Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient

Abstract

Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies. Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies. Most patients with COVID-19 have a mild or asymptomatic disease course; however, about 19% require admission to an intensive care unit (ICU) because of multiorgan failure.1Hannah Ritchie EO-O DB, Edouard M, Joe H, Bobbie M, Charlie G, Max R. Coronavirus (COVID-19) hospitalizations. https://ourworldindata.org/coronavirus. Accessed December 2020.Google Scholar These severe infections can result in up to 60% mortality.2Gupta A Madhavan MV Sehgal K et al.Extrapulmonary manifestations of COVID-19.Nat Med. 2020; 26: 1017-1032Crossref PubMed Scopus (1504) Google Scholar,3Mokhtari T Hassani F Ghaffari N Ebrahimi B Yarahmadi A Hassanzadeh G. COVID-19 and multiorgan failure: A narrative review on potential mechanisms.J Mol Histol. 2020; 51: 613-628Crossref PubMed Scopus (185) Google Scholar Furthermore, signs of hepatobiliary damage have been observed in 14%–53% of patients with severe presentations of COVID-19.4Jothimani D Venugopal R Abedin MF Kaliamoorthy I Rela M. COVID-19 and the liver.J Hepatol. 2020; 73: 1231-1240Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly damage the biliary ducts by binding to angiotensin-converting enzyme 2 (ACE2) on the surface of cholangiocytes; the particularly low abundance of ACE2 on hepatocyte surfaces suggests that SARS-CoV-2 may not directly infect the liver parenchyma.4Jothimani D Venugopal R Abedin MF Kaliamoorthy I Rela M. COVID-19 and the liver.J Hepatol. 2020; 73: 1231-1240Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar Other potential mechanisms of hepatotoxicity include hyperinflammation and hypoxia-associated metabolic derangements.5Li H Liu L Zhang D et al.SARS-CoV-2 and viral sepsis: observations and hypotheses.Lancet. 2020; 395: 1517-1520Abstract Full Text Full Text PDF PubMed Scopus (728) Google Scholar Histopathologic changes in the liver include hepatic steatosis, portal fibrosis, ductal proliferation with lymphocytic infiltrates, lobular cholestasis, and acute liver-cell necrosis with central-vein thrombosis.6Lax SF Skok K Zechner P et al.Pulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome : Results From a Prospective, Single-Center. Clinicopathologic Case Series.Ann Intern Med. 2020; 173: 350-361Crossref PubMed Scopus (486) Google Scholar,7Díaz LA Idalsoaga F Cannistra M et al.High prevalence of hepatic steatosis and vascular thrombosis in COVID-19: A systematic review and meta-analysis of autopsy data.World J Gastroenterol. 2020; 26: 7693-7706Crossref PubMed Google Scholar Patients with pre-existing cirrhosis appear to be at higher risk of mortality from COVID-19.8Marjot 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: 567-577Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Acute liver failure (ALF) attributable to COVID-19 is exceptionally rare.9Melquist S Estepp K Aleksandrovich Y et al.COVID-19 presenting as fulminant hepatic failure: a case report.Medicine (Baltimore). 2020; 99 (e22818.)Crossref PubMed Scopus (20) Google Scholar,10Haji Esmaeil Memar E Mamishi S Sharifzadeh Ekbatani M et al.in an 11-year-old boy.Arch Pediatr. 2019; 2020: 502-505Google Scholar Liver transplantation (LT) remains the best treatment option for decompensated cirrhosis and ALF. However, Transplantation Society Guidelines recommend that LT candidates have resolved COVID-19 symptoms with two negative PCR tests done at least 24 hours apart before proceeding to LT.4Jothimani D Venugopal R Abedin MF Kaliamoorthy I Rela M. COVID-19 and the liver.J Hepatol. 2020; 73: 1231-1240Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar Herein, we report a case of ALF resulting in LT in a patient with COVID-19 and ongoing SARS-CoV-2 polymerase chain reaction (PCR)-positivity. An 18-year-old, previously healthy African-American woman presented with 3 days of fever, nausea, vomiting, diarrhea, epigastric pain, shortness of breath (day 0), and known recent SARS-CoV-2 exposure. At presentation to the hospital (day 3), she tested positive for SARS-CoV-2 by PCR from a nasopharyngeal (NP) sample. Vital signs demonstrated blood pressure 133/66 mmHg, pulse 103, respiratory rate 28 breaths per minute, temperature 37.5°C, and oxygen saturation as low as 80% on ambient air. Physical examination revealed scleral icterus and epigastric tenderness. Notable laboratory results (Table 1) included severe coagulopathy, hyperbilirubinemia (total12.7 mg/dl, direct 9.1 mg/dl), aminotransferase elevations (AST 596 U/L, ALT 37 U/L), profound hemolytic anemia (hemoglobin =4.5 g/dl, MCV = 133.6, reticulocyte 13.4%, peripheral smear -mild spherocytosis), elevated creatinine (7.5 mg/dl). Arterial blood gas demonstrated a pH = 7.17, pO2 = 39 mmHg, pC02 = 24, and bicarbonate =9 mmol/L. Her Quick COVID-19 Severity Index (qCSI) Risk11Haimovich AD Ravindra NG Stoytchev S et al.Development and validation of the quick COVID-19 severity index: a prognostic tool for early clinical decompensation.Ann Emerg Med. 2020; 76: 442-453Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar was high-intermediate for risk of critical illness at 24 hours, defined by oxygen requirement (>10 L/min by low-flow device, high-flow device, noninvasive, or invasive ventilation) or death.TABLE 1Index laboratory tests at presentation and the day of liver transplantationLabIndexTransplantLabIndexTransplantLabIndexTransplantWBC37.318.1Na+125146CoV-PCRPositivePositiveHGB4.57.5K+5.54.4CK6,5122,529MCV133.698.7HCO3723Ferritin99,2309,455PLT17139Creatinine7.502.57CRP24519.9Haptoglobin<14—BUN3836Ammonia64125INR6.92.8Ca2+6.88.5Lactate199.5Fibrinogen91190Glucose98136ESR17—D-Dimer14,372—AST596545Uric acid2.4—LDH>2,2501,563ALT37419Copper4.74—T. Bilirubin12.721.9ALP2150Ceruloplasmin21.1—D. Bilirubin9.117.2ALB2.12.7 Open table in a new tab Evaluation for acute hepatitis including viral, autoimmune serologies, and acetaminophen levels were negative. Serum inflammatory markers were markedly elevated including ferritin (99,230 mcg/L) and C-reactive protein (245 mg/L). A normal ceruloplasmin (21.1 mg/dl) was noted along with a low alkaline phosphatase (21 U/L) and uric acid (2.4 mg/dl) and an elevated serum copper (4.67 mcg/ml). Urine copper quantification was precluded by anuria. A slit lamp examination did not identify Kayser–Fleischer rings. Chest radiography did not show any consolidations or pleural effusions. Computed tomography of the abdomen and pelvis demonstrated nonspecific mesenteric stranding, a normal appearing liver, and splenomegaly (14.8 cm). Liver ultrasonography showed a slightly hypoechoic hepatic echotexture. Bone marrow biopsy revealed mild hemophagocytosis. The patient’s timeline is shown in Figure 1. She was admitted to a dedicated COVID-19 ICU. Intermittent hemodialysis (IHD) was initiated (day 4) and continuous renal replacement therapy (CRRT) was started on day 6. Treatment for SARS-CoV-2 included 2 units of convalescent plasma (day 5–6). Hepatic and renal failure precluded the use of remdesivir. Due to a direct antiglobulin test (gel-based assay) that was positive (regular direct antiglobulin test, tube-based assay, was negative) and ongoing hemolysis, intravenous (IV) methylprednisolone 125 mg daily was administered. Transjugular liver biopsy was recommended by the liver transplant team (day 4) given concern for Wilson’s disease (WD) but was not performed due to rapidly rising INR, eventually exceeding 20. Genetic testing for WD was obtained. Despite supportive care, the patient progressively deteriorated and met criteria for ALF with hepatic encephalopathy (HE), coagulopathy, and absence of known prior liver disease. Although the patient had an abnormal hepatic echotexture on ultrasound, and the spleen was mildly enlarged, there were no specific findings of portal hypertension or clear evidence of cirrhosis on CT imaging. On day 14, patient had progressive HE (plasma ammonia 111 mcmol/L) despite lactulose and rifaximin. She continued to require higher respiratory support receiving 65% Fio2 by Optiflow requiring endotracheal intubation and mechanical ventilation. The chest radiograph prior to intubation demonstrated bilateral airspace opacities and retrocardiac consolidation. Albumin dialysis using the Molecular Adsorbent Recirculating System (MARS) was initiated as a potential bridge to transplant (four consecutive daily sessions). An intracranial pressure monitor could not be placed due to coagulopathy. Head CT was performed on days 11, 12, 14, and 16 that did not demonstrate overt cerebral edema but did show subtle narrowing of the lateral and third ventricle suggestive of subtle edema. Prolonged video electroencephalogram demonstrated diffuse, severe disturbances in cerebral function but no evidence of seizures or epileptiform activity. Extensor posturing and myoclonic jerks were noted on exam despite MARS, but this improved with institution of IV hypertonic saline. Neurologists following the patient daily, noted intact brainstem reflexes, and did not see any signs of irreversible brain injury. On day 16, and after extensive multidisciplinary review, she was listed for liver transplant as status 1A (calculated MELDNa = 53), despite a persistently positive NP SARS-CoV-2 PCR, and absence of SARS-CoV-2 antibodies. PCR cycle threshold (Ct) values were consistently between 14 and 16 (Table 2). The presumptive diagnosis was ALF secondary to WD, but atypical COVID-19-related liver disease could not be completely excluded. The patient was hemodynamically stable on CRRT, not requiring vasopressor support at the time of listing. She was receiving FiO2 of 0.30 by mechanical ventilation with new left lower lobe consolidation and mild patchy infiltrate in the right lung base. Empiric IV ceftriaxone, vancomycin, and anidulafungin were initiated. Serial blood cultures remained negative. Ferritin and C-reactive protein had improved to 7491 mcg/L and 8.6 mg/L, respectively (Table 1).TABLE 2Severe acute respiratory syndrome coronavirus-2 polymerase chain reaction timelineDays since initial symptoms37111314151617aDay of liver transplant.2127SARS-CoV–2 PCR nasopharyngeal swab++++++++–SARS-CoV–2 PCR bronchoalveolar lavage+Ct value22.9bReal-time reverse transcription polymerase chain reaction, SARS-CoV-2, molecular detection.14-20cReal-time reverse transcription polymerase chain reaction, influenza A and B, SARS-CoV-2, PCR, rapid.14-20cReal-time reverse transcription polymerase chain reaction, influenza A and B, SARS-CoV-2, PCR, rapid.23.3bReal-time reverse transcription polymerase chain reaction, SARS-CoV-2, molecular detection.30.8bReal-time reverse transcription polymerase chain reaction, SARS-CoV-2, molecular detection.Abbreviations: Ct, cycle threshold; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.a Day of liver transplant.b Real-time reverse transcription polymerase chain reaction, SARS-CoV-2, molecular detection.c Real-time reverse transcription polymerase chain reaction, influenza A and B, SARS-CoV-2, PCR, rapid. Open table in a new tab Abbreviations: Ct, cycle threshold; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. The patient underwent a deceased donor LT on day 17. The intraoperative course was unremarkable. The explant demonstrated cirrhosis, confluent hepatocyte necrosis, and steatohepatitis (Fig S2a, Fig S2b). Quantitative copper was 1200 mcg/dry weight liver, confirming WD. The genetic analysis later demonstrated two pathogenic variants of the ATP7B gene (amino acid change: p.H1069Q [His1069Gln]; amino acid change: p.D730Gfs*25 [Asp730Glyfs*25]). Postoperatively, her liver ultrasound demonstrated patency of all vascular anastomoses with normal waveforms. The immunosuppression regimen consisted of standard steroid taper, with basiliximab (20 mg IV on day 17 and day 21), which is our standard regimen for patients with renal failure. Mycophenolate mofetil was held due to COVID-19.12Colmenero J Rodríguez-Perálvarez M Salcedo M et al.Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.J Hepatol. 2021; 74: 148-155Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Tacrolimus was initiated on day 21. Remdesivir was started immediately posttransplant (200 mg Per NG tube day 1, 100 mg days 2–10). On day 21 (4 days post transplant), the PCR Ct value was 30.8 (Table 2), and the PCR resulted negative on day 27 (10 days post transplant). No antibodies to SARS-CoV-2 were detected on days 4 and 15. The SARS-CoV-2 PCR on the explant was positive. The patient was extubated on day 27. Shewas maintained on CRRT until day 37, transitioned to IHD and ultimately regained renal function off IHD with a current creatinine of 0.91 mg/dl. Currently, she has a stable, moderately elevated transaminase levels (AST = 109, ALT = 173 U/L, total bilirubin of 1.3 mg/dl). The alkaline phosphatase increased to >1000 U/L and a liver biopsy on day 47 demonstrated mild zone 3 injury without evidence of T cell–mediated rejection. Ultrasound with Doppler of the allograft at that time was normal. She also had severe weakness in a lower motor neuron pattern and diffuse muscle pain. Creatinine kinase was elevated to a peak of 6512 U/L and urine myoglobulin was positive indicating rhabdomyolysis. There was concern for COVID-19-related myopathy; prednisone was initiated at 60 mg per os daily with significant improvement in myalgias. An EMG demonstrated a diffuse myopathic process. 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