Low prevalence and disease severity of COVID‐19 in post‐liver transplant recipients—A single centre experience

Abstract Coronavirus disease 2019 (COVID‐19) caused by a novel coronavirus called severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) is driving a present day global pandemic. Immunosuppressed patients are regarded as a high‐risk cohort. The following is a short report on COVID‐19 in liver transplant recipients (n = 5) from a high volume UK liver transplant unit with a large follow‐up cohort (n = 4500). Based on this limited data, liver transplant recipients appear to have a low incidence of COVID‐19, with less severe symptoms than expected, when compared with the general population and other solid organ recipients. This possibly could be related to self‐isolation adherence and/or the ‘ideal’ level of immunosuppression that favourably modulates the immune response to COVID‐19.

The present report is a summary of our experience of  in post-liver transplant recipients.

| C A S E S
Our Unit follows up nearly 4500 post-liver transplant patients, of which 25% were transplanted as children. To date, only five adult patients have been identified as having COVID-19 and none have died (see Tables 1 and 2 for demographic and clinical data summary).
Two of these patients are awaiting re-transplantation (patient 1 + 2). Patient 1 is a slim man of 36 years with no significant co-morbidity who was originally transplanted for familial amyloid polyneuropathy in 2011. Development of a diffuse cholangiopathy led to him being relisted for redo liver transplant. He had been admitted for resitting of a blocked percutaneous transhepatic cholangiogram drain and during the admission developed a cough and low-grade fever. He was found to be SARS-CoV-2 RNA PCR positive on Day 15 of his inpatient stay, with chest X-ray (CXR) demonstrating some consolidation.
Otherwise, he had reasonable graft function, but was lymphopenic from hypersplenism. No changes were made in his maintenance IS which was a low-dose calcineurin inhibitor (CNI). He was managed conservatively and discharged for self isolation. Presently, he is suspended from the transplant waiting list until 2 nasopharyngeal swabs are SARS-CoV-2 RNA PCR negative. On the other hand, Patient 2, is an obese gentleman of 54 years, transplanted for Chronic Budd Chiari in 2004 with comorbidities of type 2 diabetes, high cholesterol and hypertension. Listed for retransplantation on the basis of small vessel veno-occlusive disease causing recurrent ascites. In the community, he developed symptoms of cough and fever leading to an emergency admission to his local hospital. He was found to be SARS-CoV-2 RNA PCR positive and required non-invasive ventilatory support in the form of continuous positive airway pressure. As part of his COVID-19 management, his maintenance IS was changed from mycophenolate mofetil (MMF) and prednisone, to prednisone alone at a higher dose. He is clinically improving but remains inpatient and suspended from the transplant waiting list.
In the remaining patients, three did not have typical COVID respiratory symptoms. Patient 3 (54 years, male) was 6 years post his second transplant for primary sclerosing cholangitis (PSC). He had no significant comorbidity apart from a high body mass index (BMI) and a longstanding end ileostomy for management of his ulcerative colitis. He presented with headache, vomiting, photophobia and fever, leading to the admitting differential diagnosis of meningitis vs COVID-19. Lumbar puncture and CT head were normal, CXR was clear, but he was found to be SARS-CoV-2 RNA PCR positive. He was discharged after 3 days to continue with self isolation and no changes were made in his maintenance IS of CNI, azathioprine and prednisone. In Patient 4 (23 years, male), the presenting symptoms were of chest wall pain and fever. Their background history was of

Key points
Liver transplant recipients appear to have a low incidence of COVID-19, with less severe symptoms, when compared with the general population and other solid organ recipients.
TA B L E 1 Liver transplant recipients with COVID-19 demographic, comorbidities and underlying liver disease. Data summary for individual patient (pt), including age in years (y), sex (male: M or female: F), race, body mass index (BMI), date of liver transplant (LT), indication for primary LT and for redo or for relisting  There is also emerging evidence that the severe forms of SARS resulting in death are associated with an enhanced inflammatory response and cytokine storm. 10 As a consequence, a number of clinical trials initiated for COVID-19 are targeting the immune response, such as tocilizumab, a monoclonal antibody directed against interleukin-6

| D ISCUSS I ON
to reduce cytokine levels. In a pilot study on 21 Chinese patients with severe COVID-19 pneumonia, tocilizumab was reported to improve lung function 11 and has also been demonstrated to be of benefit, in a renal transplant patient with COVID-19. 12 Ongoing randomized control trials will substantiate these observations. None the less, these preliminary observations are supportive of the view that IS may have a beneficial role in COVID-19 management, rather than per se increase the risk of COVID-19 pneumonia and death. 5,13 However, the reported COVID-19 deaths in post-liver transplant patients to date (n = 3), had low levels of IS but all had underlying comorbidities. 13 In order to understand the role of IS/immune modulation in the context of COVID-19 management, more good quality data adjusted for established COVID-19 risk factors (eg BMI, age, gender, ethnicity, co-morbidity) from the different solid organ recipient groups is needed.
By undertaking such an analysis, will establish whether high levels of IS combined with lymphocyte depletion, is allowing a high viral load to become the main driver of the inflammatory response. Thereby, explaining the observation that renal transplant recipients appear more vulnerable to COVID-19 than liver transplant recipients. 14 Fortunately, in the present series, the SARS-CoV-2 RNA PCRpositive liver transplant recipients have had in the most part mild symptoms that have not needed aggressive changes in management.
For patients with mild self-limiting symptoms we have not made any changes in IS. However, if there is clinical concern, our IS strategy is withdrawal of anti-proliferative agents (ie azathioprine, MMF) and to maintain low levels of CNIs and if need be, increase the dose of steroids. Otherwise, standard of care is as for other COVID-19 patients, that is supportive or a given therapy within a context of a clinical trial.
In general, patients with COVID-19 present with symptoms of viral pneumonia such as dry cough, fatigue, headache and high temperature that in the second week of infection can rapidly progress to respiratory failure. 3 But, COVID-19 like other viral infections can underlie atypical presentations which are of note in the immunosuppressed. 15 In the present series, a number of the liver transplant recipients had atypical symptoms, such as photophobia, headache and chest pain which is in contrast to previous reports. 5,13 Atypical presentations of COVID-19 have also been reported in elderly frail patients and in other solid organ transplant recipients. 15,16 Highlighting, that in the present era constant vigilance is needed to minimize the spread of COVID-19 in the healthcare environment between patients and healthcare providers.
In conclusion, liver transplant recipients appear to have a low incidence of COVID-19, with less severe symptoms than expected compared to the general population and other solid organ recipients, possibly related to self-isolation adherence and/or level of immune response suppression to COVID-19.

CO N FLI C T O F I NTE R E S T
None of the authors have any conflict of interest to declare.