensive-care patients to hospitals in other parts of the country due to the limited availability of beds and related care resources in their original hospitals.  As LT patients require a substantial amount of healthcare support, not less due to the vulnerability incurred by immunosuppression, and regular monitoring of surgical and post-operative complications, their needs are incompatible with what the NHS could give. Moreover, as patients with chronic liver diseases are more likely to experience severe COVID-19 and death than the general COVID-19 patient population,  shielding is recommended. They are advised against visiting clinical settings where there is greater likelihood of contracting infections.
Liver Transplant, COVID-19 and Recipient Outcomes
This prompts the question of whether LT activity should be reduced at all during the pandemic, provided that healthcare resources could be better allocated. One way of answering this is to judge whether LT patients are more likely to suffer from sub-par clinical outcomes owing to COVID-19. Four factors are considered imperative: (a) mortality rates, (b) likelihood of contracting more severe disease, (c) COVID-19-induced reduction in graft efficacy (i.e. liver injury) and need of re-transplantation, and (d) change in immunosuppression regimen. Five multi-centre, large-scale studies were carried out to investigate the outcomes and epidemiology of LT patients infected with COVID-19: (1) Nationwide study in Spain (Spanish Study);  (2) Multi-centre Study utilising COVID-Hep and SECURE-Cirrhosis registries (Oxford Study);  (3) COLD Consortium in the US (US Study);  (4) French SOT COVID study (French Study);  and (5) an international, multi-centre study in Europe (European study).  The studies are comparable due to similar methodologies and LT cohort sizes. This article examines how they have addressed the aforementioned factors and what more can be done.
Figure 3: The four important issues concerning post-liver transplant patients infected with SARS-CoV-2: (a) mortality rate, (b) rate of severe COVID-19, (c) possible liver injury and the risk of re-transplantation, and (d) changes in immunosuppression regimen. (Created with Biorender.com)
(a) Mortality Rates
Contrary to common intuition, current evidence indicates that LT patients with COVID-19 experience lower mortality rates than their non-LT counterparts. In the Spanish Study, the mortality rate was 18% with a median interval from hospital admission of 7 days. This might seem higher than the overall mortality rate of 14.8%, but the discrepancy was attributable to that LT patients were older (65.34 10.96 years). After age and gender adjustment, the number of observed deaths in the LT cohort was slightly lower than that of expected deaths (standardised mortality ratio: 95.55; 95% CI: 94.25-96.85). The US Study displayed a slightly higher statistic, at 22.3% (n=25). The Oxford Study found 19% (n=28) LT patients died, relative to 27% (n=167) in the non-LT cohort. The association was statistically significant (p=0.046). LT also did not significantly increase the risk of death in patients with COVID-19 infection (absolute risk difference: 1.4% [95% CI -7.7 to 10.4]). In the French Study, the general 30-day mortality rate was 20.0%, where the rate was higher among hospitalised patients (28.1%). In the European Study, the fatality rate was estimated at 12% (95% CI: 5-24%), while the rate was higher again in hospitalised patients (17%, 95% CI: 7-32%).
(b) Likelihood of contracting more severe disease
LT is associated with more severe form of COVID-19. This issue can be evaluated from three angles: hospitalisation, ICU admission, and use of mechanical ventilation. In the Spanish Study, severe COVID-19 was defined as needing mechanical ventilation, admission to ICU, and/or death. 86.5% of the cohort were hospitalised (n=96) and 31.5% (n=35) met the criteria for severe COVID-19. 39.6% experienced respiratory insufficiency (n=44) and 19.8% (n=22) required respiratory support after a median of 5 days from admission. 8.1% (n=9) of the entire cohort received invasive ventilation. 10.8% (n=12) were admitted to ICU.
In the Oxford Study, risk differences were assessed between the LT and non-LT cohorts. The LT cohort experienced higher risk in all parameters characteristic of severe disease (hospitalisation, requirement for intensive care, ICU admission, invasive ventilation) except death. However, the differences in hospitalisation and requirement for intensive care were not significant, since the 95% confidence intervals (CI) were not entirely positive (hospitalisation: + 6.5% [-1.1 to 12.9]; requirement for intensive care: + 1.6% [-10.3 to 8.6]). 82% (n=124) of the LT cohort were hospitalised. 28% (n=43) were admitted to the ICU and 20% (n=30) received invasive ventilation.
In the US Study, 72.3% (n=81) were hospitalised and 37.0% (n=30) were admitted to the ICU. 23.2% (n=26) were placed on mechanical ventilation.
In the French Study, 73.6% (n=67) were hospitalised, and 18.7% (n=17) were given mechanical ventilation. This study used a composite endpoint of severe disease defined as the cumulative incidence of ICU admission, mechanical ventilation, or death. The cumulative incidence of the endpoint up to the 30th day is 33.0% (95% CI: 22.6-42.0%) in the entire cohort. It is significantly higher in hospitalised patients (44.8%, 95% CI: 31.5-55.5%).
In the European Study, 65% (n=37) were hospitalised. However, only 7% (n=4) of all patients were admitted to the ICU, similar to the rate in the Spanish Study. Moreover, 14% (n=8) of all patients received non-invasive ventilation, with 7% (n=4) having received invasive ventilation.
All five studies exhibited high proportions of hospitalisation in LT patients, with the difference across the studies being 21.5%. In terms of ICU admission, the rates shown in the Spanish and European studies were significantly different from those obtained from the other studies. Actual ICU admission and hospitalisation do not necessarily reflect disease severity due to differences in local protocols and potential referral bias owing to LT status. Moreover, the sample sizes are significantly smaller than traditional epidemiological cohorts (since liver transplants are not as frequently performed as other surgical procedures). They should thus be interpreted with caution. Proportions of LT patients having received mechanical ventilation are similar across the cited studies. A possible error is the difference in the use of terms. Since the Oxford Study used the term ‘invasive ventilation’ instead of ‘mechanical ventilation’, there would be a difference in percentages if the Study did not construe the two as synonymous.
All in all, LT patients are more likely to contract more severe disease than their non-LT counterparts.
(c) Graft Efficacy and Need for Re-transplantation
The Spanish Study showed 2.7% (n=3) developed liver graft dysfunction. None, however, suffered from graft loss. In the French study, no one suffered from graft loss as well. This was not a studied outcome in the Oxford Study and the European study. The US Study found 34.6% of the LT cohort had liver injury during COVID-19 infection, significantly lower than non-LT patients with chronic liver disease (47.5%). A predominantly hepatocellular pattern was shown, with statistically-significant increases from baseline in peak levels of AST (median, 19 vs 41 IU/L; p<0.001), ALT (median, 23 vs 32 IU/L; p<0.001) and ALP (median, 100 vs 120 IU/L, p=0.007). Bilirubin increased slightly (median, 0.6 vs 0.7, p=0.03) and albumin (indicative of hepatic synthetic function) decreased significantly (3.7 vs 2.8; p<0.001). In a small sub-study of LT patients with clinical resolution of COVID-19, levels of AST, ALT and ALP were significantly decreased. All parameters were, nonetheless, still higher than baseline. This raises concerns as to whether COVID-19 has caused irreversible hepatocellular damage and weakened the efficacy of the graft. A longer follow-up period for such patients is required to see if liver function can ever return to normal. If yes, a median period should be sought. Given the scarceness of donated livers during the pandemic, as well as logistical constraints, any decision to implement re-transplantation must be taken after thorough consideration. This also supports the idea that alternative medical therapy for non-urgent cases can be more efficacious in the long-term than liver transplantation, especially for those anchoring higher propensities in COVID-19 infection (e.g. positive diabetic status).
More studies are required to elucidate the mechanisms of liver injury in COVID-19 patients. Three mechanisms are proposed to date: (1) direct viral infection, (2) drug-induced hepatotoxicity, and (3) immunological injury.  It is likely that they intersect rather than act independently. Mechanism (1) is fraught with doubts. Although SARS-CoV-2 is detected in the liver, the viral load is low where viral inclusions are not observed.  Moreover, ACE2, a receptor for the spike protein of SARS-CoV-2, is expressed in much lower levels in the liver.  If mechanisms (2) and (3) do account for greater extent of liver injury, as confirmed in studies featuring larger cohorts, future research should stress more on drug combinations used for COVID-19 and post-LT immunosuppression regimens respectively, as well as possible interactions between them. In light of the prevalence of COVID-19, pandemic-related liver injury is not likely to disappear soon. Clinical trials should be performed on experimentally-promising hepato-protective drugs like glycyrrhizin, curcumin and resveratrol.  Ursodeoxycholic acid, with proven efficacy in primary biliary cholangitis, also demonstrates hepatoprotective effects.  Randomised controlled trials are required to assess its applicability in LT patients regardless of prior aetiology.
(d) Change in Immunosuppression Regimen
One important issue is whether the use of immunosuppressants in LT patients can modulate the outcomes of COVID-19 infection. Patients receive induction and maintenance immunosuppression after LT. Induction prevents acute cellular injury within the first few months of transplantation. Corticosteroids are the mainstay of treatment, accompanied by at least one more immunosuppressant. Research in antibodies such as tocilizumab (IL-6 inhibitor) is promising.  Maintenance is achieved through a triple regimen comprising tacrolimus, azathioprine and prednisolone. Mycophenolate mofetil, an anti-metabolite, can be used to reduce the use of steroids. Within 3-6 months, single or double therapy is used instead, with a calcineurin inhibitor (e.g. tacrolimus, cyclosporin A) being the fundamental component. 
Notwithstanding the traditional thinking that immunosuppression leads to higher risk of contracting COVID-19 thus contributing to higher mortality, intensive immunosuppression was found to significantly reduce COVID-19-related hospital mortality by 65% and invasive mechanical ventilation by 71%.  Immunosuppression can decrease the magnitude of harm resultant from the hyperinflammatory state observed in severe COVID-19. A research gap exists regarding the effects of different immunosuppressant regimens in reducing the incidence of severe COVID-19 and associated mortality. Moreover, there are also worries that suppressed immunity during the disease course leads to impaired viral clearance and worsened long-term outcomes.
In the Spanish Study, univariate analyses showed that tacrolimus and cyclosporine were non-significantly associated with lower risk of severe COVID-19 in hospitalised LT patients (RR: 0.54 (95% CI: 0.29-1.07), p=0.079 vs 0.76 (95% CI: 0.18-3.22), p=0.708). Corticosteroids were non-significantly associated with higher risk (RR: 1.53 (95% CI: 0.72-3.22), p=0.262). Mycophenolate mofetil use was significantly associated with the highest risk of severe COVID-19 (Univariate analysis- RR: 2.62 (95% CI: 1.25-5.49), p=0.011; Multivariate analysis- RR: 3.94 (95% CI: 1.59-9.74), p=0.003). Kaplan-Meier curves showed its negative prognostic impact, especially at doses higher than 1,000 mg/day. Significantly less time was required to reach severe COVID-19 in patients receiving higher doses.
A different picture is seen in the Oxford Study. Calcineurin inhibitor use was non-significantly associated with higher risk of death in LT patients (Univariable analysis- OR: 1.67 (95% CI: 0.36-7.81), p=0.515; Multivariable analysis- OR: 3.73 (95% CI: 0.26-52.41), p=0.329). Anti-metabolite use in general (not specific to mycophenolate mofetil) was associated with non-significantly lower risk instead (Univariable analysis- OR: 0.74 (95% CI: 0.32-1.69), p=0.472; Multivariable analysis- OR: 0.68 (95% CI: 0.23-2.01), p=0.484). Prednisolone use showed conflicting trends. It was associated with lower risk in the univariable analysis, but higher risk in the multivariable analysis (Univariable analysis- OR: 0.77 (95% CI: 0.34-1.79), p=0.549; Multivariable analysis- OR: 1.74 (95% CI: 0.55-5.50), p=0.345). Having said so, both associations were statistically insignificant.
In the US Study, no correlation between liver injury and immunosuppressant use was statistically significant. In univariate analysis, tacrolimus, mycophenolate mofetil and prednisolone (low dose) were all non-significantly associated with higher risk of mortality in the LT cohort (OR: 3.45 (95% CI: 0.39-29.47), p=0.424 vs OR: 1.73 (95% CI: 0.66-4.51), p=0.337 vs OR: 1.41 (95% CI: 0.50-3.96), p=0.592). Cyclosporine A was the only immunosuppressant to illustrate a lower risk (OR: 0.75 (95% CI: 0.67-0.84), p=0.332), albeit statistically insignificant.
In the French Study, mTOR inhibitors and steroids were associated with higher risk of severe disease (using the composite endpoint; respective HRs: 1.23, 95% CI: 0.51-2.99; 1.46, 95% CI: 0.63-3.36). Moreover, calcineurin inhibitors were associated with lower risk (HR: 0.74, 95% CI: 0.31-1.81). Mycophenolate mofetil showed no effect (HR: 1.00, 95% CI: 0.50-1.99) on the likelihood of more severe disease. The data for azathioprine was too scarce to allow any meaningful conclusions to be drawn. Having said so, all studied correlations were not statistically significant.
In the European study, the data regarding immunosuppression were presented in a different manner. Overall speaking, 39% (n=22) of the cohort experienced a reduction in immunosuppression, while 7% (n=4), discontinuation. The most patients received calcineurin inhibitors for baseline immunosuppression (including both monotherapy and dual therapy with mycophenolate mofetil). Most patients receiving calcineurin inhibitors (75%) also exhibited no modification in their immunosuppression regimen throughout the disease course. No regression analyses were performed to assess the associations between changes in immunosuppression and patient outcomes. Interestingly, more patients who survived had reduced their degree of immunosuppression (40% vs 29%). More hospitalised patients had their immunosuppressive dose reduced (44% vs 25%), possibly due to more regular monitoring by healthcare professionals. Patients with ARDS and those without have similar rates of immunosuppression reduction (36% vs 39%). The cohort who discontinued immunosuppression was too small to draw any definite conclusions.
The vast variations in the studies should be noted. This can be ascribed to the differing correlations analysed (immunosuppressant use and mortality vs immunosuppressant use and severe COVID-19). It can also be due to small cohort sizes which are capable of producing statistical aberrances. The fact that different immunosuppressants strike different associations can be attributed to their effects on (1) the virus, and (2) immunity. Calcineurin inhibitors are found to reduce viral replication in patients afflicted by COVID-19.  This dispels fears that suppressed immunity automatically translates to aggravated viral accumulation. The clinical utility of calcineurin inhibitors against COVID-19 can be inferred to be recognised by medical practitioners. In the European Study,  most patients on calcineurin inhibitors experienced no modification of their immunosuppressive regimens. The same effect can be seen for mycophenolate mofetil. However, the observed cytopathic effect of SARS-CoV-2 is not affected.  Mycophenolate mofetil operates via a different mechanism to calcineurin inhibitors. Instead of inhibiting IL-2 metabolism through blocking cellular signalling, it inhibits the production of guanosine monophosphate (GMP) by blocking inosine-5’-monophosphate dehydrogenase (IMPDH). The fact that purine metabolism is especially important to lymphocytes explains its potent effect in down-regulating lymphocytic proliferation. 
Since individual drugs do not contribute to statistically-significant associations, future research should focus on drug combinations which can result in the best clinical outcomes for LT patients with COVID-19.
Figure 4: The mechanism of action of cyclosporine A, a calcineurin inhibitor which inhibits T-cell function. NFAT = Nuclear factor of activated T-cells. (Created with Biorender.com)
Table 1: Clinical characteristics and outcomes of adult, post-liver transplant patients with COVID-19 reported by selected studies.
Data are either presented as median (inter-quartile range) or n (%). All figures are rounded to the nearest integer. Non-transplant comparison cohorts are not included in this table. Colmenero et al (2020), and Dumortier et al (2020) calculated a composite end-point (admission to ICU, mechanical ventilation, and death) to indicate severe disease. Becchetti et al (2020) is a multicentre, prospective study recruiting patients from 19 secondary and tertiary liver transplant centres across Europe, with Inselspital, University Hospital of Berne being the coordinating centre. Only patients older than 18 years of age are included. ICU = intensive care unit; N/A = not reported or not applicable; the duration of hospital stay was calculated on the premise that the patients were eventually discharged from in-patient care. Immunosuppression regimen changes are not recorded here due to the variations in which they were reported by the cited studies.
From the five studies, although more LT patients experienced severe forms of COVID-19, mortality rates were significantly lower than non-LT patients. Preliminary data support the idea of maintaining pre-pandemic levels of liver transplantation, provided that safety measures such as social distancing are complied. Due to the emergence of new COVID-19 infection waves, corresponding pressure has been applied to healthcare resources. Although COVID-19 infection is not strong enough a reason to avoid an otherwise important surgical procedure, where they are not mutually exclusive, better health administration strategies need to be synthesised for striking a cleaner balance between the interests of patients with severe COVID-19, and the welfare of patients with chronic diseases. Results regarding graft injury and the need for re-transplantation, as well as immunosuppressant regimens, should be interpreted with caution. More large-scale studies should be performed to confirm related findings.
In addition, it is glib to suggest that all answers are acquired. Needless to say, challenges remain. Livers from patients with COVID-19 are ineligible for transplantation which exacerbates organ scarcity. Research can be done to determine whether such organs are, by default, ineligible, and whether clinical evidence of COVID-19 resolution is sufficient to render it otherwise. Patient fear is also significant. Rees and colleagues described the significance of COVID-19-related fear in patient refusal of receiving routine medical care.  It may also explain why the numbers of transplants performed and living donors identified decreased relative to pre-pandemic levels in the UK.
More studies are also required to see if the findings here are reproducible in non-white cohorts, since all three studies utilised databases from majority-white nations. Current data suggest Blacks and Asians are more likely than their white counterparts to contract COVID-19. Asian ethnicity is also associated with ICU admission and death.  The control, non-LT cohort in the Oxford Study is recruited from Oxford, England solely, even though the LT cohort is gathered from multiple centres. Moreover, such large-scale studies should be performed in countries with higher burden of Hepatitis B, which also experience higher prevalence of hepatocellular carcinoma. For example, China had a pooled estimated prevalence of Hepatitis B infection of 6.89% (95% CI:5.84–7.95%) from 2013-2017.  Liver transplant is expected to be more robust and/or necessary by indication.
Furthermore, studies are required to illustrate the association between COVID-19 and acute complications of LT. All three studies feature long median transplant-to-infection times (Spanish Study: 8.75 (IQR 2.92-14) vs Oxford Study: 5.00 (IQR 2-11) vs US Study: 4.00 (IQR 11) years). It is still unknown whether COVID-19 modifies the risks of hepatic artery and portal vein thrombosis, post-transplant bleeding and biliary stenosis.
1. Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020;395(10223):507-513. doi:10.1016/s0140-6736(20)30211-7.
2. Lembach H, Hann A, McKay S et al. Resuming liver transplantation amid the COVID-19 pandemic. The Lancet Gastroenterology & Hepatology. 2020;5(8):725-726. doi:10.1016/s2468-1253(20)30187-4.
3. Merola J, Schilsky M, Mulligan D. The Impact of COVID‐19 on Organ Donation, Procurement, and Liver Transplantation in the United States. Hepatol Commun. 2020. doi:10.1002/hep4.1620.
4. Manara A, Mumford L, Callaghan C, Ravanan R, Gardiner D. Donation and transplantation activity in the UK during the COVID-19 lockdown. The Lancet. 2020;396(10249):465-466. doi:10.1016/s0140-6736(20)31692-5.
5. Haydon G, Neuberger J. Liver transplantation in cirrhotic patients with diabetes mellitus. Liver Transplantation. 2001;7(3):234-237. doi:10.1053/jlts.2001.22329.
6. Qu Z, Oedingen C, Bartling T, Schrem H, Krauth C. Organ procurement and transplantation in Germany during the COVID-19 pandemic. The Lancet. 2020;396(10260):1395. doi:10.1016/s0140-6736(20)32213-3.
7. Kee T, Jeong J, Ha J et al. Transplantation in Asia during the coronavirus disease-19 (COVID-19) pandemic: briefs from member countries of the Asian Society of Transplantation. Korean Journal of Transplantation. 2020;34(2):71-77. doi:10.4285/kjt.2020.34.2.71.
8. Cho W. Organ donation in Korea in 2018 and an introduction of the Korea national organ donation system. Korean Journal of Transplantation. 2019;33(4):83. doi:10.4285/jkstn.2019.33.4.83.
9. Darby A, Hiscox J. Covid-19: variants and vaccination. BMJ. 2021:n771. doi:10.1136/bmj.n771
10. Hutchinson S. Covid: Intensive-care patients moved hundreds of miles. BBC News. https://www.bbc.co.uk/news/health-56483444. Published 2021. Accessed March 25, 2021.
11. Marjot T, Moon AM, Cook JA, et al. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study. J Hepatol. 2021;74(3):567-577. doi:10.1016/j.jhep.2020.09.024.
12. Colmenero J, Rodríguez-Perálvarez M, Salcedo M et al. Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients. J Hepatol. 2020;74(1):148-155. doi:10.1016/j.jhep.2020.07.040.
13. Webb G, Marjot T, Cook J et al. Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study. The Lancet Gastroenterology & Hepatology. 2020;5(11):1008-1016. doi:10.1016/s2468-1253(20)30271-5.
14. Rabiee A, Sadowski B, Adeniji N et al. Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID‐19): U.S. Multicenter Experience. Hepatology. 2020;72(6):1900-1911. doi:10.1002/hep.31574.
15. Dumortier J, Duvoux C, Roux O et al. Covid-19 in liver transplant recipients: the French SOT COVID registry. Clin Res Hepatol Gastroenterol. 2021;45(4):101639. doi:10.1016/j.clinre.2021.101639.
16. Becchetti C, Zambelli M, Pasulo L et al. COVID-19 in an international European liver transplant recipient cohort. Gut. 2020;69(10):1832-1840. doi:10.1136/gutjnl-2020-321923.
17. Zhang C, Shi L, Wang F. Liver injury in COVID-19: management and challenges. The Lancet Gastroenterology & Hepatology. 2020;5(5):428-430. doi:10.1016/s2468-1253(20)30057-1.
18. Chau TN, Lee KC, Yao H et al. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology. 2004; 39: 302-310.
19. Pirola C, Sookoian S. COVID-19 and ACE2 in the Liver and Gastrointestinal Tract: Putative Biological Explanations of Sexual Dimorphism. Gastroenterology. 2020;159(4):1620-1621. doi:10.1053/j.gastro.2020.04.050.
20. Muriel P, Rivera-Espinoza Y. Beneficial drugs for liver diseases. J Appl Toxicol. 2008;28(2):93-103. doi:10.1002/jat.1310.
21. Kim D, Yoon S, Ji S et al. Ursodeoxycholic acid improves liver function via phenylalanine/tyrosine pathway and microbiome remodelling in patients with liver dysfunction. Sci Rep. 2018;8(1). doi:10.1038/s41598-018-30349-1
22. Moini M, Schilsky ML, Tichy EM. Review on immunosuppression in liver transplantation. World J Hepatol. 2015;7(10):1355-1368. doi:10.4254/wjh.v7.i10.1355.
23. Farid S. Liver transplantation. Surgery (Oxford). 2020;38(7):389-397. doi:10.1016/j.mpsur.2020.04.011.
24. Mayor S. Intensive immunosuppression reduces deaths in covid-19-associated cytokine storm syndrome, study finds. BMJ. 2020:m2935. doi:10.1136/bmj.m2935.
25. Hage R, Schuurmans MM. Calcineurin Inhibitors and COVID-19. Reumatologia Clinica. 2020 Sep. DOI: 10.1016/j.reuma.2020.09.001.
26. Han Y, Yang L, Duan X et al. Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids. 2020. doi:10.1101/2020.05.05.079095.
27. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant. 1996 Feb;10(1 Pt 2):77-84.
28. Rees C, Rutter M, Sharp L et al. COVID-19 as a barrier to attending for gastrointestinal endoscopy: weighing up the risks. The Lancet Gastroenterology & Hepatology. 2020;5(11):960-962. doi:10.1016/s2468-1253(20)30268-5.
29. Sze S, Pan D, Nevill C et al. Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 2020;29-30:100630. doi:10.1016/j.eclinm.2020.100630.
30. Wang H, Men P, Xiao Y et al. Hepatitis B infection in the general population of China: a systematic review and meta-analysis. BMC Infect Dis. 2019;19(1). doi:10.1186/s12879-019-4428-y.
Conflicts of Interest Statement: I declare no conflicting interests.
Funding Disclosure Statement: I declare no funding interests.