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\begin{document}

\title{Unique Hepatic Manifestations of COVID-19 Induced Immune Dysregulation
in Children Corresponding Author: Julia Kleinhenz, MD, University of
Chicago Comer Children's Hospital; Division of Gastroenterology,
Hepatology \& Nutrition. Email: julia.kleinhenz@uchospitals.edu}



\author[1]{Julia Kleinhenz}%
\author[1]{Ellen Wagner}%
\author[2]{Sarah Afzal}%
\author[1]{Homa Shaarbaf}%
\author[3]{Jorge Luis De Avila}%
\author[4]{Ruba Azzam}%
\affil[1]{University of Chicago Division of the Biological Sciences}%
\affil[2]{Stanford Medicine}%
\affil[3]{University of Chicago Pritzker School of Medicine}%
\affil[4]{University of Chicago}%


\vspace{-1em}



  
  \date{June 03, 2024}


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\selectlanguage{english}
\begin{abstract}
The two cases we present are the first to demonstrate novel
manifestations of COVID-19- related interaction between the liver and
the immune system in pediatric patients. Written informed consent was
obtained from the parent/guardian to publish this report in accordance
with the journal's patient consent policy.%
\end{abstract}%



\sloppy


\textbf{Unique Hepatic Manifestations of COVID-19 Induced Immune
Dysregulation in Children}

\textbf{Corresponding Author}

Julia Kleinhenz, MD

\emph{julia.kleinhenz@uchospitals.edu}

University of Chicago, Department of Pediatric Gastroenterology,
Hepatology \& Nutrition.

5841 S. Maryland Ave., Chicago IL 60637

773-702-1220

\textbf{Co- Authors}

Ellen Wagner, MD

University of Chicago, Department of Pediatric Gastroenterology,
Hepatology \& Nutrition.

Sarah Afzal, MD

Stanford University, Department of Pediatrics

Homa Shaarbaf, MD

University of Chicago, Department of Pediatrics

Jorge Luis De Avilia

University of Chicago School of Medicine

Ruba Azzam, MD MPH

University of Chicago, Department of Pediatric Gastroenterology,
Hepatology \& Nutrition.

\textbf{Conflicts of Interest}

The authors whose names are listed immediately above certify that they
have no affiliations with or involvement in any organization or entity
with any financial interest (such as honoraria; educational grants;
participation in speakers' bureaus; membership, employment,
consultancies, stock ownership, or other equity interest; and expert
testimony or patent-licensing arrangements), or non-financial interest
(such as personal or professional relationships, affiliations, knowledge
or beliefs) in the subject matter or materials discussed in this
manuscript.

\textbf{Introduction}

COVID-19 was originally identified as a respiratory illness with
emerging literature highlighting extrapulmonary manifestations ranging
from neurological to dermatological, inclusive of gastrointestinal and
hepatobiliary complications. In adult literature, between 10 and 58\% of
hospitalized patients with COVID-19 have elevated liver enzymes,
predominantly transaminitis with aspartate aminotransferase (AST) higher
than alanine aminotransferase (ALT). Transaminitis greater than five
times the upper limit of normal is uncommon, as are significant
elevations in alkaline phosphatase. COVID-19 associated liver injury
(known as COVALI) is postulated to result from direct virus-mediated
hepatocyte damage via angiotensin converting enzyme-2 (ACE-2) receptor,
ischemic/hypoxic bystander injury, cytokine-driven and immune-mediated
damage, or antiviral drug-related liver injury. COVALI in adult studies
is typically mild and self-limiting.

Medical literature on liver injury associated with COVID-19 in children
is more limited and spans from single center cohorts to case reports,
covering both respiratory COVID-19 as well as the unique multi-system
inflammatory syndrome (MIS-C). A study of 291 patients (220 with
COVID-19 and 71 with MIS-C) had an overall rate of elevated ALT of 36\%,
31\% in COVID-19 cases and 51\% in MIS-C cases. Severe liver injury,
denoted as ALT \textgreater{} 200 U/L, was noted in 8\% of children with
COVID-19 and 4\% with MIS-C with one child with MIS-C and acute liver
failure that recovered\emph{(Perez et al. 2021)}. No matter
straightforward COVID-19 or more severe development of MIS-C, those with
elevated ALT had more severe disease with higher rates of multisystem
organ dysfunction, respiratory failure, and longer hospitalization as
well as ICU stay\emph{(Perez et al. 2021)}.

Few case reports have described pediatric patients presenting with acute
liver failure in the context of acute COVID-19 infection. While recovery
with native liver was the more common outcome, at least one case had a
fatal outcome\emph{(Sgouropoulou et al. 2021)}.

\textbf{Consent}

Written informed consent was obtained from the patient's parent/guardian
to publish this report in accordance with the journal's patient consent
policy.

\textbf{Case Presentations}

In this brief report, we present two cases of pediatric patients who had
unique presentations of immune dysregulation targeting mainly the liver
post COVID-19 infection. The first developed COVID-19-associated acute
liver failure and aplastic anemia necessitating a liver transplant,
while the other developed phospholipid syndrome presenting as acute
portal vein thrombosis and hepatic abscess formation.

\textbf{Case 1}

A previously healthy ex-full-term two-year-old female presented with a
two-day history of abdominal pain, non-bloody, non-bilious emesis, and
jaundice. Four months prior to presentation, both the patient and her
unvaccinated parents tested positive for SARS-CoV-2 via RT-PCR nasal
swab. They all had mild cough and runny nose that resolved over a ten
day period. Three days prior to her presentation, she developed cough,
congestion, jaundice and tactile fever.

The patient's medical history was significant for minor viral upper
respiratory infections. She had never been hospitalized nor had surgery,
did not take daily medications or endorse any allergies. The family
history was negative for liver diseases.

The patient's vital signs on initial presentation were within
appropriate limits for age. She had scleral icterus, generalized
jaundiced skin, and multiple bilateral lower extremity bruises each
measuring 2 to 3 cm in diameter and concentrated at the mid-shins. Her
lung examination was normal. She had no hepatomegaly nor splenomegaly,
and the rest of her physical exam was otherwise unremarkable.

The patient's initial diagnostic assessment was notable for
transaminitis with ALT: 1,902 U/L, AST: 2,158 U/L, leukopenia 4.9 x
10\textsuperscript{3}/uL, thrombocytopenia: 75 x
10\textsuperscript{3}/uL, and a prolonged INR at 1.4. Her respiratory
viral panel was positive for SARS-CoV-2 and Parainfluenza 3.

Her abdominal ultrasound demonstrated an echogenic liver parenchyma with
no focal lesions.

Liver biopsy showed acute hepatitis with patchy hepatic necrosis and
dropout. Her complete blood count stayed stable but her transaminitis
rose alongside INR. INR peaked at 5.4 on the ninth day of admission
despite Vitamin K infusions. Ammonia level went up to 250 ug/dL and she
started manifesting hepatic encephalopathy. A second liver biopsy was
performed on day 10 showing massive necrosis. Immunostains revealed a
predominant population of CD8+ T-cells that were present in both the
lobules and portal tracts. There were fewer CD4+ T-cells and CD20+
B-cells (which were primarily located within the portal tracts). In
addition, the CD163 immunostain highlighted a significant infiltrate of
macrophages within the lobules. She was urgently listed for a liver
transplant as status 1A.

On the 12\textsuperscript{th} day of admission, the patient received an
orthotopic left lateral liver transplant.

The patient tolerated surgery well and made significant progress in her
post-transplant course. However, her anemia and thrombocytopenia
worsened to hemoglobin \textless{} 5.6 g/dL and platelets \textless{} 10
x10\textsuperscript{3}/uL requiring serial transfusions of packed red
blood cells and platelets. She also developed leukopenia and neutropenia
with absolute neutrophil count (ANC) below 500. A bone marrow biopsy
confirmed the diagnosis of idiopathic aplastic anemia.

She was treated per aplastic anemia protocol with intravenous
immunoglobulin (IVIG), anti-thymocyte globulin (ATG),
methylprednisolone. Her immunosuppression regimen was switched from
tacrolimus to cyclosporine.

At three months post-treatment for aplastic anemia, her hemoglobin
stabilized in the 9-11g/dL range, platelets ranged between 100 -120 x
10\textsuperscript{3}/uL, and her liver chemistry panel remained within
normal ranges.

\textbf{Case 2}

A 9-year-old female with a past medical history of nutritional iron
deficiency anemia presented to the emergency department with a three
week history of subjective fevers, diarrhea, three kilogram weight loss,
and abdominal pain. Upon initial presentation, she was febrile,
tachycardic, and had right upper quadrant abdominal pain.

Initial lab work was significant for leukocytosis of 23.4
x10\textsuperscript{3}/uL, CRP: 152 mg/L and ESR: 47 mm/hr. She had a
negative SARS-CoV-2 via RT-PCR nasal swab and a positive anti-SARS-CoV-2
N antibodies. The evaluation for autoimmune, viral infections,
acetaminophen level were negative. D-dimer was elevated at 8.5ug/ml,
fibrinogen: 424 mg/dl, ferritin: 617 ng/mL. Her liver chemistry panel
had normal transaminases but a low albumin at 2.3mg/dL. Abdominal
computed tomography (CT) was performed and showed scattered clusters of
low-attenuation areas in both liver lobes and opacification of the right
and left portal vein, suggestive of possible thrombosis.

Further imaging with MRI MRCP with and without contrast revealed a 1.4
cm inflammatory focus in the periphery of the right hepatic lobe
concerning for an abscess as well as diffuse right portal vein
thrombosis. Vancomycin and ceftriaxone were initiated and a 7 fr drain
was placed by the interventional radiology team in the right-sided liver
abscess. Twenty cc of frank pus was drained, which subsequently
grew\emph{Streptococcus constellatus} . Attempt at intervening on the
focus on the left lobe did not yield drainable fluid collection. Immune
deficiency workup was performed and negative, including a negative CGD
test (Dihydrorhodamine Flow Cytometric Test).

Hypercoagulation studies were performed to evaluate the underlying cause
of thrombosis, and she was found to have an abnormal LA/APS studies
concerning for antiphospholipid syndrome. Anti-phos Serine/PT IGM
antibodies were positive. Her Cardiolipin and beta 2 glycoprotein
antibodies were negative. DRVVT, aPTT, and dilute prothrombin initial
clotting times were all prolonged and continued to be prolonged after
mixing tests. The DRVVT screen was elevated at 58.8 seconds (normal
range is less than 40.1 seconds), PTTLA screen was elevated at 53.3
seconds (normal range is less than 42.6 seconds), and the Dilute
Prothrombin Time Screen was elevated at 71.8 seconds (normal range 46.9
seconds). These results eliminated the possibility of coagulation factor
deficiency and were consistent with the presence of factor inhibitors,
such as those present in anti-phospholipid syndrome.

The patient was discharged on anticoagulation therapy with low molecular
weight heparin and oral amoxicillin/clavulanate to follow up outpatient
for repeat testing of LA/APS panel, abdominal imaging and vascular
Doppler. The only notable trigger for new-onset antiphospholipid
syndrome in this patient was past COVID-19 infection.

\textbf{Discussion}

\emph{Pediatric Acute Liver Failure \& Immune Dysregulation}

Acute liver failure (ALF) is a fast accelerating process with high
morbidity and mortality. In recent years, more research has gone into
investigating the immune component of ALF, especially in
indeterminate-pediatric acute liver failure (I-PALF) where most common
etiologies of ALF including viral, vascular, metabolic, drugs/toxins are
ruled out and no definitive precipitating cause could be found. I-PALF
accounts for over 30\% of cases of PALF. Recent studies have revealed
evidence towards immune-mediated processes in I-PALF. In addition,
I-PALF patients are more likely to develop aplastic anemia, which by
itself is a disease process also mediated by immune dysregulation

\emph{(Xing et al. 2014).}

The Pediatric Acute Liver Failure (PALF) Group reported on an
interferon-gamma (IFN-\selectlanguage{greek}γ\selectlanguage{english}) -related inflammatory activity in patients with
PALF that is associated with survival with native liver. In contrast,
interleukin 6 (IL-6) and IL-8 producing pathways were associated with
patients demise \emph{(Xing et al. 2014)}. Other groups have found a
group of CD8+ T-cells in patients with I-PALF, proposing this could be a
histologic biomarker for PALF due to immune dysregulation. This study
was multicenter, included a cohort of 37 I-PALF and 18 PALF patients
with known etiologies. Both cohorts had their liver tissue stained for
T-cells, B-cell, macrophages, perforin and tissue resident-memory T
cells. CD8+ immunohistochemical staining was found significantly
abundant (82\%) in the I-PALF group compared to the known diagnosis
group (7\%) with p-value less than 0.0001. In addition, CD8+ cells were
positive for perforin (effector function) and were flagged as
CD103-positive (resident memory phenotype).

Liver tissue from other processes such as autoimmune hepatitis can also
demonstrate ranges of CD8+ dense staining, thus CD8+ staining should not
be considered as pathognomonic of I-PALF, but rather a sign of liver
injury. These findings have led to the use of the newer nomenclature
``activated CD8 T-cell hepatitis.''

Another defining feature of activated I-PALF is age factor. Patients
affected by I-PALF are younger than those with established diagnoses,
inferring that the developing immune system is susceptible to this kind
of immune-mediated injury\emph{(Narkewicz et al. 2018)}.Vodovotz et al.
dived into the immune pathways segregating cohorts of patients by age:
infant, toddler, young childhood, older childhood and adolescent. They
found an age-associated maturity of the immune system that flips
patients to a differential of inflammatory pathways, which could shed
light on outcomes of patients with PALF\emph{(Vodovotz et al. 2020)}.

\emph{Pediatric Acute Liver Failure \& Aplastic Anemia}

Aplastic anemia is most commonly seen with infections such as infectious
hepatitis, EBV, CMV, parvovirus B19, and HIV. However, there is a
correlation between I-PALF and increased risk of developing aplastic
anemia (AA) and early signs of bone marrow dysfunction. There are
similarities between AA and I-PALF as they are more immune-driven
processes involving CD8+ T-cells and high levels of inflammatory
cytokines. AA is a well-described condition that may develop
concomitantly with acute hepatitis (hepatitis-associated aplastic anemia
(HAAA)) or following liver transplant in patients with fulminant liver
failure. The first report of AA after ALF was in 1987 by Stock et al.
Further cases have described it primarily in pediatric patients with
I-PALF \emph{(Itterbeek et al. 2002)}. Mechanistic studies of HAAA have
described immunologic dysregulation as the main pathogenesis: activated
CD8+ T cells are cytotoxic to myelpoietic bone marrow cells, T-cell
clones are formed early on in acute hepatitis, these clones attack
similar target antigens including hepatocytes and myeloid
cells\emph{(Ikawa et al. 2013)}.

\emph{Pediatric Acute Liver Failure \& Antiphospholipid Syndrome}

The antiphospholipid syndrome (APS) is an entity on its own (also known
as primary APS) and is also associated with systemic lupus erythematosus
(SLE). Prevalence of APS in SLE is approximately 25\%\emph{(Singh et al.
2013)}. The pathophysiology of this syndrome remains unclear as is the
why/when of antiphospholipid antibodies (aPL) generation. A combination
of genetic and environmental factors play a role. Known triggers are
commonly viral and bacterial infections. Trauma, surgery, immune
abnormalities, anticoagulation withdrawal, parasitic and fungal
infections, along with some malignancies have also been connected to the
etiology of this condition.

APS is defined by presence of aPL and a vascular thrombosis and/or
complication of pregnancy. The thrombotic episodes range from
superficial thrombophlebitis to myocardial infarction, stroke, and
catastrophic APS (CAPS). CAPS may develop in less than 1\% of APS
patients and involves multiple blood clots that develop over a short
time frame. These clots impair microcirculation and lead to multisystem
organ injury most commonly in brain, lungs, and kidneys.

More recently, research has shown a coagulopathy associated with
COVID-19, which suggests an immune-mediated pathway reminiscent of APS
and the severe form of CAPS\emph{(Serrano et al. 2021)}. Xiao et al.
reported COVID patients with multiple aPL positivities had a higher
incidence of cerebral infarction compared to patients who were
negative\emph{(Xiao et al. 2020)}. Complement activation has been linked
to COVID-19 and contributes to APS pathogenesis (in murine models); the
association between the two needs further investigation\emph{(Fischetti
et al. 2005)}.

\textbf{Conclusion}

The two cases we present are the first to demonstrate novel
manifestations of COVID-19- related interaction between the liver and
the immune system in pediatric patients. While activated CD8+T cell
hepatitis and hepatitis-associated aplastic anemia (HAAA) are defined
and well-reported on in the literature, we herein report the first
association with the novel COVID-19 infection. We also report another
manifestation of immune dysregulation post COVID infection that could
potentially represent an atypical manifestation of MIS-C in the form of
antiphospholipid (APL) syndrome leading to portal vein thrombosis.

These two pediatric cases shed light on the integral role that COVID
plays in the initiation of a pro-inflammatory state that may serve as a
trigger for the propagation of unregulated inflammatory cascade and
immune dysregulation. It will be important to keep COVID- related
activated CD8\textsuperscript{+} T-cell hepatitis in the PALF
differential as well as COVID- related APL and thrombotic events,
especially as pediatric case rates continue to increase. While COVID-19
infections are often reported as `mild' in pediatric patients, it is
important to keep rare and severe post-COVID complications in mind, both
as clinicians as well as community members who are integral in promoting
vaccination efforts.

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