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\begin{document}

\title{Hepatopulmonary Syndrome with Noncirrhotic Portal Hypertension Diagnosed
Following Acute SAR-CoV-2 Infection}



\author[1]{Eric Mull}%
\author[1]{Rachel Ronau}%
\author[1]{Brent Adler}%
\author[1]{Stephen Kirkby}%
\author[1]{Jaimie D. Nathan}%
\author[1]{Alexander Weymann}%
\author[1]{Archana Shenoy}%
\author[1]{Grace Paul}%
\affil[1]{Nationwide Children's Hospital}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Discussed is the case of a 13-year-old male with no significant past
medical history, who presented to the hospital for evaluation of
multisystem inflammatory syndrome in children (MIS-C). He arrived with
findings of conjunctivitis, strawberry tongue, tachycardia at rest, and
hypoxemia with oxygen saturation of 85\%. The patient was recently
hospitalized 1 week prior for viral pneumonia and hypoxemia due to
SARS-CoV-2. During his inpatient stay he received combination therapy of
remdesivir and dexamethasone. Following, he weaned to room air and his
pulse oximetry (SaO2) order was switched to intermittent with floor
vitals prior to his discharge.%
\end{abstract}%



\sloppy


Hepatopulmonary Syndrome with Noncirrhotic Portal Hypertension Diagnosed
Following Acute SAR-CoV-2 Infection

To the Editor,

Discussed is the case of a 13-year-old male with no significant past
medical history, who presented to the hospital for evaluation of
multisystem inflammatory syndrome in children (MIS-C).~
He~arrived~with~findings~of conjunctivitis, strawberry tongue,
tachycardia at rest, and hypoxemia with oxygen saturation of 85\%.~The
patient~was recently hospitalized 1 week prior for viral pneumonia and
hypoxemia due to SARS-CoV-2. During his inpatient stay he received
combination therapy of remdesivir and dexamethasone.~Following,~he
weaned to room air and his pulse oximetry (SaO2) order was switched to
intermittent with floor vitals~prior to his~discharge.

Upon this re-admission,~the~patient re-developed a supplemental oxygen
(O2) requirement of 3 liters via nasal canula to maintain saturation
above 90\%. Pulmonary was involved following a negative workup for
MIS-C, which included inflammatory markers, electrocardiogram, and
chest~X-ray. Initial recommendations included 5 days of azithromycin (1
day 500 mg, 4 days 250 mg) for anti-inflammatory effects~and 5 days~of
prednisone 60 mg~daily with~hypoxemia believed to be due
ventilation/perfusion (V/Q) mismatch.

The patient remained unable to wean supplemental oxygen and
even~with~support, he~was only able to SaO2 of~92\%. Corticosteroids
were extended for a total of 7 days, added ipratropium bromide every 6
hours for a total of 4 treatments, and broadened our differential
diagnosis for causes of hypoxemia to include diffusion defects and
veno-arterial shunting.~~An echocardiogram~was performed to evaluate for
pulmonary hypertension and left ventricular dysfunction~that
were~previously observed in SAR-CoV-2 infections;~the study
revealed~normal heart function. Computerized tomography angiogram (CTA)
was completed and~showed~occasional scattered patchy opacities~without
evidence~of pulmonary embolism.

As care continued,~it was noted that~the~patient had developed
progressive polycythemia over a two-week time frame with elevations in
hemoglobin to a max of 18.6 g/dL (Reference Range {[}RR{]}: 12.5-16.4
g/dL) and hematocrit to 53.7 \% (RR: 37.0-49.0\%).~Resolving 4 days
after initiation of supplemental oxygen,~suggesting chronic
hypoxemia.~At this time, the patient began~mometasone/formoterol~100 mcg
2 puffs twice a day. He remained stable and was discharged home with
supplemental oxygen of 1.5 L/min with an increase to 4 L/min with
activity.

Shortly afterwards, he was readmitted for worsening hypoxemia at home.
Given that he remained clinically~well,~other than inability to wean to
room air, a CT chest without contrast was obtained. Pulmonary findings
were unremarkable with no signs of arteriovenous malformations. However,
abnormal vasculature was seen in the upper abdominal omentum, the
perisplenic and perigastric regions concerning for varices and
collateral vasculature (Figure 1). This raised concerns for portal
hypertension. A follow up abdominal ultrasound with Doppler did show
normal portal venous flow, as well as heterogeneous echotexture of the
liver consistent with diffuse hepatocellular disease.

Due to growing concern for intrapulmonary shunting,~an echocardiogram
with contrast was conducted and showed agitated saline bubbles appearing
in the left atrium after 4 beats, suggesting a right-to-left shunt. This
finding was consistent with the results of a 6-minute walk test
where~the~patient had~desaturations as~low a 78\% while on room air with
no~significant~improvement noted on 6 L/min.~~Pulmonary function testing
(PFT) was completed with evaluation of diffusion capacity for carbon
monoxide (DLCO) moderately impaired at 55\% predicted for~his~age and
height (RR: 75-140\%).

Hepatology was consulted and~the~patient underwent a liver biopsy. The
histopathology showed subtle abnormalities in the liver parenchyma:
patchy mild portal chronic inflammation, focal lobular inflammation, and
focal minimal peri-central sinusoidal dilatation. No fibrosis,
cholestasis or steatosis was seen (Figure 1). Hepatic venogram performed
with a second liver biopsy, resulting in a normal portosystemic gradient
of 5 mmHg. Subsequently, direct portography with portal pressure
measurements and splenic venogram with splenic pulp pressure
measurements were performed. These were~consistent with non-cirrhotic
portal hypertension.~An arterial blood gas (ABG) was obtained to
calculate the Alveolar-arterial (A-a) gradient. His blood gas showed a
pH of 7.35 (RR: 7.35-7.45), partial pressure of carbon dioxide 52 mmHg
(RR: 36-46 mmHg), partial pressure of oxygen (PaO2) 62 mmHg (RR: 80-105
mmHg), and a base excess of~2.4 mmol/L.~His PaO2~represented~moderate
hypoxemia,~with the~severe range measuring at 60 mmHg or lower. Expected
A-a gradient for his age was 7.3 mmHg and calculated was 47.7
mmHg,~representing significant V/Q mismatch.

Without evidence of primary parenchymal lung disease on extensive
evaluation, the best unifying diagnosis to explain his persistent
hypoxemia was idiopathic noncirrhotic portal hypertension (NCPH) with
hepatopulmonary syndrome (HPS).~~The patient~was listed and successfully
underwent~a liver~transplant with significant improvement in his
symptoms. A year out from initial diagnosis,~the~patient~was~weaned off
supplemental oxygen outside of strenuous activity and only~required~0.2
liters per minute with activity.

This unique case highlights a rare condition that is even rarer in the
pediatric population, particularly outside of associated cirrhosis. HPS
is a condition first described in 1977~\textsuperscript{{[}1{]}},
but~not formally named until 1990\textsuperscript{{[}2{]}}. The hallmark
is the presence of the triad including: intrapulmonary vascular dilation
(IPVD) and abnormal arterial oxygenation in the setting of advanced
liver disease, portal hypertension, or congenital portosystemic shunts
(CPSS)\textsuperscript{{[}3{]}}. Prevalence of this
condition~occurs~between 9\%-20\% of children with end-stage liver
disease, with the prognosis once diagnosed being
poor\textsuperscript{{[}4{]}}. Presentation can be severe with an
insidious onset that often extends the time from presentation to
diagnosis.

Clinically, HPS is characterized by the presence of increased A-a
gradient on room air, with or without
hypoxemia\textsuperscript{{[}3{]}}. Most cases are seen with associated
cirrhosis (up to 40\%) and a liver biopsy may be beneficial.~~ HPS~may
develop in noncirrhotic portal hypertension,~congenital portosystemic
shunt (CPSS),~and ischemic hepatitis\textsuperscript{{[}3,4{]}}.~~A
previously~reported case report of HPS caused by~NCPH~showed similar
findings on histologic review of liver biopsy including dilated
sinusoids and portal spaces\textsuperscript{{[}5{]}}.

Although exact~pathogenesis is not fully understood, there are three
postulated mechanisms~that may play~a~key role~in impaired oxygenation:
They are V/Q mismatch, intrapulmonary shunting, and limitation of oxygen
diffusion\textsuperscript{{[}3{]}}. Patients may be asymptomatic during
the early stages of the disease, but typical symptoms~include:~dyspnea
on excretion or at rest, growth retardation, cyanosis, and digital
clubbing. Dyspnea is the most frequent symptom of progression and when
it occurs upon standing,~it is known as platypnea; hypoxemia exacerbated
in the upright position is known as orthodeoxia, which is seen in
20-80\% of patients\textsuperscript{{[}1,3{]}}.

Chest radiography and PFT tend to be nonspecific; however,~abnormal DLCO
is frequently observed\textsuperscript{{[}1{]}}. It is essential to
confirm the presence of hypoxemia by blood gas analysis and to
demonstrate IPVD, which can be done via a contrast-enhanced
transthoracic echocardiogram\textsuperscript{{[}3{]}}. Confirming the
diagnose HPS, also requires impaired oxygenation be
shown\textsuperscript{{[}4{]}}. An ABG are the most sensitive and
recommended diagnostic modality\textsuperscript{{[}1{]}}. An elevated
A-a gradient \textgreater{} 20 mm Hg is pathologic and important in HPS
diagnosis\textsuperscript{{[}5{]}}. However, due to the invasive nature
of ABG measurements, they are often -- particularly in pediatric
patients -- substituted with simple pulse oximetry which does have a
reasonable sensitivity and specificity for diagnosing
HPS\textsuperscript{{[}6{]}}

At present, liver transplantation is the only curative and life-saving
therapy, by reversing the intrapulmonary vascular shunting and
hypoxemia. It has also been shown to provide complete resolution of gas
exchange abnormalities in the vast majority of
patients\textsuperscript{{[}3{]}}.

Eric S. Mull, DO\textsuperscript{ab}, Rachel Ronau,
DO\textsuperscript{ab}, Brent Adler DO/MD\textsuperscript{c}, Stephen
Kirkby, MD\textsuperscript{abd}, Jaimie D. Nathan MD\textsuperscript{e},
Alexander Weymann MD\textsuperscript{f}, Archana Shenoy
MD\textsuperscript{gh}, Grace Paul, MD\textsuperscript{ab}

\textsuperscript{a}Division of Pulmonary
Medicine;\textsuperscript{b}Department~of
Pediatrics;\textsuperscript{c}Department of Radiology;

\textsuperscript{d}Division of Pulmonary, Critical Care, and Sleep
Medicine, Ohio State University Wexner

Medical Center; \textsuperscript{e}Department of Abdominal
Transplantation and Hepatopancreatobiliary
Surgery;\textsuperscript{f}Division of Pediatric Gastroenterology,
Hepatology and Nutrition;

\textsuperscript{g}Department of Pathology and Laboratory Medicine,
Nationwide Children's Hospital;

\textsuperscript{h}Department of Pathology, The Ohio State University
College of Medicine

Columbus, Ohio

Institution: Nationwide Children's Hospital; Columbus, OH

Funding Source: None

Financial Disclosure: None

Conflicts of Interest: None

Reference:

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\tightlist
\item
  Tumgor G. Cirrhosis and hepatopulmonary syndrome. World J
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\item
  Noli K, Solomon M, Golding F, Charron M, Ling SC. Prevalence of
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\item
  Lee WS, Ong SY, Foo HW, Wong SY, Kong CX, Seah RB, Ng RT. Chronic
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\item
  Borkar VV, Poddar U, Kapoor A, Ns S, Srivastava A, Yachha SK.
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\item
  Yilmaz S, Dursum M, Canoru\selectlanguage{ngerman}ç F, Bayan K, Karabulut A, Akay H. A severe
  (type II) hepatopulmonary syndrome in a patient with idiopathic portal
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\item
  Arguedas MR, Singh H, Faulk DK, Fallon MB. Utility of pulse oximetry
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\end{enumerate}

\textbf{Hosted file}

\verb`HSP Figure 1.docx`  available at \url{https://authorea.com/users/326440/articles/642592-hepatopulmonary-syndrome-with-noncirrhotic-portal-hypertension-diagnosed-following-acute-sar-cov-2-infection}

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