key: cord-0978759-jjhpwgfa authors: Heinz, Nicole; Griesemer, Adam; Kinney, Joanna; Vittorio, Jennifer; Lagana, Stephen M.; Goldner, Dana; Velasco, Monica; Kato, Tomoaki; Lobritto, Steven; Martinez, Mercedes title: A case of an Infant with SARS‐CoV‐2 hepatitis early after liver transplantation date: 2020-06-25 journal: Pediatr Transplant DOI: 10.1111/petr.13778 sha: 0b8bfda5d11f237fedb5b5d5610d8a69987f1bab doc_id: 978759 cord_uid: jjhpwgfa We present a case of a pediatric liver transplant recipient diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection four days after receiving a living donor liver allograft from her mother. The recipient was a 6‐month‐old with end‐stage liver disease due to biliary atresia and failed Kasai. The infant had an uncomplicated implantation, excellent graft function and down‐trending liver enzymes until developing fevers, diarrhea, and moderate respiratory distress requiring non‐invasive respiratory support. SARS‐CoV‐2 testing (nasal swab Polymerase Chain Reaction) was positive on post‐operative day (POD) 4. Liver enzymes peaked ~1000 U/L (5‐fold higher than the previous day) on POD 6. Histology demonstrated a mixed picture of moderate acute hepatitis and classical elements of mild to moderate acute cellular rejection. Her hepatitis and respiratory symptoms improved coincident with completing treatment with hydroxychloroquine, reduced immunosuppression, and intravenous gamma globulin (IVIG). was considered an urgent procedure. The team decision to proceed with the transplant contemplated the rate of progression of chronic liver failure, the risk of patient mortality before the epidemic abated, the perceived lower risk at the onset of the epidemic compared to the weeks/months ahead and the fact that neither the donor nor recipient demonstrated signs or symptoms of SARS-CoV-2 infection. There were no surgical complications, and mechanical ventilation was discontinued on post-operative day (POD) 1. She received our standard immunosuppression protocol with steroid induction and triple weight-based maintenance medications (see Table 1 ). On POD 3, the donor developed transient sore throat and cough. She did not have fever, shortness of breath or desaturations. Figure 1 ). Given the clinical respiratory decompensation, the evening dose of mycophenolate mofetil (MMF) was held but was restarted the following morning after clinical improvement. A 5-day course of hydroxychloroquine at 7.5 mg/kg/dose was started immediately after confirming SARS-CoV-2 infection on POD 4. Daily WBC count persisted above 15.9 ×10 3 /µL (lymphocytes ~45%) and QTc intervals remained within expected limits during hydroxychloroquine therapy. Between POD 5 and 6 the recipient became persistently febrile for 20 hours despite treatment with acetaminophen, but her respiratory symptoms did not worsen. She was started on empiric piperacillin-tazobactam after collecting urine and blood samples for culture with unrevealing results. Laboratory tests were notable for erythrocyte sedimentation rate 4 mm/h (0-20 mm/h), creatinine kinase 80 U/L (40-308 U/L), troponin T high sensitivity 16 ng/L (<14 ng/L), lactate dehydrogenase 1206 U/L (190-420 U/L), ferritin 1090 ng/mL (13-150 ng/mL), and procalcitonin 0.18 ng/mL (< = 0.08 ng/mL). Gastrointestinal PCR and Clostridium difficile studies sent to evaluate persistent diarrhea were negative. In addition to her 3 immunosuppressive agents, the patient received additional prophylactic medications as per center protocol (oral aspirin, enoxaparin, valganciclovir, nystatin, sulfamethoxazole/trimethoprim, and ursodiol). Liver enzymes had been trending downward as expected since the LT; however, on POD 6, there was a sudden significant elevation of liver enzymes (see Table 1 , Figure 2 Mycophenolate As of POD 22, respiratory symptoms continued to improve and diarrhea that had previously persisted despite stopping MMF and magnesium supplements, was abating. The evolving clinical recovery picture was generally reflected by improving liver enzymes and resolution of respiratory symptoms and diarrhea. The team entertained using the mother as a potential source of convalescent serum 7 once enough time had elapsed (3-6 weeks) but given her persistent positive NP PCR for SARS-CoV-2 she could not donate and no other donor was available before patient recovery. Follow-up evaluation in the outpatient clinic on POD 30 was notable for resolution of all symptoms including diarrhea, but liver enzymes were again elevated in the setting of a subtherapeutic tacrolimus trough (Table 1, Figure 2) . A repeat liver biopsy was obtained. Histology demonstrated that the lobular apoptotic activity had largely resolved and was now absent to minimal ( Figure 3C ). Portal tracts were expanded by a mixed inflammatory infiltrate consisting of lymphocytes, histiocytes, and scattered eosinophils. Portal vein endotheliitis and mild to moderate bile duct injury in the majority of the portal tracts were noted. Essentially, these are the classical findings of ACR ( Figure 3D ). The diagnosis rendered was moderate ACR (Banff score 6 = 2+2 + 2) and resolved viral hepatitis. The patient received a single intravenous bolus of methylprednisolone 10 mg/kg follow by an oral prednisolone recycle starting at 2 mg/kg/day. Tacrolimus dose was optimized, and MMF was restarted (15 mg/kg/dose BID). On POD 36 the patient remained clinically well, liver enzymes had improved and tacrolimus trough was at target. The sequence of post-operative events, vital signs, and laboratory values are detailed in Table 1 and Figures 1 and 2. The respiratory manifestations of SARS-CoV-2 infection have received the most attention given the high mortality associated with acute respiratory distress syndrome (ARDS). 1 However, up to 60% of infected patients have elevated liver enzymes and these elevations appear higher in more severe cases. 8 cipients in our center appears to be higher than that in the general population. 9 The respiratory symptoms in this case are also similar to those reported in the largest pediatric series by Lu et al Like our case, the authors reported that 8.8% of their cases had diarrhea but did not include any specifics regarding hepatic biochemical profile. 2 The biochemical pattern in their report was primarily hepatitis supporting that the liver insult is mainly one of parenchymal injury. The main histological feature of moderate acute/lobular hepatitis, which was attributed to SARS-CoV-2, is different from the report by Xu et al 8 The histological features we attributed to SARS-CoV-2 are similar to other acute viral hepatidities. 4 We know by experience plasma as means of passive immunity through the administration of viral-specific antibody. Given that this patient presented early during the New York outbreak, not enough time had passed (usually 3-6 weeks) to find a suitable donor, our institution has developed all the regulatory and logistic work-flow to offer this therapeutic alternative. Finally, we want to share the off-label use of hydroxychloroquine in this age group without appreciable side effects, but of unproven efficacy. The role of IVIG has not been explored as a therapeutic option for SARS-CoV-2 infection especially in this case where IVIG available at that time would not be expected to have significant or any SARS-CoV-2 specific antibodies. This patient received IVIG to address low serum globulin levels and reports supporting the antimicrobial efficacy of IVIG in immunocompromised subjects. 11 The improvement of liver enzymes and diarrhea after its administration may have been coincidental. The authors have no conflict of interest related to this work. https://orcid.org/0000-0003-4894-2024 Mercedes Martinez https://orcid.org/0000-0001-6128-0155 Clinical characteristics of coronavirus disease 2019 in China SARS-CoV-2 infection in children Coronaviruses and immunosuppressed patients. 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