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298 J. C. Alejos and M. Husain
feeding regimen. Infants, particularly those who
have never fed orally, may require a nasogastric
tube (NGT) for enteral feeding for a prolonged
period. Some may require a percutaneous gastrostomy tube placement or a surgical gastrostomy tube if they are unable to wean off NGT
feeding in the setting of oral aversion or poor
PO tolerance.
Immunosuppression
Immunosuppression in pediatric HTx recipients has been largely guided by protocols in
the adult population and clinical experience.
Review of the PHTS database demonstrates
that while the use of induction therapy results in
decreased episodes of graft rejection, the overall
survival in both the low and high-risk groups is
unchanged. After transplantation, it is becoming increasingly common for induction therapy
to be the starting point for immunosuppression
followed by maintenance therapy. The evidence
on induction therapy remains equivocal. There
is reportedly no difference in survival 14 days
post-transplant [3]. Review of the PHTS data
from 2001 to 2014 demonstrated 73% of newly
transplanted patients received induction therapy.
Of the group 48% were given ATG (from rabbits
or horses) while the remaining 25% were given
interleukin 2 receptor blockers (basiliximab)
[56, 57]. Induction therapy is useful for children with a low urine-output post-operatively to
delay commencement of nephrotoxic calcineurin
inhibitors. Maintenance regimens are normally
based on a CNI such as tacrolimus or cyclosporine. The antiproliferative drug mycophenolate mofetil (MMF) can be used in combination
and has been shown to have superiority over
azathioprine in adults [58]. Also in certain cases
mTor inhibitors such as sirolimus or everolimus can be used in combination with a CNI.
Early studies have suggested an increased time
to cardiac allograft vasculopathy [56]. There is
evidence to suggest that steroid-avoidance regimens can achieve equally good outcomes with
fewer side effects in children who are not sensitized [59]. The side effects of these medications
also play a role in guiding the immunosuppression regimen. CNIs are known to be nephrotoxic. For this reason, renal function is closely
monitored. At a certain point, it may be necessary to move to a renal-sparing protocol. This
may include MMF and mTor inhibitors, which
are both hepatically cleared. MMF is more
commonly known for its GI side effects, so an
enteric-coated form can be utilized. Compliance
must be reiterated, especially as the patient
becomes older and more independent.
Infection
Taking precautions to prevent infection is an
essential part of the post-operative management
plan. Infection is a leading cause of mortality
early on after transplantation. The usual sources
of infection for the surgical patient—lines,
drains, and catheters—are replaced in the operating room and should be removed as soon as
possible after transplantation. The most common
pathogens in the postoperative period are coagulase-negative staphylococci as well as staph
aureus (MSSA or MRSA) [60]. A prophylactic,
short course of intravenous antibiotics is given
in the immediate postoperative period. This is
typically a first-generation and/or vancomycin.
Patients who require prolonged intensive care or
patients already colonized with MRSA require
coverage with vancomycin. Prophylaxis for
Pneumocystis jirovecii is initiated in all patients.
The risk for this is highest in the first 6 months
post-transplant. Patients previously on MCS
therapy are at increased risk of fungal infections (particularly Candida and Aspergillus).
Although fluconazole can be administered prophylactically, caution is needed because of the
interaction with CNIs. Fluconazole inhibits
the cytochrome P450 system that is required
for CNI metabolism. Therefore, an appropriate dose reduction is required for tacrolimus.
The serologic status for CMV of both the donor
and recipient is central in determining the risk
for the recipient. It is strongly recommended to
use prophylactic therapy when there is a mismatch, especially with donor (D)+/recipient
29924 Pediatric Heart Transplantation
(R)−. Prophylaxis is still recommended in cases
of R+/D− however, the duration of therapy
may vary. The data for prophylaxis for EBV is
inconsistent [60]. While the current prophylaxis
may prevent the onset of EBV viremia, frequent
monitoring is paramount.
Rejection Surveillance
Despite significant advances in the field of pediatric HTx, acute and chronic rejection remain
important causes of morbidity and mortality.
Endomyocardial biopsy (EMB) is the current
gold standard for diagnosing allograft rejection.
Children are monitored closely in the days following transplantation for symptoms and signs
of early rejection. Any abdominal pain, tachycardia, new arrhythmias, and oliguria should be
investigated further with an ECG and possibly
EMB to exclude rejection. However, there is no
consensus on the optimal surveillance protocols,
and there remain significant differences across
institutions in the use of routine surveillance
biopsies to detect asymptomatic rejection [61].
Traditional cardio-diagnostic modalities, including echocardiography, electrocardiography, and
CMR, are regaining their popularity in rejection
surveillance, along with serum biomarkers such
as BNP (or NT-proBNP) and donor-specific
antibodies (DSAs). Furthermore, novel noninvasive methods for detecting asymptomatic
rejection, such as immune cell function assay
[62], gene expression profiling [63, 64], and
circulating donor-derived cell-free DNA (dd cfDNA), [65] have similarly emerged as suitable
alternatives to routine surveillance biopsies.
Rejection
Allograft rejection is generally categorized temporally and subcategorized based on type. For
example, hyperacute rejection occurs intraoperatively or within hours of transplantation. Acute
rejection occurs within the first week to 1-month
post-transplantation. Chronic or late rejection
occurs > 1 year post-transplantation. While the
risk of rejection is the highest in the first year
post-transplantation, reported data from two
large registries, including PHTS and ISHLT,
have shown a decline in rejection in the first
year post-transplantation, as well as an overall
decline in rejection over time [8, 66]. Allograft
rejection is also characterized based on the type
of rejection noted on EMB. Specifically, cellular or antibody-mediated. Cellular rejection
is mediated by cytotoxic T-cells, while B-cells
are implicated in antibody-mediated rejection.
There are also benign findings in the form of
non-specific inflammation called Quilty lesions
that may be found on routine surveillance biopsies, which has only been observed in the CNI
era [67]. Treatment for acute rejection is multifaceted and depends on various factors, including but limited to time post-transplant, type and
grade of rejection based on EMB, clinical presentation, hemodynamic effect, co-morbidities,
and confounding co-factors such as infection
or non-adherence to maintenance immunosuppression. Typical treatment is with intravenous
corticosteroids and may involve IVIG, plasmapheresis, adjustment of immunosuppression
depending on the etiology, and initiation of
novel monoclonal antibody treatment protocols.
Long-Term Complications
Cardiac Allograft Vasculopathy
Long-term or late complications beyond 1-year
post-transplantation continue to decline over
time. However, with improvements in survival, the development of cardiac allograft
vasculopathy (CAV) and chronic rejection are
of increasing concern. In children who survive to three years post-transplantation, CAV
is a leading cause of death after graft failure [3, 8] (Fig. 24.7). Risk factors for long-
term or late rejection include early rejection,
presence of anti-HLA antibodies, older age,
African American race, and non-adherence
[68]. Specific risk factors for the development
of CAV include older recipient age, older donor
age, recipient black race, transplant era, no
300 J. C. Alejos and M. Husain
Fig. 24.7 Relative incidence of leading cause of
death in pediatric heart transplants (December 2005–
June 2018). Source Pediatric Heart Transplantation
induction therapy, early and recurrent episodes
of rejection, and re-transplantation [69, 70].
From a symptoms standpoint, it is important to
note that children with CAV often lack ischemic
chest pain but may experience abdominal discomfort instead due to compromised end-organ
perfusion to the gut. It is common for syncope
or sudden death to be the first clinical manifestation of CAV in children. As such, surveillance coronary angiograms are frequently part
of the long-term management plan and remain
the current gold standard for diagnosing CAV.
The degree of CAV is classified on a standardized ISHLT-graded system that additionally
takes into account echocardiographic parameters. Other modalities, including intravascular
ultrasound, cardiac MRI, and optical coherence
tomography, have been previously proposed as
complementary or alternative tools for the diagnosis of CAV. Although intravascular ultrasound
has shown to be more sensitive for detecting
CAV in adults, this has yet to be proven in children. Consequently, its use varies by institution
and is limited to older children due to the size of
the available catheters. From a pathophysiologic
standpoint, CAV results in diastolic dysfunction
Statistics-2019 slides, JHLT. 2019 Oct; 38(10): 1015–
1066, publicly available at: https://ishltregistries.org/
downloadables/slides/2019/heart_pediatric.pptx
due to microvascular disease. This eventually
progresses to systolic dysfunction and carries
a poor survival rate. While there are no definitive treatment options currently available, statins
have been shown to slow the development and
progression of CAV in adult studies. Many
maintenance protocols for the management of
pediatric HTx recipients employ statin therapy.
Although beta-blockers may also provide benefits owing to their anti-ischemic effects, they
are rarely used in this setting. As with adults,
interventional techniques, such as stenting,
do not improve outcomes, highlighted by the
52% graft loss at one-year post-procedure [71].
Retransplantation remains the only effective
treatment once systolic failure ensues.
Infection and Malignancy
The lifelong immunosuppression endured by
children puts them at risk of infection from
a broad spectrum of pathogens. Most infections are successfully treated; however, infection remains the second most common cause
of death in the first month after transplantation
30124 Pediatric Heart Transplantation
and the most common reason for re-hospitalization in the first year post-transplantation
[3]. Both opportunistic pathogens and ordinary
pathogens afflict immunosuppressed children.
Bacterial infections, specifically in the blood
and lungs, predominate in the first month, while
viral infections peak at two months [72]. Any
signs of infection after transplantation should
be treated empirically and immediately with
broad-spectrum antibiotics until the causative
pathogen is identified. A blood culture and/
or endotracheal culture, if the patient is intubated, should be obtained to identify a source,
and antibiotics should be appropriately tailored
once the culture has been speciated and sensitivities have resulted. Antifungal coverage may
be indicated on occasion. A full infection screen
should be done, and the chest radiograph should
be examined for evidence of pneumonia. Serum
biomarkers of inflammation, including white
blood cell count with a differential, C-reactive
protein, and procalcitonin, should be obtained
and trended. CMV infection remains a concern in this patient population. It predominantly
affects the lungs and gastrointestinal tract, typically causing viral pneumonia requiring varying degrees of respiratory support based on its
severity and diarrhea resulting in malabsorption,
poor weight, and abdominal pain, respectively.
Although it is common for CMV prophylaxis
to be used in recipients who receive hearts from
CMV-positive donors, its use has been shown to
have no impact on the long-term complications
of transplantation, such as the development of
CAV or mortality [73]. Infection from CMV is
detected with either PCR or pp65 antigen testing. Early detection usually results in successful treatment with ganciclovir or valganciclovir.
EBV is similarly an important pathogen in the
transplant recipient. Children are more susceptible than adults to EBV-induced PTLD. This is
because immunity to EBV is typically acquired
in adulthood. EBV infection can be difficult
to identify as, even in the immunosuppressed
patient, it can be asymptomatic or present with
mild, non-specific symptoms. However, children
with positive serology for EBV pre-transplant
are still at risk. In addition to the disease itself,
PTLD is a concern because the treatment—typically involving reduction of immunosuppression, can cause rebound rejection and lead to
graft failure. This, in fact, accounts for half of
deaths in children diagnosed with PTLD.
Survival and Outcomes
Survival in pediatric HTx has shown considerable improvements over the last decade. Longterm survival in children now surpasses that of
adults. Post-transplant survival was impacted
by the era during which the transplant was performed. The 1-year post-transplant survival
improved to 92% between 2012 and 2017. This
improved survival across all age groups. Oneyear survival in recipients < 1 year of age is
89%, 92% in recipients between 1 and 10 years
of age, and 94% in recipients 10–17 years of
age. Differences in 1-year survivals were also
noted between different diagnoses; however,
they were improved over the prior era. Survival
among recipients with the diagnosis of dilated
cardiomyopathy, congenital heart disease, and
retransplantation were 95, 88, and 91%, respectively (Fig. 24.8). 5-year conditional survival
was 91.2% in infants less than one year, 92.3%
in recipients between 1 and 10 years, and
88% in children 11–17 years (Fig. 24.9). The
decrease in survival in the older age group may
be impacted by compliance issues [74]. In evaluation of the different eras, there is a significant
difference in freedom from CAV (Fig. 24.10).
Data from the ISHLT shows that ten-year survival is 12% less for congenital heart disease
patients than for cardiomyopathy patients.
Equity
Children of minority race or ethnicity have been
shown to have worse outcomes [75]. Children of
black race are sicker at the time of listing. This
leads to increased use of a VAD as a bridge to
transplant. Early post-VAD outcomes are equal
between white and non-white recipients [75]. Of
note is the increase in graft loss after 1 year for
302 J. C. Alejos and M. Husain
Fig. 24.8 Kaplan–Meier survival in pediatric heart
transplants by recipient age group and diagnosis (January
2005–June 2017). Source Pediatric Heart Transplantation
Fig. 24.9 Freedom from CAV conditional on survival
to discharge in pediatric heart transplants by recipient
age and era (January 1996–June 2013). Source Pediatric
Heart Transplantation Focus Theme, JHLT. 2021 Oct;
Statistics-2019 slides, JHLT. 2019 Oct; 38(10): 1015–
1066, publicly available at: https://ishltregistries.org/
downloadables/slides/2019/heart_pediatric.pptx
40(10): 1023–1072, Publicly available at: https://ishltreg-
istries.org/downloadables/slides/2021/Pediatric_Heart_
Transplantation_Focus_Theme.pptx
24 Pediatric Heart Transplantation
303
Fig. 24.10 Freedom from CAV by era in pediatric heart
transplants (January 1995–June 2017). Source Pediatric
Heart Transplantation Statistics-2019 slides, JHLT. 2019
black patients as well as those of lower socioeconomic status [76]. At the time of listing, black
children are older and sicker. They also face an
increased waitlist mortality [77]. This was independent of patients receiving induction therapy
as well as the incidence of treated rejection. A
survey of clinicians from the Pediatric Heart
Transplant Society demonstrated an implicit
preference for individuals who are white and
of higher socioeconomic status, as well as an
explicit bias for educated people [78]. This warrants further investigation into how these biases
impact clinician behavior.
Summary
Since 1967, when Adrian Kantrowitz became
the first pediatric patient to undergo a HTx,
there have been major advances in the field.
Survivals have improved on both the pre-and
post-transplant sides. Waitlist survival has
improved due to improved algorithms for the
treatment of heart failure, aggressive donor
utilization strategies, and improved access to
Oct; 38(10): 1015–1066, publicly available at: https://
ishltregistries.org/downloadables/slides/2019/heart_pediatric.pptx
suitable VAD, especially in the infant population. Post-transplant survivals continue to
improve with improved regimens of immunosuppression and invasive and non-invasive techniques for monitoring rejection. The expertise
of the congenital heart surgeons, pediatric transplant cardiologists, and multidisciplinary team
members has resulted in improved survival and a
positive quality of life.
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