Long COVID-19 Liver Manifestation in Children

Abstract

Objectives: 

Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury.

Methods: 

This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome.

Results: 

We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative.

Conclusions: 

We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

What Is Known

• Hepatic injury during acute coronavirus disease 2019 (COVID-19) disease is common.
• Post-COVID-19 cholangiopathy has been reported in adults.

What Is New

• We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children: acute liver failure and hepatitis with cholestasis.
• Common radiologic features included increased periportal echogenicity, dilated biliary ducts, portal edema, and gallbladder wall thickening.
• Common histologic features included ductular reaction, portal and sinusoidal congestion, and portal and parenchymal lymphocytic infiltrates.
• Systemic corticosteroid treatment might be beneficial in patients with similar presentations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. While manifestations are most commonly respiratory, gastrointestinal and hepatic manifestations have been reported extensively (^1,2). The most common liver abnormality is elevated liver transaminase levels during acute disease. Severe disease has been associated with higher rates of liver injury (²).

In children and adolescents, COVID-19 is generally mild (³); however, multisystem inflammatory syndrome (MIS-C) is a serious possible consequence (⁴). in this age group, liver involvement was described with acute COVID-19 and with MIS-C. Mostly, transaminases were elevated, without hepatic synthetic dysfunction, though acute liver failure was also reported (^5–7). Children who developed elevated alanine aminotransferase were at risk of a more severe disease course, including longer hospitalization and stay in the intensive care unit (ICU).

Post-COVID-19 cholangiopathy has been increasingly reported in adults, and includes prolonged cholestasis and secondary sclerosing cholangitis (SSC) (^8–16). To our knowledge, the literature includes only 1 case report of post-COVID-19 transient hepatitis in children (¹⁷).

Our aim was to investigate the entity of liver injury following COVID-19 disease in children. We present 5 pediatric patients who recovered from COVID-19 and later presented with liver injury in 2 distinct patterns. We describe the clinical course and outcomes.

METHODS

This case series describes 5 patients hospitalized in Schneider Children’s Medical Center of Israel during 2021 due to liver injury. One patient was transferred from another hospital. All had a positive SARS-CoV-2 polymerase chain reaction (PCR) test prior to presentation or positive SARS-CoV-2 IgG antibody at presentation. The data collected from medical records included demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. The institutional review board approved the research.

RESULTS

We describe 5 pediatric patients who presented with liver involvement after COVID-19 infection. We distinguished 2 patterns: acute liver failure that required liver transplant and acute hepatitis with cholestasis.

Patients With Acute Liver Failure

Patient 1

In February 2021, a 3-month-old infant presented with fever and tested positive for SARS-CoV-2 infection. He was born at 36 gestational weeks with a low birthweight of 2300 g. Otherwise, he was healthy, with normal growth and development. He did not receive any medical treatment, nor was he admitted to the hospital. At day 21 from the COVID-19 diagnosis, he presented to the emergency department (ED) with 4 days of progressive jaundice. Body temperature and vital signs on arrival were normal. Physical examination was significant only for jaundice. Laboratory tests were aspartate tranaminase (AST) 2078 IU/L, alanine transaminase (ALT) 1440 IU/L, gamma-glutamyl transferase (GGT) 63 IU/L, alkaline phosphatase (ALP) 2042 IU/L, total bilirubin 18.5 mg/dL with direct bilirubin 14.5 mg/dL, albumin 4 g/dL, ammonia 184 µg/dL, international normalized ratio (INR) 5.5. Coagulopathy did not resolve with vitamin K administration. He was admitted to the ICU with a diagnosis of acute liver failure. Laboratory workup for infectious and metabolic causes was negative (Table 1). SARS-CoV-2 IgG antibody was positive (3474 AU/mL). Trio whole exome analysis was performed for the patient and his parents. Additionally, a panel-based approach analysis was performed for regions related to an acute liver failure phenotype including NBAS and SCYL1 variants. Two missense variants in a compound heterozygous state in gene MAN2B2 were detected- c.112G>A; p.Asp38Asn and c.1211T>C; p.Leu404pro. Variants of this gene were described by Verheijen et al in a patient who did not have liver disease (¹⁸). As these specific variants were not described in patients with liver failure in the literature or in our local database, they were classified as variants of uncertain significance with low probability to cause disease. Abdominal ultrasound showed increased periportal echogenicity and was otherwise unremarkable (Fig. 1A). As liver synthetic functions continued to deteriorate and he became encephalopathic, he was listed for liver transplantation. Due to further deterioration, on day 32 he underwent live donor left lateral liver transplantation from his father. Histology from the liver explant demonstrated pericentral and panlobular necrosis, prominent cholangiolar proliferation, and lymphocytic infiltrates, both in the portal area and the parenchyma. Staining was negative for adenovirus, Epstein–Barr virus (EBV), cytomegalovirus (CMV), Herpes simplex virus (HSV), and SARS-CoV-2 (Fig. 2A–C). The patient recovered well and continues ambulatory follow up at the liver transplant clinic.

TABLE 1. - Laboratory workup

Patient number	Infectious workup	Additional workup
1	Hepatitis A	Blood amino acid level
	Hepatitis B	Urinary organic acid level
	Hepatitis C	Carnitine level
	CMV	Acyl-carnitine level
	EBV	Lactate
	VZV	Pyruvate
	HSV	Congenital disorder of glycosylation test
	HHV6	Thyroid function
	Enterovirus	Ceruloplasmin
	HIV	Copper blood level
	Parvovirus	Alpha-1-antitrypsin
	Adenovirus
2	Hepatitis A	Blood amino acid level
	Hepatitis B	Urinary organic acid level
	Hepatitis C	Carnitine level
	CMV	Acyl-carnitine level
	EBV	Lactate
	VZV	Very long chain fatty acid test
	HSV	Urinary reducing substances test
	HHV6	Thyroid function
	Enterovirus	Ceruloplasmin copper blood level
	HIV	Alpha-1-antitrypsin
	Parvovirus
	Adenovirus
3	Hepatitis A	Thyroid function
	Hepatitis B	Ceruloplasmin
	Hepatitis C	Copper blood level
	CMV	Alpha-1-antitrypsin
	EBV	IgG
	VZV	ANA antibodies
	HHV6	F-actin
	Enterovirus	Anti-LKM antibodies
	HIV	Celiac screen
4	Hepatitis A	Thyroid function
	Hepatitis B	Ceruloplasmin
	Hepatitis C	Copper blood level
	EBV	IgG
	CMV	ANA antibodies
	HHV6	F-actin
	Enterovirus	Anti-LKM antibodies
	HIV	Celiac screen
5	Hepatitis A	Thyroid function
	Hepatitis B	Ceruloplasmin
	Hepatitis C	Lactate
	EBV	Blood amino
	CMV	Alpha-1-antitrypsin
	Parvovirus	IgG
	Adenovirus	ANA antibodies
		F-actin
		Anti-LKM antibodies
		Celiac screen

ANA = antinuclear antibodies; CMV = cytomegalovirus; EBV = Epstein–Barr virus; VZV = varicella-zoster virus; HHV6 = human herpesvirus 6; HIV = human immunodeficiency virus; HSV = Herpes simplex virus; IgG = immunoglobulin G; LKM = liver kidney microsomal.

FIGURE 1.: Abdominal ultrasound findings. Ultrasound showed increased periportal echogenicity (A, B), dilated biliary ducts (D, F), periportal edema (A, B), and gallbladder wall thickening (C, E, G).

FIGURE 2.: Liver biopsy of patients 1–4. Histology from the liver explant demonstrating: (1) lymphocytic infiltrates both in the portal area and the parenchyma (A, D, G, J: magnification ×20, B, E, H, K: magnification ×200, hematoxylin-eosin staining. F, I: CD3 immunostaining; magnification ×100). (2) pericentral and panlobular necrosis (B, E). (3) cholangiolar proliferation (keratin 7 staining; C: magnification ×100, L: magnification ×40).

Patient 2

In May 2021, a 5-month-old infant presented to the ED with 2 days of jaundice, dark urine, and acholic soft stools. Medical history was positive for hypospadias and gastroesophageal reflux without medical treatment. Ten days prior to admission, he had worsening of regurgitation and refusal to eat, and was started on several days of Gaviscon treatment, followed by anti-reflux formula, with resolution of symptoms. On arrival, his fever was 38.0°C, with normal vital signs. Physical examination was notable for jaundice and hepatomegaly. Laboratory tests were AST 2265 IU/L, ALT 2219 IU/L, GGT 124 IU/L, ALP 1034 IU/L, total bilirubin 7.7 mg/dL with direct bilirubin 4.5 mg/dL, albumin 4.3 g/dL, ammonia 110 µg/dL. INR was 1.85 after vitamin K administration. He was admitted to the ICU for further workup. During his admission, he developed secondary hemophagocytic lymphohistiocytosis (HLH) with cytopenia, high ferritin level, hypofibrinogenemia, elevated IL-2 levels, and hemophagocytes on liver histology. Genetic sequence analysis and deletion/duplication testing of 407 genes as a part of a primary immunodeficiency panel was performed due to HLH. This panel includes NBAS variant. Results included one variant in the NOD2, gene which is known as a risk for Crohn disease, and three variants with uncertain clinical significance in gene factors CIITA, DOCK8, and WDR1. He was listed for liver transplant as his INR continued to rise. On day 7 from admission, he deteriorated clinically, with encephalopathy, and subsequently underwent live donor liver transplantation (left lateral segment) from his mother. Laboratory workup for infectious and metabolic causes was positive for adenovirus PCR in whole blood (Table 1). SARS-CoV-2 IgG antibody was positive (2629 AU/mL). Abdominal ultrasound demonstrated hepatomegaly, dilated biliary ducts, periportal edema, and gallbladder wall thickening (Fig. 1B, C). Histology from the liver explant demonstrated massive panlobular necrosis with areas of predominantly pericentral necrosis, prominent cholangiolar proliferation, and hepatocanalicular cholestasis. Sinusoids had extensive mononuclear infiltration and signs of hemophagocytosis. Staining was negative for adenovirus, EBV, CMV, HSV, and SARS-CoV-2 (Fig. 2D–F). Postoperatively, he had positive PCR for CMV and adenovirus, and was treated with ganciclovir and cidofovir. The HLH resolved spontaneously without specific therapy. Liver stainings were negative for 3 viruses that potentially caused secondary HLH, namely CMV, adenovirus, and COVID-19.

Patients With Acute Hepatitis With Cholestasis

Patient 3

In December 2020, a previously healthy 8-year-old boy tested positive for SARS-CoV-2 infection. He had very mild symptoms and was tested as his mother tested positive. He did not receive any medical treatment, nor was he admitted to the hospital. On day 130 from COVID-19 diagnosis, he presented to the ED with a week of abdominal pain and vomiting, and 2 days of jaundice. He was not febrile, his vital signs were normal, and his physical examination showed jaundice with hepatomegaly. Laboratory tests were AST 3598 IU/L, ALT 3561 IU/L, GGT 167 IU/L, ALP 496 IU/L, total bilirubin 8.1 mg/dL with direct bilirubin 5.1 mg/dL, albumin 4.2 g/dL, and ammonia 50 µg/dL. INR was 1.5 after vitamin K administration. Laboratory workup for infectious, autoimmune, and metabolic causes was negative (Table 1). Abdominal ultrasound demonstrated mild hepatomegaly, prominent bile ducts, and gallbladder wall edema (Fig. 1D, E). He had a liver biopsy on the fourth day of admission. Histology was notable for portal and sinusoidal congestion, cholangiolar proliferation, and prominent lymphocytic and eosinophilic infiltrates in both portal spaces and the lobules. Staining was negative for adenovirus, EBV, CMV, HSV, and SARS-CoV-2 (Fig. 2G–I). Following a working diagnosis of post-COVID-19 cholestasis, methylprednisolone 2 mg/kg/d was initiated. Both hepatocellular and cholestatic enzymes improved rapidly, as did INR. He was switched to oral prednisone and then gradually weaned over 4 months (Fig. 3). His liver enzymes completely normalized after 4 months and have remained normal since.

FIGURE 3.: Liver enzymes and total bilirubin level during disease course. The red arrow indicates initiation of steroid treatment.

Patient 4

In January 2021, an 8-year-old boy presented with fever and cough, and tested positive for SARS-CoV-2 PCR. He did not receive any medical treatment, nor was he admitted to the hospital. He had BMI above the 97th percentile for his age and known mildly elevated AST and ALT (79 IU/L and 47 IU/L, respectively), which were thought to be secondary to nonalcoholic fatty liver disease. On day 94 after the COVID-19 diagnosis, he presented to the ED with 3 days of fever up to 39°C, abdominal pain, vomiting, diarrhea, and jaundice. His body temperature and vital signs were normal; physical examination showed hepatomegaly and jaundice. Laboratory tests were AST 1551 IU/L, ALT 2439 IU/L, GGT 95 IU/L, ALP 499 IU/L, total bilirubin 10.3 mg/dL with direct bilirubin 6.2 mg/dL, albumin 4.2 g/dL, ammonia 71 µg/dL, and INR 1.2. Laboratory workup for infectious, autoimmune, and metabolic causes was negative (Table 1). SARS-CoV-2 IgG antibody was positive (376 AU/mL). Abdominal ultrasound demonstrated bile duct dilatation and gallbladder wall thickening (Fig. 1F, G). A liver biopsy after 13 days admission revealed portal and sinusoidal congestion, cholangiolar dilatation and proliferation, and prominent lymphocytic and eosinophilic infiltrates in both portal spaces and the lobules. Staining was negative for adenovirus, EBV, CMV, HSV, and SARS-CoV-2 (Fig. 2J–L). Two days after liver biopsy, he was started with systemic steroid treatment. ALT, AST, GGT, bilirubin, and ALP levels gradually decreased, and normalized after 4 months, during which steroids were weaned (Fig. 3). Two months after presentation, he was diagnosed with aplastic anemia. Targeted next generation sequencing and analysis for bone marrow failure gene panel was found negative. He had a successful bone marrow transplant in September 2021 and is well.

Patient 5

In September 2021, a previously healthy 13-year-old boy presented with 5 days of weakness, diarrhea, and abdominal pain. His body temperature and vital signs were normal. A physical examination detected jaundice. Laboratory tests were AST 2901 IU/L, ALT 9376 IU/L, GGT 141 IU/L, ALP 396 IU/L, total bilirubin 12 mg/dL with direct bilirubin 8.8 mg/dL, albumin 3.8 g/dL, ammonia 62 µg/dL, and INR 1.2. A test for SARS-CoV-2 infection was positive. He was admitted to the hospital with gradual clinical and laboratory improvement without medical treatment, his liver enzymes normalized 39 days post-infection. On day 53 from COVID-19 diagnosis, he presented to the ED with 10 days of vomiting and abdominal pain. His fever and vital signs were normal. He had jaundice, hepatomegaly, and right upper quadrant abdominal tenderness on a physical examination. Laboratory tests were AST 8501 IU/L, ALT 10560 IU/L, GGT 66 IU/L, ALP 445 IU/L, total bilirubin 10.4 mg/dL with direct bilirubin 6.6 mg/dL, albumin 3.6 g/dL, and ammonia 214 µg/d. INR was 2.75 after vitamin K administration. Laboratory workup for infectious, autoimmune, and metabolic causes was negative (Table 1). Abdominal ultrasound was normal. On the day of admission, he was started with systemic steroid treatment. ALT, AST, and ALP levels gradually decreased (Fig. 3). Steroid therapy has been gradually weaned and his liver enzymes remain normal.

DISCUSSION

We describe 2 clinical phenotypes of hepatic manifestations associated with a previous recent COVID-19 disease: acute liver failure and acute hepatitis with cholestasis. Severe cholestasis has mainly been reported in adults (^8–15,19). The two patients with acute liver failure were infants (aged 3 and 5 months). Three patients who presented with acute hepatitis with cholestasis were older (aged 8–13 years). Sgouropoulou et al reported a 5-year-old pediatric patient who presented with transient acute hepatitis after SARS-CoV-2 infection (¹⁷). Antala et al described a 6-month-old infant who presented with acute liver failure as a subacute presentation of COVID-19 disease (⁷). On admission he tested positive for SARS-CoV-2 PCR. Twenty-four hours later, he tested negative for SARS-CoV-2 PCR and positive for SARS-CoV-2 IgG antibody. As PCR tests may stay positive for weeks or even months after acute infection, this is in fact might be post-COVID-19 acute liver failure. Of interest, acute liver failure occurred only in infants.

Our 5 patients, and the 2 patients that were described in the literature (^7,17) had asymptomatic or mild presentation of COVID-19 disease. Reports in adults mainly entail severe cholangiopathy, mostly consistent with SSC after prolonged ICU admission during severe acute COVID-19 illness (^8–15,19). The clinical manifestation of the pediatric patients suggests that the pathogenesis is not related to the severity of acute disease.

In our series, cholangiopathy appeared up to several months after COVID-19 diagnosis. One patient had hepatitis during the acute phase of COVID-19 disease, with resolution, and later hepatitis and cholestasis. Similarly, Roth et al reported three patients with prolonged and severe cholestasis during recovery from critical COVID-19 (⁹). Peak liver enzymes occurred at 103–172 days from COVID-19 disease. Our findings corroborate the report of a patient with severe cholestasis 58 days after admission with critical COVID-19 (⁸). Faruqui et al described twelve patients with cholangiopathy after recovery from COVID-19 (¹⁰). The mean time from COVID-19 disease to diagnosis of cholangiopathy was 118 days (range 138–319). Tafreshi et al and Klindt et al each reported a patient with SSC few months post-COVID-19 disease (^13,14). A 5-year-old child was described as presenting with post-COVID-19 transient hepatitis; however, the timing of infection was unknown as the diagnosis was based on serology (¹⁷). The UK Health Security Agency reported 3 patients with positive COVID-19 PCR test in the 8 weeks prior to admission with hepatitis (²⁰). For 4 of our patients, the mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 74.5 days (range 21–130). As COVID-19 was diagnosed in the fifth patient based on serology testing, the time from COVID-19 disease was unknown.

Similar to descriptions in adults, for 4 of our patients, ultrasound studies showed bile duct or gallbladder involvement. Specifically, findings were significant for hepatomegaly, dilated biliary ducts, periportal edema, or gallbladder wall edema and thickening. In adults, ultrasound findings are mostly significant for focal strictures of intrahepatic bile ducts, with intraluminal sludge and casts, compatible with the radiological hallmark of SSC (^8–15,19).

Liver histology showed some similarities between patients. The biopsies were significant for cholangiolar proliferation, portal and sinusoidal congestion, portal lymphocytic infiltrates, and eosinophilic infiltrates along with inflammatory infiltrate of the liver parenchyma. Caramaschi et al (²¹) published a systematic review of histopathological findings in liver biopsies of adults with COVID-19. The most common findings were centrilobular congestion and steatosis that was associated with preexistent obesity and diabetes mellitus. Additional findings described in adults were hepatocyte necrosis, mild to moderate lymphocytic infiltrate in the periportal zone, cholestasis with canalicular bile plugs, ductular reaction, and nuclear pleomorphism of cholangiocytes (^8–15,19). In contrast to adult cohorts, in our pediatric cohort, there was no steatosis. This may imply that the steatosis observed in the adult cohort was related to other comorbidities rather than COVID-19. Stains for SARS-CoV-2 and for adenovirus in our patients were negative.

Recently, there have been increasing reports of children with severe acute hepatitis in the United Kingdom, Europe, the United States, Israel, and Japan. In England and Scotland, 68% and 50% of cases, respectively, tested positive for adenovirus, primarily detected in the blood (^20,22). The etiology of the cases is still not clear as adenovirus usually results in severe hepatitis in immunocompromised hosts. Nonetheless, the increased incidence of adenovirus in the described cases prompted us to further determine if our reported cases may also be associated with adenovirus infection. The histologic features of adenovirus hepatitis include extensive areas of liver cell necrosis with minimal inflammation, intranuclear inclusions, positive immunohistochemistry stain for viral antigens in infected hepatocyte (²³). Specimens described by the European Centre for Disease Prevention and Control included 6 explanted livers and 8 biopsies from English and Scottish cases (²⁰). Adenovirus immunohistochemistry has been reported from 9 of the 14 samples to date and showed immunoreactivity in the intra sinusoidal lumen but not in residual hepatocytes. One case underwent adenovirus PCR of liver tissue which was negative. Marsh et al described liver biopsies from six patients demonstrated various degrees of hepatitis with no viral inclusions observed, no immunohistochemical evidence of adenovirus, and no viral particles identified by electron microscopy (²⁴). In our cohort, we performed adenovirus immunohistochemistry stain for all patients who had a liver biopsy performed or liver explant. The adenovirus stain was negative in all, and the histologic features were not suggestive of adenovirus hepatitis. Three patients had adenovirus PCR performed from whole blood, and in one, it was positive. However, as the liver histology was not suggestive of adenovirus infection, we did not consider it as the culprit for the hepatitis.

SARS-CoV-2 was identified in 15% of reported cases in the United Kingdom on admission; there were further 3 cases had tested positive within the 8 weeks prior to admission (²⁰). Ongoing serological testing is ongoing. Brodin and Arditi hypothesized that those new cases of severe acute hepatitis in children could be a consequence of adenovirus infection in children previously infected by SARS-CoV-2 and carrying viral reservoirs, as murine experiments showed for adenovirus and Staphylococcal-enterotoxin-B (²⁵).

Mechanisms that have been suggested for liver injury during acute disease and after recovery of COVID-19 infection include direct viral damage, immune-mediated injury, ischemia, hypercoagulability state, and drug-induced injury (²). The molecular mechanism suggested for direct viral damage is the presence of angiotensin-converting enzyme 2 (ACE2) receptor in the gut, cholangiocytes, and hepatocytes to which SARS-CoV-2 binds through spike (S) protein and enters the cell (^26,27). Zhao et al also revealed that SARS-CoV-2 infection impairs the barrier and bile acid transporting functions of cholangiocytes in human liver ductal organoids ex vivo (²⁸). Post-COVID-19 cholangiopathy was previously suggested as secondary to ischemic or drug-related injury following severe COVID-19 disease. However, none of our patients had severe disease, suggesting that the mechanism may be related to the ACE2 receptor, which is abundant on cholangiocytes.

Another suggested mechanism is immune-mediated dysregulation and injury. Autoimmune and auto-inflammatory diseases such as MIS-C have been reported in children and young adults with long COVID-19 (⁴). In adults, autoimmune diseases including Idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, abnormal thyroid function, autoimmune hemolytic anemia, and primary biliary cholangitis were reported after COVID-19 disease (^16,29–31). As viruses may induce type II and IV hypersensitivity reactions in addition to their specific cytopathic effect. COVID-19-mediated autoimmunity is also a possible etiology for the liver disease (³²). Another mechanism suggested was that inflammation and dysregulated immune responses following SARS-CoV-2 infection might act as environmental insults that lead to pathologies in predisposed individuals (³³). SSC, which presents in some adults after severe disease, is also associated with auto-inflammatory diseases and inflammatory syndromes (¹⁴). Another example of immune dysregulation, together with the overproduction of cytokines, is secondary HLH (³⁴). Secondary HLH has also been documented in SARS-CoV patients (³⁵). Our patient described as patient 2 presumably had secondary HLH; this might support an immune-mediated mechanism. In our cohort all patients did not meet the diagnostic criteria for MIS-C; none had multiorgan failure, patients 3 and 5 had no fever, and patients 1, 2, and 4 lacked elevated inflammatory markers (³⁶).

Due to the possible immune-mediated mechanism and increasing reports of the need for corticosteroids in treating MIS-C patients, we decided to treat our 3 older patients with systemic corticosteroids. Following initiation of treatment, liver enzymes and bilirubin improved substantially. Although this suggests possible benefit of the treatment, self-improvement might have occurred as well.

CONCLUSIONS

In conclusion, our pediatric patients who recovered from COVID-19 and later presented with liver injury showed 2 distinct patterns. Although the sample is small, our patients shared clinical, radiological, and histopathological characteristics. Our hypothesis that the mechanism of liver manifestation is either a post-infectious immune reaction similar to MIS-C, or an immune dysregulation causing priming to other infectious agent such as adenovirus by a prior infection with SARS-CoV-2, is supported by our histology findings. Further investigations in this direction are warranted. As immune-mediated injury is a possible etiology, systemic corticosteroid treatment might be beneficial in such context.