key: cord-0783451-1dwfv8k8
authors: Yuksel, Muhammed; Akturk, Hacer; Mizikoglu, Ozlem; Toroslu, Ertug; Arikan, Cigdem
title: A single‐center report of COVID‐19 disease course and management in liver transplanted pediatric patients
date: 2021-06-02
journal: Pediatr Transplant
DOI: 10.1111/petr.14061
sha: afef36e3d25efdaf648db3974c20072f3e4921e7
doc_id: 783451
cord_uid: 1dwfv8k8

BACKGROUND: In 2019, SARS‐CoV‐2 causing COVID‐19 emerged. Severe COVID‐19 symptoms may evolve by virtue of hyperactivation of the immune system. Equally, immunocompromised patients may be at increased risk to develop COVID‐19. However, treatment guidelines for children following liver transplantation are elusive. METHODS: As a liver transplantation center, we diagnosed and followed up 10 children (male/female: 8/2) with a median age of 8.5 years (IQR: 5.2–11.0), with COVID‐19 post‐liver transplant between March 2019 and December 2020. COVID‐19 diagnosis was based on PCR test and or florid X‐ray findings compatible with COVID‐19 in the absence of other cause. We retrospectively collected clinical and laboratory data from electronic patient records following written consent from patients/parents. RESULTS: Nine patients were diagnosed as definitive (PCR positive) with one patient being diagnosed as probable COVID‐19. Seven patients recovered without any support whereas three were admitted for non‐invasive oxygenation. Lymphopenia and/or high levels of serum IL‐6 were detected in four patients. Six patients mounted anti‐SARS‐CoV‐2 antibodies at median 30 days (IQR: 26.5–119.0) following COVID‐19 diagnosis. Antibiotic therapy, favipiravir, anakinra, and IVIG were used as treatment in 4,1,1 and 2 patients, respectively. Furthermore, we kept the tacrolimus with or without everolimus but stopped MMF in 2 patients. Importantly, liver allograft function was retained in all patients. CONCLUSIONS: We found that being immunocompromised did not affect disease severity nor survival. Stopping MMF yet continuing with tacrolimus was an apt treatment modality in these patients.

In 2019, SARS-CoV-2 causing COVID-19 emerged first in China and spread throughout the world in 2020, which the World Health Organization declared as a pandemic. 1,2 A plethora of studies have already shown that patients with severe COVID-19 symptoms suffer from an uncontrolled hyperactivation of the immune system. 1, [3] [4] [5] Several studies reported deranged liver enzyme levels ranging from 14% to 74% COVID-19 patients. [6] [7] [8] Yet it is to be clarified whether immunosuppressed pediatric patients underwent LT fair well pertaining to their general status as well as the allograft liver. Hitherto, pediatric case reports of LT or kidney transplantation and COVID-19

are documented though current data are insufficient to guide appropriate treatment strategies. 1, [9] [10] [11] Here, we report the demographics, clinical, and laboratory parameters of ten pediatric LT patients diagnosed with COVID-19, by PCR, who were followed at our pediatric gastroenterology and hepatology department between March 2019 and December 2020.

We performed a retrospective review of the medical charts of 

Standard IST protocol was used (tacrolimus) in all cases unless otherwise specified. Steroids were uniformly weaned off within 9 months post-transplant according to patients' status. If required, MMF or mTOR was added. Decisions to adjust tacrolimus dose and to introduce other immunosuppressive medications were made on a case-by-case basis, as determined by graft function, primary disease, and ongoing complications such as allergy, EBV viremia, and development of PTLD. Trimethoprim sulfamethoxazole and acyclovir/ganciclovir were administered to all patients as post-transplant prophylaxis.

Throat and nose swab sample were taken to perform a PCR assay in the clinical routine laboratory by using commercial kits (EZ1 Mini Kit for RNA extraction and QIAprep&amp Viral RNA kit for PCR, both from Qiagen) to screen for the COVID-19 virus. 12 SARS-CoV-2 spike protein-specific IgG antibody testing was done with commercially available SARS-Cov-2 IgG Quant Reagent Kit. 13 Patient with fever,   respiratory symptoms with radiologic evidence typical for COVID-19   was accepted as possible COVID-19 infection in absence of other   causative agents. Furthermore, we have classified COVID-19 patients according to the severity of the disease as asymptomatic, mild,   moderate, and severe, based on the clinical characteristic, labora- tory results, and chest radiography findings. Asymptomatic: cases with a positive PCR test without any clinical and radiological findings. Mild: cases with upper respiratory tract infection symptoms, such as fever, fatigue, myalgia, cough, sore throat, nasal flow with normal respiratory system examination. Moderate: cases with pneumonia with complaints of fever and cough but without the symptoms of dyspnea and hypoxemia or cases with findings of COVID-19 on chest computed tomography scan without any symptoms. Severe:

Cases with fever and cough in the early period who develop dyspnea and central cyanosis within a week (arterial oxygen saturation of <92%). Critical: cases who develop acute respiratory distress or respiratory failure rapidly, and who tend to develop shock, encephalopathy, myocardial affection, coagulation dysfunction, and acute kidney injury. 14

Demographic and clinical characteristics of the patients were summarized using frequency and percentage for categorical variables, and median (interquartile range) for continuous variables, in case of non-normality. All analyses were performed using SPSS 26 statistical software. Alpha was set as 0.05 for statistical significance. (Tables 1 and 2 ).

Regarding laboratory parameters, prior to COVID-19, the median lymphocyte count was 3 × 10 3 /mm 3 (IQR: 1.7-3.6) but was 2.3 × 10 3 /mm 3 (IQR: 1.4-3.9) following the infection whereas D dimer-max was 815.0 ng/ml (IQR: 475.0-2048.0) ( Table 2 ). The median CRP-max levels were 35.5 (IQR: 2.2-72.7) during the infection.

The chest X-ray showed abnormalities in 30% of patients (Table 2) .

Liver tests were normal in 7 patients at diagnosis whereas three (cases 2, 9, and 10) patients had elevated liver tests of whom two patients (cases 9 and 10) had already raised GGT prior to the infection due to biliary problem. Moreover, serum IL-6 was observed in 4 patients. Interestingly, the median values for total white blood cell count, number of platelets, and hemoglobin fell following infection whereas lymphocyte counts did not alter. Similarly, the median ALT, AST, GGT, and LDH levels appeared to be lower after COVID-19.

However, no alteration was statistically significant (Tables 1 and 2 ).

Immunosuppressive regimens were adjusted in 2 of 10 children namely the cessation of MMF. The tacrolimus blood level was kept between 3 and 5 ng/dl. Three out of ten patients received steroids 1 mg/kg/day, favipiravir, and enoxaparin (patient 2, 3, 7). Respiratory insufficiency occurred in 2 patients (patient 2 and 7) and they required non-invasive respiratory support for 2 and 5 days, respectively. Patients 6 who developed severe pulmonary involvement received a single dose of anakinra with azithromycin, meropenemteicoplanin combination. Patients 6 and 7 also received IVIG (Table 2) . 

To the best of our knowledge, this is the first case series of 10 pediatric LT patients contracting SARS-CoV-2. In this report, we presented the characteristics and outcomes of liver transplanted children with COVID-19. The main features of this case series are favorable outcomes and majority of children did not require hospitalization and successfully followed up as outpatients with close tele-interview.

The current understanding is that children with native liver tend to experience a milder COVID-19 disease course, as opposed to adults, even when co-morbidities are present. 15 Additionally, tacrolimus and prednisolone were stopped. By virtue, the patient developed acute kidney failure and liver failure with coagulopathy and heart failure and died. The remaining patients continued to receive immunosuppressive drugs at either same or reduced doses.

Given the lack of solid scientific evidence, the therapeutic approach against COVID-19 varied. In our cohort, the first step of treatment was to cease IST drugs other than tacrolimus and mTOR. patients. Furthermore, as SARS-CoV-2 virus is continuously mutating resulting in more (and likely less) infectious and harmful variants, our conclusions may not be applied in other counties in the future.

A real-time follow-up of SARS-CoV-2 virus mutation and its consequences is mandatory for customised policymaking.

In summary, based on the data available from individual cases and our case series we conclude that the most appropriate treatment manner in SARS-CoV-2 infected LT pediatric patients is to maintain the IS treatment regimen without MMF as it is highly associated with lymphopenia. The main source of infection was the parents/siblings demonstrating that LT patients/relatives require tight follow-up preferably by phone with the nurse transplant coordinator at each center to report any health issue but more importantly to raise awareness pertaining to the risks the first-degree relatives constitute for the patients. Importantly, transplanted children are able to develop antibodies against COVID-19. However, one ought to focus on antibody kinetics such as the presence, the amount and type of neutralizing antibodies to understand the long-term effects of COVID-19 infection in pediatric liver transplant recipients.

All authors declare no conflict of interest. 

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Cigdem Arikan https://orcid.org/0000-0002-0794-2741

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