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\begin{document}

\title{Lung Transplantation as An Intervention for Pediatric Pulmonary
Hypertension}



\author[1]{Ernestina Melicoff}%
\author[2]{Don Hayes}%
\author[3]{Christian Benden}%
\affil[1]{Baylor College of Medicine}%
\affil[2]{University of Cincinnati}%
\affil[3]{University of Zurich}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Lung transplantation is recognized as a treatment option for selected
patients with end-stage lung disease and pulmonary vascular disorders.
Overall, pulmonary hypertension (PH) is the second most frequent
indication for children requiring lung transplantation. Pediatric lung
transplantation can be complex; in PH patients timing for listing and
the perioperative management can be particularly challenging making
interdisciplinary collaboration with the referring PH team essential.
Because pediatric patients typically have preserved cardiac index and
exercise tolerance even with advanced disease, they should be referred
early even if they do not meet the proposed criteria for listing by
ISHLT published in 2015: NYHA functional class III or IV without
improvement, cardiac index \textless{} 2 liters/min/m\^{}2, mean right
atrial pressure of \textgreater{} 15 mmHg. Bridging strategies with
extracorporeal support should be determined at time of listing prior to
transplantation anticipating the possibility of clinical deterioration.
Bilateral lung transplantation using cardiopulmonary bypass to provide
hemodynamics stability is the standard practice in pediatric centers.
The immediate post-transplant period is characterized by dramatic
normalization of PVR as well as changes in the RV and LV physiology and
function which can be life-threatening. Induction, immunosuppression,
prophylaxis and surveillance are not different from patients without PH.
Overall, outcomes in pediatric lung and heart-lung transplant patients
for PH are not different from those children undergoing lung or
heart-lung transplant for other indications. In fact, long-term survival
is superior in children with idiopathic PH compared to other diseases,
there is also a dramatic improvement in quality of life in most
recipients%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Pediatric lung transplantation has been performed in selected centers
for three decades, and it is today an accepted therapy in carefully
selected pediatric candidates with progressive pulmonary and pulmonary
vascular disease, delivering an overall survival benefit and improved
health-related quality of life \textsuperscript{1-5}. More than 100 lung
transplant procedures are performed in the pediatric age group per year
worldwide according to the most recent Thoracic Transplant Registry
Report of the International Society for Heart and Lung Transplantation
(ISHLT) \textsuperscript{6}. Pediatric lung transplants are performed
predominately at North American centers; in Europe, leading pediatric
lung transplant programs are located in Hannover, London, and Vienna.
However, the majority of centers in North America, Europe and Australia
do five or fewer pediatric lung transplants per year and mostly
candidates older than age five years \textsuperscript{6}. Overall,
cystic fibrosis (CF) is the most common underlying disease in pediatric
lung transplantation \textsuperscript{6}. In children between one and 10
years of age, CF and idiopathic pulmonary arterial hypertension (IPAH)
are the most common underlying primary indications for lung
transplantation. Overall, IPAH is the second most frequent indication
for children requiring lung transplantation, and in children aged one to
five years IPAH and other forms of PH are the most common
indication\textsuperscript{6}.

In general, pediatric lung transplant is an exceedingly complex
medical-surgical endeavor requiring a multidisciplinary approach and
close interdisciplinary collaboration. The surgical approach is often
challenging due to previous surgery, the pre-transplant morbidities of
the transplant candidates and the frequency of imperfect donor-recipient
lung size matching. Additionally, overseeing and modulating
immunosuppression in infants and children with developing immune systems
with frequent viral infections is imposing. In addition, psychosocial
aspects are potential hurdles to achieve good outcomes, particularly in
adolescents \textsuperscript{1}.

\textbf{CANDIDATE SELECTION AND LISTING}

Timing for referral and listing is always challenging for lung
transplant candidates, particularly with any form of pulmonary
hypertension (PH). PH as an indication for lung transplanation
highlights the importance of interdisciplinary collaboration between the
referring pulmonary hypertension and transplant center teams. As a
general rule, patients should be considered for transplantation when
they are at high risk of death within 1 to 2 years or have unacceptable
quality of life, can survive the wait for organs and the surgery itself
and have a high chance of living a near normal life after lung
transplantation \textsuperscript{7}. Patients with severe forms of PH
like alveolar capillary dysplasia, pulmonary veno-occlusive disease
(PVOD), pulmonary capillary hemangiomatosis and pulmonary vein stenosis,
can progress rapidly to respiratory failure, making early referral
vital\textsuperscript{8}. Patients with IPAH or other forms of pulmonary
vascular disease that meet the following criteria should be referred for
evaluation: NYHA functional class III or IV, rapidly progressive
disease, and optimized use of targeted pulmonary hypertension treatment
(\textbf{Table 1} ). Early referral gives the lung transplant e and
families the opportunity to address barriers identified during
evaluation. Contraindications to pediatric lung transplant include
conditions that predispose the patient to a poor post-transplant
outcome, such as poor adherence to therapy and concomitant organ failure
not suitable to transplant~\textsuperscript{8}. Timing of listing should
take into consideration waiting time (patient's blood type and size,
local policy regarding priority \textsuperscript{9}), center's expertise
related to extracorporeal support \textsuperscript{10} and the patient's
disease trajectory. Listing should be considered when patients meet the
following criteria \textsuperscript{7}: NYHA functional class III or IV
without improvement after 3 months of combination therapy including
prostanoids, cardiac index \textless{} 2 liters/min/m\^{}2, mean right
atrial pressure of \textgreater{} 15 mmHg. However, it has been noted
that pediatric patients often have preserved cardiac index and no
elevation of right atrial pressure even with advanced
disease\textsuperscript{11}. Furthermore, children often have preserved
exercise tolerance at a later stage of disease than adults making
exercise intolerance potentially too late a marker of severe
disease\textsuperscript{12}. Other risk factors that predict poor
survival include: significant hemoptysis, pericardial effusion,
progressive right heart failure, von Willebrand factor levels of
\textgreater{} 240\%, elevated uric acid levels, and persistently
elevated plasma levels of brain natriuretic peptide \textgreater{} 180
pg/mL \textsuperscript{8}.

\textbf{WAIT LIST MANAGEMENT AND BRIDGING STRATEGIES}

Waitlist management is aimed at increasing the patient's prospect of
survival while waiting and improving post-transplant outcomes. In
general, it includes nutritional, physical rehabilitation and
adjustments of targeted PH pharmacotherapy as indicated. For pulmonary
vascular disorders the interventions are aimed at maximizing pulmonary
blood flow and improving oxygen delivery and may include diuretics,
anticoagulation, supplemental oxygen, and other therapies targeted at
the pulmonary vasculature. Atrial septostomy and Pott's shunt procedures
are reserved for patients with refractory pulmonary
hypertension\textsuperscript{13}, these therapies will be further
discussed in other manuscripts in this Supplement \{references from the
Editor\}.

Extracorporeal life support is an invasive, potentially life-sustaining
technology that can be used in patients with persistent right
ventricular failure without response to medical treatment. Historically
veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was
considered a contraindication as a bridge to lung transplantation due to
poor outcomes \textsuperscript{14}. Survival has improved due to
advances in ECMO technology, anticoagulation and enhanced experience in
leading pediatric centers with high priority ECLS teams. Veno-venous
ECMO has been used in selected clinical PH patients whereby oxygenated
blood can be directed through a large atrial septal defect into the left
atrium. More recently the group at Texas Children's Hospital bridged two
PVOD patients with VA-ECMO using central cannulation approach (Gazzaneo
MC, personal communication). Preliminary discussion about bridging
strategies should take place during the evaluation and should be
determined by the time of listing in the event of clinical deterioration
before organs become available. These bridging strategies should be
limited to centers with standardized best practice
protocols\textsuperscript{15}.

\textbf{OPERATIVE STRATEGIES AND BLTX VS HLTX}

The standard surgical approach for patients with PH is bilateral lung
transplantation under cardiopulmonary bypass. Heart-lung transplantation
is usually only performed in patients with PH and irreparable cardiac
defect \textsuperscript{16}. Furthermore, heart-lung blocs have been
increasingly rare in the USA with seven or fewer heart-lung transplants
performed in the pediatric age group in each of the last ten years
(UNOS.org reference). Furthermore, clinical experience has shown good
recovery of cardiac function in virtually all infants, children and
adolescents with severe PH who survive the early post-operative period.
Single lung transplant is rarely performed in pediatrics, particularly
for patients with PH due to adverse outcomes like pulmonary edema and
graft dysfunction \textsuperscript{17}.

Cardiopulmonary bypass (CPB) is used in pediatric patients due to
challenges utilizing double lumen endobronchial tubes in small airways
to provide single lung ventilation \textsuperscript{17}. As well, in PH
patients, CPB provides hemodynamic stability in presence of increased
pulmonary vascular resistance (PVR) \textsuperscript{18}. In some adult
transplant centers, ECMO has become the preferred intra-operative
support as it is associated with reduced complications and improved
survival \textsuperscript{19}. ECMO can also be extended
post-operatively to support patients either to prevent or in selected
patients with significant graft dysfunction \textsuperscript{20}.

\textbf{POST- (H)LTX MANAGEMENT}

Physiologic changes observed immediately after lung implantation with
normalization of PVR should be anticipated; there is an increase in
cardiac output and increase in left ventricular (LV) filling with acute
LV dilation. This acute change in myocardial length-tension relationship
can lead to LV failure. LV failure predisposes to elevation in
post-capillary pulmonary vascular pressures which can lead to pulmonary
edema and classic features of primary graft dysfunction. At the same
time, RV dilation is immediately reduced resulting in a different
length-tension alteration which may also compromise RV function, which
is commonly compromised going into surgery. Treatment includes
protective ventilator strategies, appropriate pressor support and fluid
management to maintain normovolemia; beta-blockers may be considered to
limit cardiac output. Post-operative ECMO support should be considered
within 48 hours for patients with unrelenting low cardiac output and/or
low lung compliance requiring PIP \textgreater{} 35 cmH2O and FiO2
\textgreater{}0.6 \textsuperscript{15}. Induction, immunosuppression,
prophylaxis and surveillance are not different from patients without
PH\textsuperscript{8}.

\textbf{PATIENT OUTCOMES}

In 1992, the group at St. Louis Children's Hospital reported successful
lung transplantation for advanced pulmonary hypertension in five
children with congenital heart disease \textsuperscript{21}. An early
study published in 1996 examined outcomes in 24 children with pulmonary
hypertension for lung transplantation and reported that seven patients
did not meet criteria for listing with seven eventually transplanted (8
died, 2 still active on waitlist at time of study) \textsuperscript{22}.
Using both univariate and multivariate analysis (Cox regression), these
investigators identified poor functional status at the time of referral
defined as New York Heart Association (NYHA) Functional Class III or IV
was significantly associated with and predicted death
before~transplant\textsuperscript{22}. An important conclusion at that
time when lung transplantation was in early development as a treatment
option for children with PH, especially candidates with
advanced~pulmonary hypertension, was that late referral was a major risk
factor for death on the waiting list and for early complications after
implantation. In a subsequent study from St. Louis published in 2002 of
100 patients after lung transplantation for PH, 45~patients with PH had
higher early mortality post-transplant than other pulmonary indications
for transplant \textsuperscript{23}. A single-center study of 53
pediatric lung and heart-lung transplant recipients in Hannover, Germany
found that IPAH as an indication for transplant did not significantly
influence post-transplant mortality in both univariate and multivariate
analyses \textsuperscript{24}.

Investigating the effect of lung transplantation on IPAH, another report
from St. Louis examined 26 children (1.6-18.9 years of age) referred for
lung transplant with 19 transplanted and seven died on the
waitlist\textsuperscript{25}. Median survival for IPAH compared
favorably to all~pediatric~lung transplant~recipients, 5.8 vs. 4.5
years\textsuperscript{25}. The analysis by these investigators found
that survival was independent of pre-transplant~variables, which
included age, weight, intravenous inotropes,
intravenous~pulmonary~vasodilators, and right-sided cardiac pressure
severity \textsuperscript{25}. For those children who died on the
waitlist, the differences compared to the transplanted group included
significantly higher incidence of supra-systemic right heart pressures
and hemoptysis\textsuperscript{25}.

A multi-center, retrospective study by the International~Pediatric~Lung
Transplant Collaborative evaluated outcomes of lung transplant for IPAH
in 23 children IPAH with median survival to children who underwent
heart-lung transplantation~for pulmonary vascular disorders and lung
transplantation~for other indications\textsuperscript{26}. These
investigators reported an overall mortality of 4\% at 3 months
post-transplant with a median survival for children of 45 months
(2-123)\textsuperscript{26}.

To summarize our review of the literature of studies investigating lung
transplant outcomes for PH in children shows cohort size studies vary
from five to 23 children, with one-year post-lung transplant survival
rates ranging between 87-100\%. Schaellibaum et al
\textsuperscript{26}estimated a 3-year survival of 84\%, and Goldstein
et al\textsuperscript{25} reported a 5-year survival of 61\%. With
limited literature on this important topic in the pediatric population,
a recent study was performed using the United Network for Organ Sharing
(UNOS) Registry to evaluate outcomes for children with IPAH after lung
and heart-lung transplantation \textsuperscript{27}. Between May 2005
and December 2015, 75 children (10\selectlanguage{ngerman}±6 years) underwent transplant for
IPAH (47 lung transplant, 18 heart-lung transplant) with 5-year survival
rates of 61\% for lung transplant and 48\% for heart-lung transplant,
with no differences found in survival comparing lung to heart-lung
transplant (\emph{p} \selectlanguage{english} =\selectlanguage{english} 0.680) \textsuperscript{27}.

Looking at the most recent report of the ISHLT Registry, children with
IPAH had the best post-lung transplant survival as determined by the
Kaplan-Meier method (\textbf{Figure 1} ) compared to other pulmonary
diagnoses \textsuperscript{28}. However, the cohort of children with PH
not IPAH had inferior outcomes across all indications for lung
transplant (\textbf{Figure 1} ) \textsuperscript{28}. Limiting the
analysis to conditional one-year post-lung transplant survival, children
with IPAH had a median survival of 12.4 years with a signficant
improvement in the outucomes for children with PH not IPAH
(\textbf{Figure 2} ) \textsuperscript{28}.

The overall survival in the lung transplant and heart-lung transplant
cohorts was not significantly different from survival among children
undergoing lung transplant or heart-lung transplant for other
indications, respectively \textsuperscript{27}. Older age at transplant
was associated with significantly lower mortality after transplantation
(\emph{p} \selectlanguage{english} =\selectlanguage{english} 0.036), while no clinical factors such as lung allocation
score for children \textgreater{} 12 years of age), status 1A listing
(heart-lung transplant cohort) and mean pulmonary artery pressure
significantly influenced survival \textsuperscript{27}. In the 54
children who were listed during the study period who did not undergo
transplant, 22 died, 14 experienced improvement of their condition,
three refused transplant, and four deteriorated so that they were too
sick to transplant \textsuperscript{27}.

Investigating critically ill pediatric patients who underwent lung
transplant, another St. Louis study examined outcomes of children
regardless of underlying diagnosis requiring preoperative and
post-operative ECMO \textsuperscript{14}. The IPAH group was the largest
who received preoperative ECMO and had the best survival rate after lung
transplant \textsuperscript{14}. IPAH trailed only cystic fibrosis as
the largest group requiring post-operative ECMO in children who were
critically ill after lung transplant, while remaining as the indication
with the best survival rate\textsuperscript{14}.

\textbf{Perspectives}

New advances in echocardiographic imaging techniques\textsuperscript{12}
and in cardiac MRI \textsuperscript{29} may provide the tools to more
accurately characterize patients with advancing disease to facilitate
the difficult decision of the timing of referral of such patients to
transplant centers.

\textbf{Acknowledgements} None.

\textbf{Conflicts of interest}

The authors have no conflict of interest to declare.

\textbf{REFERENCES}

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\textbf{Figure Legends}

\textbf{Figure 1.} Survival using the Kaplan-Meier method by diagnosis
in pediatric lung transplants perfromed between January 1992 - June
2017. CF = cystic fibrosis, ILD = interstitial lung disease, OB =
obliterative bronchiolitis, Retx = retransplant, IPAH = idiopathic
pulmonary arterial hypertension, PH = pulmonary hypertension

Modified from Hayes et al\textsuperscript{27} with \emph{permission}from
the International Society of Heart and Lung Transplantation.

\textbf{Figure 2.} Survivial using the Kaplan-Meier method conditional
on one-year surivival by diagnosis in pediatric lung transplants
perfromed between January 1992 - June 2017. CF = cystic fibrosis, ILD =
interstitial lung disease, OB = obliterative bronchiolitis, Retx =
retransplant, IPAH = idiopathic pulmonary arterial hypertension, PH =
pulmonary hypertension

Modified from Hayes et al\textsuperscript{27} with \emph{permission}from
the International Society of Heart and Lung Transplantation.\selectlanguage{english}
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