key: cord-0782446-ao6ezvul
authors: Dale, Miles; Sogawa, Hiroshi; Seyedsasdat, Arman; Wolf, David C; Bodin, Roxana; Partiula, Bernard; Nog, Rajat; Latifi, Rifat; John, Devon; Veillete, Gregory; Diflo, Thomas; Nishida, Seigo
title: Successful management of COVID-19 infection in two early post-liver transplant recipients
date: 2021-03-19
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.03.010
sha: f68f6293a43e5a9b0bd8a0bd93b49f80208f6802
doc_id: 782446
cord_uid: ao6ezvul

Background Coronavirus disease 2019 (COVID-19) has affected all facets of life and continues to cripple nations. COVID-19 has taken the lives of more than 2.1 million people worldwide (23), with a global mortality rate of 2.2% (23). Current COVID-19 treatment options include supportive respiratory care, parenteral corticosteroids, and Remdesivir. Although COVID-19 is associated with increased risk of morbidity and mortality in patients with comorbidities, the vulnerability, clinical course, optimal management, and prognosis of COVID-19 infection in patients with organ transplants has not been well described in the literature (9, 13). The treatment of COVID-19 differs, based on the organ(s) transplanted (6). Preliminary data suggested that liver transplant patients with COVID-19 did not have higher mortality rates than untransplanted COVID-19 patients (2). Table 1 depicts a compiled list of current published data on COVID-19 liver transplant patients. Most of these studies included both recent and old liver transplant patients. No distinction was made for early liver transplant patients who contract COVID-19 within their post-transplant hospitalization course. This potential differentiation needs to be further explored (14). Here, we report two patients who underwent liver transplantation who acquired COVID-19 during their post-transplant recovery period in the hospital. Case Descriptions Two patients who underwent liver transplant and contracted COVID-19 in the early post-transplant period. Treated with hydroxychloroquine, methylprednisolone, tocilizumab and convalescent plasma. Description of their hospital course, including treatment and recovery. Conclusions The management of post-liver transplant patients with COVID‐19 infection is complicated. Strict exposure precaution practice following organ transplantation is highly recommended. Widespread vaccination will help with prevention, but there will continue to be patients who contract COVID-19. Therefore, continued research into appropriate treatments is still relevant and critical. A temporary dose reduction of immunosuppression and continued administration of low-dose methylprednisolone, remdesivir, monoclonal antibodies, and convalescent plasma might be helpful in the management and recovery of severe COVID-19 pneumonia in post-liver transplant patients. Future studies and experiences from post-transplant patients are warranted to better delineate the clinical features and optimal management of COVID-19 infection in liver transplant recipients.

has affected all facets of life and continues to cripple nations. COVID-19 has taken the lives of more than 2.1 million people worldwide (23), with a global mortality rate of 2.2% (23). Current COVID-19 treatment options include supportive respiratory care, parenteral corticosteroids, and Remdesivir. Although COVID-19 is associated with increased risk of morbidity and mortality in patients with comorbidities, the vulnerability, clinical course, optimal management, and prognosis of COVID-19 infection in patients with organ transplants has not been well described in the literature (9, 13) . The treatment of COVID-19 differs, based on the organ(s) transplanted (6) . Preliminary data suggested that liver transplant patients with COVID-19 did not have higher mortality rates than untransplanted COVID-19 patients (2). Table 1 depicts a compiled list of current published data on COVID-19 liver transplant patients. Most of these studies included both recent and old liver transplant patients. No distinction was made for early liver transplant patients who contract COVID-19 within their post-transplant hospitalization course. This potential differentiation needs to be further explored (14) . Here, we report two patients who underwent liver transplantation who acquired COVID-19 during their post-transplant recovery period in the hospital.

Case Descriptions: Two patients who underwent liver transplant and contracted COVID-19 in the early post-transplant period. Treated with hydroxychloroquine, methylprednisolone, tocilizumab and convalescent plasma. Description of their hospital course, including treatment and recovery.

The management of post-liver transplant patients with COVID-19 infection is complicated. Strict exposure precaution practice following organ transplantation is highly recommended. Widespread vaccination will help with prevention, but there will continue to be patients who contract COVID-19. Therefore, continued research into appropriate treatments is still relevant and critical. A temporary dose reduction of immunosuppression and continued administration of low-dose methylprednisolone, remdesivir, monoclonal antibodies, and convalescent plasma might be helpful in the management and recovery of severe COVID-19 pneumonia in post-liver transplant patients. Future studies and experiences from post-transplant patients are warranted to better delineate the clinical features and optimal management of COVID-19 infection in liver transplant recipients.

Coronavirus disease 2019 (COVID-19) has affected all facets of life and continues to cripple nations. COVID-19 has taken the lives of more than 2.1 million people worldwide 23 , with a global mortality rate of 2.2% 23 . Current COVID-19 treatment options include supportive respiratory care, parenteral corticosteroids, and remdesivir. The "RECOVERY study" by the National Health Service in England showed 22.9% of participants in the dexamethasone arm versus 25.7% in the standard of care arm died within 28 days of study randomization 8, 24 . Remdesivir was approved by the U.S. Food and Drug Administration (FDA) in October, 2020 24 . The "Adaptive COVID-19 Treatment Trial (ACTT-1)" is a National Institutes of Health (NIH)-sponsored, multinational, randomized, double-blind, placebocontrolled trial that showed remdesivir significantly reduced the time to recovery compared to placebo.

As of 2021, the NIH recommends against the use of chloroquine, hydroxychloroquine, ivermectin, HIV protease inhibitors, and anti-IL-6 receptor monoclonal antibodies, such as sarilumab, bamlanivimab, and tocilizumab 24 . This is in contrast to early recommendations based on the limited information available at the time that the patients were transplanted 5 . COVID-19 vaccinations are currently being processed and administered worldwide, with encouraging early data for development of immunity.

Although COVID-19 is associated with increased risk of morbidity and mortality in patients with comorbidities, the vulnerability, clinical course, optimal management, and prognosis of COVID-19 infection in patients with organ transplants has not been well described in the literature 9, 13 . The treatment of COVID-19 differs, based on the organ(s) transplanted 6 . Preliminary data suggested that liver transplant patients with COVID-19 did not have higher mortality rates than untransplanted COVID-19 patients 2 . Table 1 This potential differentiation needs to be further explored 14 . Here, we report two patients who underwent liver transplantation who acquired COVID-19 during their post-transplant recovery period in the hospital.

The patient is a 65-year-old female with a history of hepatitis C-related liver cirrhosis and hepatocellular carcinoma. Her calculated MELD score was 12 with a MELD exception of 28 due to porto-pulmonary hypertension. The patient also had a history of rheumatoid arthritis, uterine fibroids, paroxysmal atrial fibrillation, candida esophagitis, herpes simplex keratitis, hepatic encephalopathy, moderate to severe porto-pulmonary hypertension, and psoriatic arthritis. On POD # 23 the patient received 400mg tocilizumab and one unit of convalescent plasma on POD#25 due to spikes in inflammatory markers: D-Dimer had increased to 18.34, Fibrinogen increased to 472, C reactive protein increased to 15, but WBC was unchanged at 5.4 (Figure 1 ). Inflammatory markers subsequently decreased after tocilizumab and convalescent plasma: D-Dimer had decreased to 5.17, Fibrinogen decreased to 333, C reactive protein decreased to 3.9, WBC was 2.4 ( Figure 1 ). Repeat SARS CoV2 RNA testing was positive POD# 31. Inflammatory markers were also increased on POD#36: D-Dimer had increased to 18.51, Fibrinogen increased to 374, C reactive protein increased to 12, but WBC had increased to 7.1 (Figure 1 ). Patient received another dose of 400mg tocilizumab and one unit of convalescent plasma.

Tracheostomy was performed on POD#41 as was she unable to wean off the ventilator. Inflammatory markers continued to downtrend: D-Dimer had decreased to 5, Fibrinogen decreased to 195, C reactive protein decreased to 0.78, and WBC was 3.4 ( Figure 1 ). She was retested for COVID PCR and was found to be negative on POD#56. On post COVID-19 exposure day #55 she tested positive for SARS-CoV2 IgG Antibody. She improved slowly, was subsequently decannulated and discharged home POD#88.

The patient is a 58-year-old woman with a history of decompensated alcoholic cirrhosis and massive ascites who was admitted for liver transplantation on March 24, 2020. The liver allograft was procured from a 35-year-old man who had sustained anoxic brain injury after an opioid overdose. Donor COVID-19 PCR undetectable. The donor was HCV antibody positive, HCV NAT negative. The estimated blood loss was 1200mL. The cold and warm ischemia time were 5 hours and 47 minutes and 35 minutes respectively.

The patient was admitted to the ICU postoperatively and started on standard immunosuppressive therapy with 2mg tacrolimus every 12 hours, 500mg mycophenolate every 12 hours, and 200mg methylprednisolone once, as well as post-transplant prophylaxis with 160mg sulfamethoxazoletrimethoprim once every other day, 450mg valganciclovir every day, and 500,000 unit nystatin as needed. Pancytopenia resulted and antibiotic coverage broadened to meropenem and micafungin. She required prone positioning for persistent hypoxemia several times. She had a trial of extubation that ultimately failed on POD#30 and was re-intubated. Repeat SARS CoV2 RNA testing was positive on POD#33. On POD#38, the patient underwent a tracheostomy. SARS CoV2 RNA testing was negative on POD#60. The patient was transferred to the inpatient physical rehabilitation unit on POD#64.

Here we report our experiences managing two early post-liver transplant patients who acquired COVID-19 during their hospital course. The outcomes of COVID-19 infection within two weeks of liver transplantation is currently unknown, but based on several case studies there is an 18-55% mortality rate in liver transplant patients who contract COVID-19 (Table 1 ). In all solid organ transplant patients, Kates, et al. found a 28-day mortality rate of 20.5% among hospitalized patients with COVID-19 9 .

As of today, temporary dosage reduction or withdrawal of immunosuppressive agents in the early stage of infection with COVID-19 is recommended as a strategy to avoid serious complications of COVID-19 12 . It is unclear how to properly dose corticosteroids in COVID-19-infected transplant recipients. High dose corticosteroids have the potential to help protect against allograft rejection while decreasing the cytokine storm seen in cases of severe COVID-19 infection 8 .

Our experience suggests the beneficial effects of early and aggressive dexamethasone and antiviral drug treatment. IL-6 inhibitors and convalescent plasma were given to our patients to treat cytokine storm. Inflammatory markers decreased dramatically in our patients following the administration of convalescent plasma and tocilizumab (Figure 1 and 2) . However, a recent study did not demonstrate efficacy of Tocilizumab 20, 24 . Therefore, we are no longer use IL-6 antagonists for treatment of COVID-19 transplant patients.

Bamlanivimab is a monoclonal antibody that is specifically directed against the spike protein of COVID-19, designed to block the virus' attachment and entry into human cells 3 . It appears to be safe when it is used to treat outpatients with moderate COVID-19 infection 3 . Conversely, this was a preliminary paper based on the BLAZE-1 trial, and when comparing the clinical outcomes the results showed minimal differences between the drug and control. Based on the demonstrated safety and potential benefit, our hospital has been using Bamlanivimab with our severe COVID-19 patients.

The management of post-liver transplant patients with COVID-19 infection is complicated. Strict exposure precaution practice following organ transplantation is highly recommended. Widespread vaccination will help with prevention, but there will continue to be patients who contract COVID-19. 

COVID-19 in an international European liver transplant recipient cohort

COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients

Pharmacotherapeutic considerations in solid organ transplant patients with COVID-19

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The Adaptive COVID-19 Treatment Trial-1 (ACTT-1) in a real-world population: a comparative observational study

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Coronavirus Disease 2019 in Solid Organ Transplant: A Multicenter Cohort Study

COVID-19 infection in solid organ transplant recipients: A singlecenter experience with patients immediately after transplantation

How should I manage immunosuppression in a kidney transplant patient with COVID-19? An ERA-EDTA DESCARTES expert opinion

Outcomes of critically ill solid organ transplant patients with COVID-19 in the United States

Transplantation in the era of the Covid-19 pandemic: How should transplant patients and programs be handled?

COVID-19 in Liver Transplant Patients: Report of 2 Cases and Review of the Literature

COVID-19 in solid organ transplant recipients: Dynamics of disease progression and inflammatory markers in ICU and non-ICU admitted patients

Modulating immunosuppression in liver transplant patients with COVID-19

A Randomized Trial of Convalescent Plasma in Covid-19

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Management of Patients with Liver Transplant and Chronic Liver Diseases During COVID-19 Pandemic: A Brief Review

Tocilizumab use in Kidney Transplant Patients with COVID-19

COVID-19 in the Early Postoperative Period of Liver Transplantation: Is the Outcome Really So Positive?

Determining risk factors for mortality in liver transplant patients with COVID-19