Recovery of moderate COVID-19 disease in a liver transplant recipient on continued immunosuppression

Background The global outbreak of severe acute respiratory syndrome coronavirus 2 has had an enormous impact on the world. It remains unclear to what extent liver transplant recipients should be considered at a higher risk of severe disease due to the limited data available. Case presentation We describe a moderate course of COVID-19 in a patient who underwent a liver transplant two years earlier due to Budd-Chiari syndrome. She presented with malaise, headache, dry cough and fever for four days. Immunosuppressive therapy with tacrolimus and mycophenolate mofetil was continued throughout the course of infection, oxygen therapy was given for a single night and the patient gradually recovered with supportive care only. Conclusions With this case report, we demonstrate that liver transplantation and immunosuppression is not necessarily associated with severe COVID-19 disease and emphasize that more information on this matter is urgently required. Withdrawal of immunosuppressive therapy could be associated with a higher mortality.


Abstract Background
The global outbreak of severe acute respiratory syndrome coronavirus 2 has had an enormous impact on the world. It remains unclear to what extent liver transplant recipients should be considered at a higher risk of severe disease due to the limited data available.

Case presentation
We describe a moderate course of COVID-19 in a patient who underwent a liver transplant two years earlier due to Budd-Chiari syndrome. She presented with malaise, headache, dry cough and fever for four days. Immunosuppressive therapy with tacrolimus and mycophenolate mofetil was continued throughout the course of infection, oxygen therapy was given for a single night and the patient gradually recovered with supportive care only.

Conclusions
With this case report, we demonstrate that liver transplantation and immunosuppression is not necessarily associated with severe COVID-19 disease and emphasize that more information on this matter is urgently required. Withdrawal of immunosuppressive therapy could be associated with a higher mortality.

Background
The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), has had an enormous impact on the world. Since the beginning of the outbreak, researchers worldwide have tirelessly tried to understand the disease. However, at this point, it remains unclear to what extent liver transplant recipients should be considered at a higher risk of severe disease due to the limited availability of studies. Consequently, we describe and discuss a case of moderate COVID-19 in a liver transplant recipient in continued immunosuppressive therapy.

Case Presentation
A 58-year-old female, who had a liver transplantation two years earlier due to Budd-Chiari syndrome, was admitted to the Department of Hepatology and Gastroenterology with malaise, headache, dry cough and fever for four days. She denied other complaints. There was no recent travel history or any known exposures to SARS-CoV2. She had a medical history of hypertension, hypercholesterolemia, obesity (BMI 37.1 kg/m 2 ) and had been treated for cholangitis shortly after her liver transplantation. The patient had no alcohol abuse and was a previous smoker but stopped before transplantation. At admittance, she had been on stable immunosuppression with tacrolimus 4 mg QD and mycophenolate mofetil 500 mg BID for more than one year. Antihypertensive therapy consisted of amlodipine 5 mg and bendro umethiazide with potassium 2.5+573 mg once daily.
On admission, the patient had a temperature of 38.6 °C, the blood pressure was 129/88 mm Hg, the heart rate 90 beats per minute, the respiratory rate 12 breaths per minute and the oxygen saturation 96% on ambient air. Her physical examination was inconspicuous and subsequent biochemistry with only modest signs of COVID-19 disease with C-reactive protein 9.8 mg/L (reference range < 8), creatinine 97 µmol/L (reference range, 45-90) and alkaline phosphatase 120 U/L (reference range, 35-105).
Leukocytes were within normal ranges (reference range, 3.5-10.0). White blood cell differential was not conducted initially. Liver parameters were normal, and plasma-tacrolimus was within therapeutic range (5.1 µg/L).
A supine chest radiograph was without evident in ltrates. Urinary dipstick was normal. An oropharyngeal swab tested positive for SARS-CoV2 RNA using reverse-transcriptase-polymerase-chain-reaction (PCR) and nasopharyngeal swab was negative for in uenza. Blood cultures were negative.
Due to penicillin allergy, she was treated intravenously with meropenem 1000 milligram TID for two days.
On day 6 after onset of symptoms, the patient was clinically stable and discharged to self-isolation with continued immunosuppressive therapy without further treatment. She denied cardiopulmonary symptoms but complained of headache.
On day 11 after onset of symptoms, the patient was readmitted to the Department of Infectious Diseases complaining of increasing fever, fatigue, headache, and dyspnoea while walking on stairs. The body temperature was 38.6 °C and the oxygen saturation on ambient air 92%. Vital parameters were stable.
Chest radiograph was still without in ltrates. Sputum was culture negative and PCR negative for Mycoplasma pneumoniae and Legionella pneumophila DNA.
After three days (day 14 after onset of symptoms), the patient improved, immunosuppressive therapy was again continued, while meropenem was discontinued and the patient was sent home to selfisolation.
Fifty days after onset of symptoms, the patient expressed a high degree of symptomatic improvement although fatigue and dyspnoea when walking outdoors and doing physical activities was still present.

Discussion And Conclusions
We describe a case of moderate COVID-19 disease in a liver transplant recipient who recovered during continued immunosuppressive therapy. Additionally, this case shows that SARS-CoV2 infection in liver transplant recipients may present with a biphasic disease pattern as commonly described in COVID-19 and with clinical features similar to non-immunosuppressed individuals (1,2). Yet, in a recent report of kidney transplant-recipients with COVID-19 in New York City, fever appeared to be less common (3).
While the literature on COVID-19 is rapidly accumulating, it remains unclear whether liver transplant recipients are at higher risk of severe COVID-19 compared with non-transplant patients and the background population. Limited data suggests that COVID-19 may lead to more severe disease outcomes in liver and other solid organ transplant recipients with overall mortality rates up to 18% (3)(4)(5). However, pre-existing medical conditions associated with severe COVID-19 such as hypertension, diabetes mellitus, chronic kidney disease, cardiovascular disease, obesity among others (2), may be more prevalent in liver transplant recipients (6), potentially increasing the risk of severe COVID-19 and blurring the impact assessment of immunosuppressive treatment in on COVID-19 disease. A recent nationwide study from Denmark, still in peer-review, found organ transplantation to be a signi cant but minor predictor for hospitalization and fatal outcome in SARS-CoV-2 PCR positive patients although only adjusting for sex and age (7).
While elevated alanine aminotransferase levels, reduced platelet counts and levels of albumin has been associated with an increased mortality (2), it has not yet been clari ed whether these ndings re ect underlying liver disease, direct liver damage or immune-mediated cell-injury. Nonetheless, abnormal liver parameters seem to be frequent in COVID-19 patients (8).
Despite the presence of co-morbidity such as obesity and hypertension in our case, which is normally associated with worse outcome in COVID-19 disease, one could speculate whether her current immunosuppressive treatment actually protected her from the severe outcome. In line with those considerations, it is currently being vividly discussed whether immunosuppression may induce protection from the viral induced hyperin ammatory syndrome characterized by cytokine storms and multi-organ failure or whether chronic immunosuppression constitutes a risk factor for severe disease (3,9). It has been suggested that all patients with severe COVID-19 should be screened for hyperin ammatory biomarkers to identify subgroups of patients for whom speci c immunosuppression could improve outcome (9). For our patient, the course of disease was moderate and elaborated biomarker analysis was not conducted although that might be useful to potentially predict severe outcome (10). Preliminary data from Lombardy, Italy did not indicate an increased risk of severe COVID-19 in liver transplants in immunosuppression and reported a low mortality rate of 3% in long-term liver transplant recipients (11).
In our case story, the patient was continued in immunosuppressive therapy without any adjustments. On the contrary, among the rst case stories of SARS-CoV2 infected liver transplant recipients published, temporary withdrawal of tacrolimus and administration of methylprednisolone 40 mg/day in a patient with severe lymphopenia was the presented (12). We speculate that increased mortality rates seen among organ transplant recipients could be associated with a reduction of immunosuppressive therapy (3).
A position paper from EASL-ESCMID has recently advised against reduction of immunosuppressive therapy and suggested that reduction should be considered only under certain circumstances (13) while other societies seems more prone to reduction (14). More studies are urgently needed to determine the implications of immunosuppressive therapy on COVID-19 disease. So, for now, adjustments in immunosuppressive therapy should be carefully individualized and factors such as COIVD-19 disease severity, degree of lymphopenia, type of immunosuppressive regimen, time from transplantation and risk of acute graft rejection should be considered.
In conclusion, more evidence on COVID-19 in liver transplant patients is urgently needed to guide clinical management as these patients represent a potentially vulnerable cohort of patients. We suggest studies are conducted rapidly to determine the signi cance of immunosuppressive therapy.