Objectives: Several studies suggest that chronic immunosuppression in pediatric liver transplant patients may affect the severity and mortality rates of SARS-CoV-2 infection.
Materials and Methods: We assessed a total of 118 pediatric liver transplant recipients for SARS-CoV-2 infection, aged 1 to 18 years, followed between March 2019 and January 2022. We compared the clinical characteristics and outcomes of SARS-CoV-2 infection in pediatric liver transplant patients to 187 non-liver transplant pediatric patients with SARS-CoV-2 infection who had been diagnosed at our institution between March 15, 2020, and December 31, 2020. Demographic data, clinical features, and laboratory findings from the patients were retrospectively collected from hospital reports and telephone inquiries.
Results: A total of 20 liver transplant patients with SARS-CoV-2 infection were identified. Median age of liver transplant recipients with SARS-CoV-2 infection was higher than non-liver transplant pediatric patients with SARS-CoV-2 (14.8 [range, 7-16] vs 6.8 [range, 2-14] years; P = .016). There were no significant differences in mild and moderate disease courses of SARS-CoV-2 infection between liver transplant recipients and non-liver transplant pediatric patients (18 [90.0%] vs 133 [71.1%] patients [P = .188] and 2 [10%] vs 49 [26.2%] patients [P = .118], respectively). Fever was less frequently observed in liver transplant patients with SARS-CoV-2 infection compared with non-liver transplant patients (55.0% vs 80.2%; P = .015). We found no intergroup differences in sex (P = .342), hospitalization rate (P = .161), and overall clinical presentation.
Conclusions: Despite the immunosuppression regi-mens, liver transplant patients in our series survived SARS-CoV-2 infection without serious sequelae and without graft rejection. Overall, liver transplant and non-liver transplant pediatric patients with SARS-CoV-2 infection experienced a mild disease course.
Key words : Children, Liver transplantation, Pediatric gastroenterogy, SARS-CoV-2 infection
The SARS-CoV-2 virus is highly contagious and has affected a large population throughout the world, which led the World Health Organization to declare SARS-CoV-2 as a pandemic on March 11, 2020.1,2 Interaction of SARS-CoV-2 with the host cells initiates a cascade of immune-mediated inflammatory reactions that may lead to a “cytokine storm” in the host body.1-3 Children appear to be less susceptible to severe SARS-CoV-2 infections than adults; however, children with chronic liver disease have a higher risk of severe SARS-CoV-2 infection, and decompensation may occur.4 The data for COVID-19 disease severity and clinical outcomes in children with solid-organ transplant are scarce.5,6 Several studies suggest that chronic immunosuppression in pediatric liver transplant (LT) recipients may predispose to increased risk for opportunistic viral or bacterial infections, although the susceptibility and mortality rates of SARS-CoV-2 in this group remain to be determined. Here, we assessed the severity and clinical features following SARS-CoV-2 infection in our cohort of pediatric LT recipients and compared those findings with non-LT pediatric patients with SARS-CoV-2 infection.
Materials and Methods
Study design and participants
In this single-center retrospective study, we evaluated medical data from LT recipients, aged 1 to 18 years, with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, who had been followed between March 2019 and January 2022 (the SARS-CoV-2 era) at Baskent University Hospital, Ankara, Turkey. We diagnosed 20 of 118 pediatric LT recipients with SARS-CoV-2 infection during the study period. Demographic data, clinical symptoms, laboratory features, medications, hospitalization status, pediatric intensive care unit (PICU) admission, mode of oxygenation, and outcomes were all documented from the electronic medical record system of Baskent University Hospital, the state-owned centralized medical record system (e-Nabiz), and telephone inquiries. We compared the demographic and clinical features of SARS-CoV-2 infection between 20 LT patients and 187 non-LT pediatric patients with SARS-CoV-2 infection who had been diagnosed at our institution between March 15, 2020, and December 31, 2020. We only included patients whose SARS-CoV-2 infection was confirmed with real-time reverse transcriptase PCR from a nasopharyngeal swab. In the LT SARS-CoV-2 group, patients were excluded if they had been diagnosed with SARS-CoV-2 infection before the LT, for unknown hospitalization status, or for diagnosis that was not confirmed by PCR. In the non-LT SARS-CoV-2 group, patients with chronic illness and with an active regimen of immunosuppressive therapy were excluded.
Serum laboratory markers of liver transplant patients with SARS-CoV-2
We evaluated patient data that had been recorded with a multi-parameter, automated hematology analyzer (CELL-DYN Ruby or CELL-DYN 3700; Abbott Laboratories) before and after the SARS-CoV-2 infection, which included aspartate aminotransferase (AST), alanine aminotransferase (ALT), international normalized ratio, C-reactive protein (CRP), and complete blood counts. Leukopenia and thrombocytopenia were defined as <4.5 × 103 cells/μL and <150 × 103 cells/μL, respectively. Lymphopenia and neutropenia were defined as <1 × 103 cells/μL and <1 × 103 cells/μL, respectively. Elevated CRP was defined as >5 mg/L.
Continuous data are presented as median values with interquartile ranges for variables without normal distributions. Descriptive statistics are presented with frequencies and percentages for discrete variables. We used the Pearson chi-square test and the Fisher exact test for categorical variables to compare the demographic and clinical features of the LT SARS-CoV-2 group and the non-LT SARS-CoV-2 group, and for continuous variables we used the Student t test. We analyzed the data with IBM SPSS software (version 26.0). A 2-sided P < .05 was considered significant.
Demographic, clinical, and laboratory features of liver transplant patients with SARS-CoV-2
There were 20 of 118 (16.9%) (male/female: 12/8) pediatric LT recipients who were diagnosed with SARS-CoV-2 infection between March 2019 and January 2022. The median age of the patients was 14.8 (interquartile range, 7-16 ) years. All 20 patients in the LT SARS-CoV-2 group had received ABO-compatible living donor LT. Immunosuppression regimens of these 20 patients were as follows: tacrolimus in 15 patients (75%), sirolimus in 3 (15%), everolimus and prednisolone in 1 (5%), and tacrolimus and prednisolone in 1 (5%). According to the criteria from Dong and colleagues7 and Fang and colleagues,8 we observed mild disease in 18 (90%) of these 20 patients and moderate disease in 2 (10%). The main presenting symptoms were as follows: fever in 11 patients (55%), cough in 8 (40%), runny nose in 5 (25%), sore throat in 6 (30%), myalgia in 4 (20%), weakness in 3 (15%), headache in 3 (15%), abdominal pain in 2 (10%), and nasal congestion in 2 (10%). Detailed demographic and clinical features are presented in Table 1 and Table 2.
None of the patients exhibited respiratory failure or loss of smell or taste. Only 2 (10%) of the 20 LT patients with SARS-CoV-2 developed respiratory symptoms that required hospitalization in the SARS-CoV-2 ward; for this group, the mean length of stay was 10 days. Both patient 1 and patient 2 required computed tomography to evaluate respiratory distress, which revealed consolidation in left lower lung and ground-glass opacity with minimal pleural effusion, respectively. Both patient 1 and patient 2 required noninvasive high-flow nasal oxygen therapy for 3 and 7 days, respectively (Table 3). Patient 1 received favipiravir treatment (1800 mg twice daily for 1 day, then 800 mg twice daily for 4 days) and azithromycin treatment (10 mg/kg/d for 1 day, then 5 mg/kg/d for 4 days), whereas patient 2 with end-stage renal disease required meropenem, vancomycin, and amikacin to treat subclavian catheter infection. Both patients did not require adjustments to their immunosuppression regimens and recovered well without graft loss or liver dysfunction.
Only 6 of 20 LT SARS-CoV-2 patients had complete blood count, biochemistry tests, and coagulation profile (Table 2). We observed elevated AST and ALT in 4, elevated CRP in 4, leukopenia in 5, thrombocytopenia in 3, and lymphopenia in 4 patients. No PICU admission or death associated with SARS-CoV-2 infection was observed in our study. Detailed epidemiological, clinical, and laboratory features of hospitalized LT SARS-CoV-2 patients are shown in Table 3.
Comparison of demographic and clinical features between liver transplant and non-liver transplant pediatric patients with SARS-CoV-2 infections
Demographic, and clinical features of SARS-CoV-2 infection in our 20 LT pediatric patients were compared with 187 non-LT pediatric patients with SARS-CoV-2 infection. The median age of patients in the LT SARS-CoV-2 group was higher than in the non-LT SARS-CoV-2 group (14.8 [7-16] vs 6.8 [2-14] years; P = .016). Fever was less frequently observed in LT patients with SARS-CoV-2 infection compared with non-LT children (55.0% vs 80.2%; P = .015). We found no intergroup differences in sex (P = .342), hospitalization rate (P = .161), and overall clinical presentation between the groups. There were no significant differences in mild and moderate disease course of SARS-CoV-2 infection between LT and non-LT pediatric patients (18 [90.0%] vs 133 [71.1%], P = .188; and 2 [10%] vs 49 [26.2%], P = .118; respectively). Demographic, clinical symptoms, and outcomes of the LT SARS-CoV-2 group versus the non-LT SARS-CoV-2 group are shown in Table 4.
In this study, we compared the clinical characteristics and outcomes of SARS-CoV-2 infection in LT versus non-LT pediatric patients at our center. Compared with adults, children have low risk of severe SARS-CoV-2 infection that could result in hospitalization or death. One of the largest epidemiological studies of children with SARS-CoV-2 infection from Turkey reported that 22.7% of the 1156 pediatric patients were asymptomatic and 57.7% had mild, 18.1% had moderate, and 1.5% had severe infection.9 Another single-center study of children with SARS-CoV-2 infection from Turkey reported that 67.5% of 206 patients had mild, 27.2% had moderate, and 2.9% had severe infection.10 Overall, our findings align with the current literature and show that children with SARS-CoV-2 infection display a mild clinical presentation.
According to the classification criteria of Dong and colleagues7 and Fang and colleagues,8 we observed in our study that 90% of the pediatric LT recipients with SARS-CoV2 infection had mild disease course and 10% had moderate disease course. None of our LT recipients required PICU care or mechanical ventilation support, and none died. These findings were consistent with the previous reports that have shown immunosuppression is not associated with severe clinical presentation and increased mortality in pediatric LT recipients.6,11 Kehar and colleagues reported that, despite immunosuppression burden, pediatric LT recipients had lower risk of severe SARS-CoV-2 infection compared with children with chronic liver diseases.11
In our study, fever was less common in LT compared with non-LT pediatric patients. This finding is consistent with a previous report of Basu and colleagues, which showed only 55% of solid-organ transplant recipients had fever during SARS-CoV-2 infection.12 Aside from fever, we found no differences in clinical presentations or hospitalization rates between LT and non-LT pediatric patients with SARS-CoV-2 infection.
We observed elevated AST and ALT levels in 4 LT patients with SARS-CoV-2 infection. Presence of angiotensin-converting enzyme-2 receptors in cholangiocytes and overwhelming local effects of systemic inflammation appear to be the main reasons for SARS-CoV-2-associated transaminase elevation.13 A recent study of 47 LT pediatric patients with COVID-19 reported that transaminase elevation was seen in 12.7% of cases.11 From this cohort, 2 patients developed acute cellular rejection in response to immunosuppression reduction.11 In our cohort, none of the LT patients required immunosuppression reduction, and they recovered well without a graft injury.
The modification of immunosuppression treatment is not preferred for LT pediatric patients with COVID-19 except in severe cases of SARS-CoV-2 infection.6,11 Furthermore, tacrolimus was reported to have a positive effect on survival in LT recipients with SARS-CoV-2 infection.14 Tacrolimus is a calcineurin inhibitor that actively blocks the early phase of T-cell activation, preventing the production of cytokines, notably interleukin 2 and interleukin 6.15,16 Interleukin 6 has been implicated in progression and severity of SARS-CoV-2 infection.16 Most of our patients receive tacrolimus according to the current immunosuppression protocol applied at our center. The possible anti-inflammatory and antiviral effect of tacrolimus might mitigate the clinical presentation and disease course in our patients.17,18
Mycophenolate mofetil (MMF), an inosine-5'-monop-hosphate dehydrogenase inhibitor, has an antiproliferative effect on T and B lymphocytes.19,20 A prospective study of 111 LT recipients who were treated with MMF reported that the MMF-treated patients had a more severe disease course for COVID-19 compared with the LT recipients who received calcineurin inhibitors.21 Recent reports have suggested that MMF and SARS-CoV-2 virus exert a synergistic depleting effect on the peripheral lymphocyte, thereby exacerbating the severity of infection.6,20 Therefore, cessation of MMF treatment is advised in LT patients with SARS-CoV-2 infection.6,20,21 In our study, none of the LT patients was receiving MMF treatment.
Mortality is low in both LT and non-LT pediatric patients with SARS-CoV-2 infection, and most do not need mechanical ventilation support or PICU admission.11 Liver transplant patients may require a modified immunotherapy regimen during an active SARS-CoV-2 infection.11,22 However, there is no significant difference between the intensity of immunosuppression and mortality, and solid-organ transplant can be a crucial life-saving treatment. Therefore, transplant should not be delayed on the basis of the ongoing SARS-CoV-2 pandemic.22
Our 2 LT recipients who required hospitalization for SARS-CoV2 infection were admitted to other tertiary centers. We collected their data retrospectively from the hospital reports and telephone inquiries. We acknowledge that the small sample size, the retrospective nature of the study, and the lack of sufficient data of transaminase levels limit our findings.
Data on SARS-CoV-2 infection in pediatric LT patients in Turkey are limited to case series.6 There is insufficient evidence of the efficacy of SARS-CoV-2-directed therapies, immunosuppression management, long-term clinical outcomes, and follow up in pediatric LT recipients.4 Large-scale studies and future data collection are essential to improve our understanding.
Despite their immunosuppressed state, LT patients in our series recovered from SARS-CoV-2 infection without serious sequelae and without graft rejection. Overall, LT and non-LT pediatric patients had mild disease course of SARS-CoV-2 infection. Maintenance immunosuppression therapy is not associated with severe SARs-CoV-2 infection in pediatric LT patients.
Volume : 20
Issue : 5
Pages : 66 - 71
DOI : 10.6002/ect.PediatricSymp2022.O22
From the 1Department of Pediatrics, the 2Department of Pediatric Gastroenterology, and the 3Department of General Surgery, Division of Transplantation, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Meraj Alam Siddiqui, Department of Pediatrics, Baskent University Faculty of Medicine, Ankara, Turkey
Phone: +90 507 828 06 49
Table 1. Demographic and Clinical Features of Pediatric Liver Transplant Patients With COVID-19
Table 2. Detailed Blood Analysis for 6 of 20 Pediatric Liver Transplant Patients With COVID-19
Table 3. Demographic and Clinical Features of 2 Hospitalized Pediatric Liver Transplant Recipients With COVID-19
Table 4. Demographic, and Clinical Symptoms, and Outcomes for SARS-CoV-2 Infection in Liver Transplant Versus Non-Liver Transplant Pediatric Patients