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\begin{document}

\title{Clinical Implications of Airway Anomalies and Stenosis in Patients with
Heterotaxy Syndrome}



\author[1]{Mei-Hwan Wu}%
\author[1]{Ching-Chia Wang}%
\author[1]{En-Ting Wu}%
\author[1]{Frank Lu}%
\author[1]{Shyh-Jye Chen}%
\affil[1]{National Taiwan University Hospital}%


\vspace{-1em}



  
  \date{June 18, 2024}


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\selectlanguage{english}
\begin{abstract}
In heterotaxy syndrome, bronchopulmonary situs usually reflects atrial
situs, resulting in either right (RAI) or left atrial isomerism (LAI).
This study determines airway anomalies and its implications in patients
with heterotaxy. This retrospective study included 223 patients with
heterotaxy syndrome who received an integrated cardiac computed
tomography evaluation. Patient database from 1995 to 2020 was reviewed.
The patients were examined by a congenital heart disease team comprising
pediatric cardiologists, radiologists, pulmonologists, and
cardiovascular surgeons. Among the 223 patients, 189 (84.8\%, M/F=1.66)
had RAI and 29 had LAI (13.0\%, M/F=0.71). Five patients had
indeterminate isomerism (2.2\%, M/F=1.5). Discordant bronchopulmonary
and atrial situs occurred in 4\% patients, while discordant
bronchopulmonary, atrial, and splenic situs occurred in 23.2\% patients.
Lower airway stenosis was observed in 61 patients (27.4\%), including
27.5\%, 20.7\%, and 60\% RAI, LAI, and indeterminate isomerism patients,
respectively (p=0.189). One patient had an intrinsic long segment lower
tracheal stenosis and received slide tracheoplasty. Initial cardiac
operation was performed in 213 patients. Higher surgical mortality
occurred in patients with RAI (19.5\% vs. none for LAI and indeterminate
isomerism, p=0.038). In patients with RAI, lower airway anomaly/stenosis
increased the duration of ventilator usage (p=0.030) but did not affect
surgical mortality. Total anomalous pulmonary venous return to systemic
veins and pulmonary venous stenosis were major surgical risk factors.
Bronchopulmonary isomerism shares a similar isomeric pattern to cardiac
atrial appendage. Lower airway anomalies/stenosis was common in patients
with heterotaxy, resulting in prolonged ventilator therapy in patients
with RAI.%
\end{abstract}%



\sloppy


\textbf{Introduction}

In humans, the thoracic and abdominal viscera are normally asymmetric
and lateralized. Heterotaxy syndrome is a rare form of congenital
anomaly caused by laterality disorder during embryogenesis. The
prevalence of isomerism was 1.36/10,000 and 0.803/10,000 live births,
reported by the European Surveillance of Congenital Anomalies and
National Birth Defects Prevention Study conducted in the United States,
respectively\textsuperscript{1, 2}. Heterotaxy syndromes are usually
associated with splenic abnormalities and are often referred to as right
(RAI) and left atrial isomerism (LAI) or asplenia and polysplenia
syndrome, respectively. Right atrial isomerism, or asplenia, is
characterized by an absent spleen and duplication of the right-sided
structures, including bilateral trilobed lungs and eparterial bronchi.
LAI, or polysplenia, is characterized by polysplenia and duplication of
the left-sided structures, including bilateral bilobed lungs and
hyparterial bronchi\textsuperscript{3}.

Complex congenital heart disease (CHD) is often observed in patients
with heterotaxy syndrome, particularly in patients with
RAI\textsuperscript{4}. Discordant thoracic and visceral situs has also
been described. An association of airway anomalies in children with CHD
has been reported, mostly in patients with tetralogy of Fallot; the most
common was cyanotic CHD. In patients with an extreme form of tetralogy
of Fallot, the incidence of airway/lung abnormalities was 31\% (detected
by computed tomography (CT) imaging), although the overall incidence of
difficult airways was around 5\%\textsuperscript{5}. Airway anomalies
associated with heterotaxy syndrome may increase perioperative risk and
long-term morbidities.

In most Western countries, patients with LAI account for more than half
of patients with heterotaxy syndrome\textsuperscript{6-9}. In contrast,
more heterotaxy syndrome patients have RAI in oriental
reports\textsuperscript{10-13}. However, the pulmonary variations and
airway anomalies in patients with heterotaxy remain unknown. Most
patients with heterotaxy syndrome need to be palliated by multiple
staged interventions to achieve a single ventricle due to the associated
complex CHD physiology. We hypothesized that the cardiac atrium and
bronchopulmonary situs isomerism subtypes were similar but were less
similar to the splenic situs. Airway anomalies may be common in patients
with bronchopulmonary laterality disorder and might affect surgical
outcomes, particularly the initial cardiac operation. Therefore, we
investigated the incidence and the clinical implications of lower airway
anomalies/stenosis in patients with heterotaxy syndrome, based on a
large cohort with extended observation.

\textbf{Materials and Methods}

Data collection was conducted in accordance with regulations, and this
study was approved by the institutional review board of our institution
National Taiwan University Hospital (Approval Number: 202109080RINC).

\textbf{Patient Cohort}

Patients with heterotaxy syndrome who were evaluated with integrated
cardiac CT (program started from June 1995) were identified from the
patient database (1995--2020) of our institution. Our institution is a
tertiary care center with a CHD program in place for more than 50 years.
Data collection included demographics, sex, cardiac diagnoses from
echocardiography, cardiac catheterization, CT, and cardiac surgeries.
Based on the surgical findings and various imaging information, the
subtype of heterotaxy syndrome for each patient was further classified
as 1) RAI, 2) LAI, or 3) indeterminate isomerism as observed in previous
studies by us and other authors\textsuperscript{8,13}.

Bronchopulmonary situs and the presence of lower airway
anomalies/stenosis were determined using CT imaging. The lower airway
anomalies/stenosis included trachea/bronchial stenosis or
trachea/bronchus malacia, which were determined with electron beam
CT\textsuperscript{14} or bronchoscopy evaluation. Direct laryngoscopy
and/or bronchoscopy were performed when indicated. Patient medical
records concerning respiratory care during the initial palliation
cardiac surgery were reviewed, including ventilator usage, intensive
care unit (ICU) stays, and hospital stays.

\textbf{Statistics}

The Statistical Package for Social Sciences (SPSS, version 15.0, SPSS
Inc., Chicago, IL, USA) was used for analysis. Statistical significance
was assessed with independent Student's t-test and ANOVA where
appropriate. Descriptive statistics were applied and nominal variables
are presented as mean with range. All p values were two-sided, and a p
value of \textless{} 0.05 indicates statistical significance.

\textbf{Results}

\textbf{Patient Characteristics}

We enrolled 223 (M/F = 1.48) patients, including 189 patients with RAI
(84.8\%, M/F = 1.66), 29 patients with LAI (13.0\%, M/F = 0.71), and 5
patients with indeterminate isomerism (2.2\%, M/F = 1.5).

\textbf{Bronchopulmonary and Splenic Situs}

The bronchopulmonary and splenic conditions are summarized
in\textbf{Table 1} . Bronchopulmonary situs was different from the
atrial isomerism in four patients with RAI and five patients with
indeterminate isomerism. Discordant bronchopulmonary and cardiac atrial
situs occurred in 4\% of patients. Asplenia occurred in 81.8\%, solitus
in 6.9\%, inversus in 6.3\%, and other splenic anomalies (lobulated
spleen) in 5.0\% of patients with RAI. Visceral splenic conditions in
patients with LAI included polysplenia (30.7\%), other spleen anomalies
(lobulated spleen) (46.2\%), inversus (15.4\%), and solitus (7.7\%). The
splenic conditions in indeterminate isomerism included inversus (40\%),
asplenia (20\%), and solitus (40\%). Discordant atrial,
bronchopulmonary, and splenic situs were noted in 23.2\% of patients (44
out of 190 patients with abdominal CT imaging during integrated CHD
imaging).

\textbf{Associated Cardiac Morphology}

The associated cardiac structural abnormalities are summarized
in\textbf{Table 2} . Total anomalous pulmonary venous return (TAPVR),
pulmonary venous stenosis, common atrium, common atrioventricular (AV)
valve, double outlet right or indeterminate ventricle, and pulmonary
stenosis/atresia were present in over 90\% of patients with RAI.
Inferior vena cava interruption was present in all except two patients
with LAI. Common atrium, common AV valve, double outlet right ventricle,
and pulmonary stenosis/atresia were also common. The morphological
characteristics of indeterminate isomerism exhibited a mixed pattern of
RAI and LAI.

\textbf{Associated Lower Airway Anomalies/Stenosis}

Lower airway anomalies/stenosis were found in 61 patients (27.4\%)
(\textbf{Fig. 1} ), and the incidence was highest in indeterminate
isomerism (3 patients, 60\%), followed by RAI (52 patients, 27.5\%) and
LAI (6 patients, 20.7\%) \textbf{Table 3} . One patient with
indeterminate isomerism had an intrinsic long segment lower tracheal
stenosis and underwent slide tracheoplasty.

\textbf{Risk Analysis for the Initial Palliative Cardiac Operation}

Initial palliative cardiac surgery was performed in 213 patients, and
surgical mortality was 16.9\%. The surgical mortality was significantly
higher in RAI (19.5\%) patients; no surgical deaths occurred in LAI and
indeterminate isomerism patients (p = 0.038) \textbf{Table 3} . The mean
length of hospital stays was 43.3 \selectlanguage{ngerman}± 65.6 days and the duration of
ventilator usage was 14.9 ± 28.6 days (n = 74). Subsequent analyses were
made in the RAI subgroup.

In patients with RAI, the presence of TAPVR to systemic veins (p
\textless{} 0.001) and pulmonary venous stenosis (p \textless{} 0.001)
were associated with higher surgical mortality. The respiratory and ICU
care are summarized in \textbf{Table 4} . The duration of ventilator
usage was significantly higher in patients with lower airway
anomalies/stenosis (p = 0.030). Although the presence of TAPVR to
systemic veins and pulmonary venous stenosis were important surgical
risks, neither significantly increased the duration of ventilator usage.

\textbf{Discussion}

The clinical implications of lower airway anomalies/stenosis in
heterotaxy syndrome, a rare form of congenital laterality defect, are
unclear. A study of our large patient cohort revealed several novel
findings. The bronchial isomerism subtype was similar to the atrial
isomerism but varied more widely in splenic situs. Congenital lower
airway anomalies/stenosis are common in heterotaxy syndrome (27.4\%) and
might increase the duration of ventilator care during the initial
palliative cardiac surgery. Nevertheless, cardiac anomalies, such as
TAPVR to systemic veins and pulmonary venous stenosis, affected surgical
mortality.

The definition of heterotaxy syndrome subtypes is usually based on the
isomeric pattern of the atrial appendages, which is determined by
surgical findings and advanced imaging, such as cardiac CT
programs\textsuperscript{3,15}. The bronchopulmonary situs pattern can
also be defined using cardiac CT imaging. In addition, the splenic situs
can be delineated by imaging extending to the upper abdomen. Clinical
recognition of heterotaxy subtypes is important because they affect
outcomes\textsuperscript{1}. In general, patients with RAI present with
common atrium, common AV valve, double outlet right ventricle, totally
anomalous pulmonary venous connection, and pulmonary
stenosis/atresia\textsuperscript{13}. The goal of treatment for patients
with RAI is to eventually achieve a single ventricle circulation. In
contrast, LAI with left bronchial isomerism is rare; congenital cardiac
malformations are less complicated in LAI, but LAI is usually associated
with interruption of the inferior vena cava. Tachyarrhythmias are common
in RAI, while bradycardia is more common in patients with
LAI\textsuperscript{13}. While asplenia occurs in patients with RAI,
multiple spleens are often present in patients with LAI.

Using CT or MRI imaging, Yim et al. described bronchopulmonary isomerism
that was discordant with the atrial isomerism in 6 out of 114 patients
(5.3\%); classic right or left isomerism of the atrial appendages,
bronchopulmonary branching, and splenic arrangement was present in
78.5\% of patients\textsuperscript{16}. In our cohort, discordant atrial
and bronchopulmonary isomerism was noted in 4.0\% of heterotaxy syndrome
patients (9/223, four patients with RAI and five indeterminate isomerism
patients). Discordant atrial, bronchopulmonary, and splenic situs were
noted in 23.2\% of patients. Thus, laterality disorders share similar
patterns for atrial and bronchopulmonary situs, but splenic situs may
vary more.

In our study, 61 patients (27.4 \%) had mild to moderate trachea or
bronchial stenosis. Although the incidence of lower airway
anomalies/stenosis is high in patients with heterotaxy syndrome, the
evaluation of airway anomalies/stenosis was seldom mentioned in the
literature. Our initial results are based on the integrated cardiac CT
program to delineate intracardiac and extracardiac structures in
heterotaxy syndrome\textsuperscript{15}. Chen et al. measured airway
anomalies in CHD patients and the associated tracheal and bronchial
stenosis were diagnosed\textsuperscript{14,17}. Maeda et al. found that
syndromic tetralogy of Fallot is usually associated with a 22q11.2
deletion, especially TOF-PA-MAPCA. Airway malacia is often observed in
patients with TOF-PA-MAPCA\textsuperscript{18}. Our patients with RAI
had the worst surgical mortality from the initial cardiac operation, and
ventilator usage was significantly longer in patients with RAI with
airway stenosis (p = 0.030). The presence of lower airway
anomalies/stenosis may lead to difficult extubations from the mechanical
ventilator even after a successful cardiovascular operation.
Nevertheless, the presence of lower airway anomalies/stenosis did not
increase surgical mortality. Although the presence of cardiac anomalies,
including systemic TAPVR and pulmonary venous stenosis, was a major risk
factor for mortality, cardiac anomalies did not prolong ventilator
usage. Preoperative integrated CHD imaging, including the pulmonary
venous return and the airway, is mandatory for the surgical plan and
postoperative intensive care strategy.

Our study is robust but still has limitations. This was a retrospective
study using previously documented cardiac CT, 3D reconstruction,
echocardiography, and bronchoscopy reports/images. In this large series,
all patients had CT, bronchoscopy, or 3D reconstruction. However, to
prevent increased radiation loading in children by dynamic multiple
phase CT scanning, the diagnosis of airway malacia was limited to a
single-phase CT evaluation. A major strength of our work is the large
heterotaxy cohort with complete cardiopulmonary evaluation from an
integrated CHD CT program since 1995. Therefore, we could clarify the
profile of lower airway anomaly/stenosis in heterotaxy.

\textbf{Conclusions}

The pattern of bronchopulmonary isomerism is often similar to the
isomeric pattern of the cardiac atrial appendage, but less similar to
the splenic situs. Lower airway anomalies/stenosis is common in patients
with heterotaxy and prolongs ventilator therapy in patients with RAI.

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