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\begin{document}

\title{Overcoming Double Jeopardy: Successful Orthotopic Heart Transplant in a
Recipient with Bacterial and Fungal Infections}



\author[1]{Paopat Munthananuchat}%
\author[1]{Bundit Naratreekoon}%
\author[1]{Narongrit Kantathut}%
\author[1]{Piya Samankatiwat}%
\author[1]{Akeatit Trirattanapikul}%
\author[1]{Teerapat Yingchoncharoen}%
\affil[1]{Mahidol University Faculty of Medicine Ramathibodi Hospital}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\textbf{Introduction}

~~~~~~~~Heart transplantation is considered an important treatment
option for advance heart failure patient who do not respond to medical
therapy. However, before surgery, contraindications for heart
transplantation should be evaluated. These contraindications may include
fixed pulmonary hypertension, active cancer, HIV infection, or active
infections with unstable conditions. {[}1{]}

Infection is a significant concern for patients undergoing heart
transplantation include pre- and post-operative period, as it may lead
to the risk of severe infections in these patients. In fact, infections
are the second leading cause of death after graft rejection within the
first 30 days following heart transplantation and the leading cause of
death beyond 30 days post transplantation. {[}2,3{]}

~~~~~~~~Bacterial infections are significant concern for patients
undergoing heart transplantation. According to a study, the incidence of
bacterial infections in these patients can be as high as 43.6\%. Common
causes of infection include pneumonia, bloodstream infections due to the
placement of central venous catheters, and infections associated with
the use of ventricular assist devices. In the past, the mortality rate
from invasive pulmonary aspergillosis in heart transplant patients was
as high as 66.7\%. However, advancements in medical treatments,
including antifungal medications, adjustment of immunosuppressive
therapy, and improved surgical techniques, have improve survival in
these patients. {[}4,5{]}

~~~~~~~~As a result, current medical guidelines recommend treating
fungal infections until symptoms, radiological findings, and laboratory
tests show improvement before proceeding with heart transplantation.
However, there are no specific recommendations for the optimal duration
of treatment before emergency heart transplantation or in cases where
the patient's condition requires urgent surgery. {[}6{]}

\textbf{History of presentation}

~~~~~~~~A previously healthy 16-year-old man presented with gradually
worsening dyspnea on~exertion for over 5 months. As the dyspnea
progressed, he had a low-grade fever for 2~days and was initially
diagnosed with congestive heart~failureand~acute~respiratory~failure at
general hospital.~Despite having treated with mechanical ventilator
support for 4~days,patient's~condition~did~not~improve, leading to a
development of~~~~cardiogenic shock.~In consequence, he was immediately
transferred to cardiac care unit (CCU) of Ramathibodi Hospital
(Ramathibodi Hospital is a university hospital providing super tertiary
care located in Bangkok city in the central region of Thailand) for
further~management.

~~~~~~~~On admission, the patient had 36.0\selectlanguage{ngerman}°C of body temperature with a
heart rate of 130 beats per minute, an oxygen saturation level of 92\%,
and a blood pressure was 85/50 mmHg. Physical examination showed engorge
neck vein, fine crepitation on both lower lung zones, normal heart
sounds without murmur, and cold extremities with delayed capillary
refill. Initial transthoracic echocardiogram revealed left ventricular
dilatation with ejection fraction of 10\%. Acute myocarditis was
suspected and underwent the insertion of venoarterial extracorporeal
membrane oxygenation (VA-ECMO) and intra-aortic balloon pump (IABP) to
stabilize hemodynamics. Furthermore, an atrial septostomy procedure was
performed to alleviate the pressure on the left ventricle. After 4 days
of intensive treatment with mechanical circulatory support, A decision
of bridge to orthotopic heart transplant was made.

~~~~~~~~Transthoracic echocardiogram after VA-ECMO placement revealed
severe left ventricular dilation with left ventricular ejection fraction
of 19\% by biplane method, global wall hypokinesia, right ventricular
systolic dysfunction, complete aortic valve closure, mild to moderate
secondary mitral regurgitation, and other valves were not significant
dysfunction. After adequate decongestion, chest X-ray showed persistent
pulmonary infiltration in the right middle lung zone (Figure 1). On the
9\textsuperscript{th}~day, the VA-ECMO was switched to biventricular
assist device (BiVAD) using CentriMag circulatory support system with
surgical configuration shown in Figure 2.
The~patient~was~then~listed~for~urgent~orthotopic hearttransplant.

\textbf{Past Medical History}

The patient had no significant medical history.

\textbf{Differential diagnosis}

~~~~~~~~Differential diagnosis on acute heart failure includes
lymphocytic myocarditis, viral myocarditis, and decompensated dilated
cardiomyopathy. Regarding the persistent infiltration observed in the
right middle lung zone, various conditions can be considered in the
differential diagnosis. These include localized pulmonary edema,
pulmonary infection such as bacterial pneumonia, pulmonary tuberculosis,
or fungal infection.

\textbf{Investigations}

~~~~~~~~A comprehensive workup of acute myocarditis conducted included
viral infection,~\emph{Mycoplasma}~\emph{pneumoniae} infection, and
toxin screening. All test results were negative. Additionally, an
endomyocardial biopsy was performed, and the pathological findings
revealed mild interstitial fibrosis and no pathological evidence of
acute myocarditis (Figure 3).

~~~~~~~~Further investigation for persistent infiltration in the right
middle lung zone was performed. A chest CT scan could not be performed
due to the unstable condition and mechanical circulatory support. As an
alternative, a lateral plain chest X-ray was done, which indicated a
suspected lesion in the superior segment of the right lower lobe (RLL).
The finding of bronchoalveolar lavage (BAL) through fiberoptic
bronchoscopy was old blood streak with mild mucosal swelling at distal
right bronchus intermedius (Figure 4). Separate BAL samples were
collected from the superior segment and posterior segment of the RLL and
were sent for aerobe culture, cryptococcal antigen,
and\emph{Aspergillus} galactomannan antigen. The aerobe culture of the
BAL fluid showed~\emph{Trichosporon asahii} and
trimethoprim-sulfamethoxazole resistant~\emph{Stenotrophomonas
maltophilia} . Additionally, the~\emph{Aspergillus} galactomannan
antigen and cryptococcal antigen test were positive from BAL fluid from
the superior segment of the RLL. Upon discussing the result of the BAL
fluid cryptococcal antigen, an additional serum cryptococcal antigen
test was performed which came back negative. This raised suspicion of a
false positive cryptococcal antigen due to cross-reaction
with\emph{Trichosporon asahii} . {[}7{]} Considering the overall test
results, the patient was diagnosed with probable invasive pulmonary
aspergillosis (IPA) in conjunction with~\emph{Stenotrophomonas
maltophilia}ventilator-associated pneumonia (VAP).

\textbf{Management}

~~~~~~~~During the initial diagnosis of cardiogenic shock, hemodynamic
stability was maintained through using mechanical circulatory support.
Medical management involved the administration of inotropic drugs. The
antibiotics and antiviral prescribed included ceftriaxone, azithromycin,
doxycycline, and oseltamivir to cover potential causes of myocarditis.
After the VA-ECMO insertion, the dosage of inotropic drugs could be
gradually reduced while still maintaining adequate
hemodynamics.~Hemodynamic parameters, mechanical circulatory
support,~and inotropic agents are summarized in Table 1.

~~~~~~~~On the 10\textsuperscript{th} day after BiVAD insertion, the
patient's hemodynamics deteriorated even though BiVAD function remains
normal and there were no mechanical complications on echocardiogram
found. Higher vasopressor doses were required to maintain mean arterial
pressure. Persistent pulmonary infiltration raised suspicion of VAP with
septic shock. Empiric antibiotics were administered, including
meropenem, vancomycin, levofloxacin, trimethoprim-sulfamethoxazole, and
colistin. After the BAL results came back. Antibiotics were changed to
meropenem, tigecycline, levofloxacin, and voriconazole. Fortunately,
after implementing intensive management, the patient's hemodynamics
improved within 24 hours. This positive response~led to an urgent
orthotopic heart transplant. However, due to active VAP with septic
shock within the past 24 hours as
well~as~the~diagnosis~of~probable~IPA,~a lower~immunosuppressive
regimen~was chosen. This regimen consisted of intravenous
methylprednisolone 500 mg and oral mycophenolic acid 540 mg administered
prior to the operation.

~~~~~~~~After the 20\textsuperscript{th} day, the patient underwent
orthotopic heart transplant. The explanted heart's pathological
examination revealed dilated cardiomyopathy without a specific etiology,
leading to the diagnosis of idiopathic dilated cardiomyopathy (Figure
5).

~~~~~~~~Following the successful transplant, the overall clinical
condition showed improvement, enabling the removal of all mechanical
circulatory support and the discontinuation of antibiotics within 7
days. Voriconazole was continued to treat probable IPA, in addition to
immunosuppressive drugs such as tacrolimus, mycophenolic acid, and
prednisolone.

\par\null

\textbf{Table 1~}Hemodynamic parameters, mechanical circulatory
support,~and inotropic agents during admission.\textbf{~}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=1000px]{figures/Hemodynamic-table/Hemodynamic-table}

\end{center}
\end{figure}

SaO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation;
CO, cardiac output; CI, cardiac index; MAP, mean arterial pressure; CVP,
central venous pressure; PCWP, pulmonary capillary wedge pressure; HR,
heart rate; SVR, systemic vascular resistance; MCS, mechanical
circulatory support; VA-ECMO, venoarterial extracorporeal membrane
oxygenation; IABP, intra-aortic balloon pump; BiVAD, biventricular
assist device



\textbf{Discussion}

\textbf{}~~~~~~~~Ramathibodi Hospital started its heart transplantation
program in May 2017. Since then, over almost seven years, the hospital
has carried out a total of 21 heart transplant surgeries, plus one
re-cardiac transplantation. Notably, the most recent procedure,
conducted in February 2024, involved a combined heart and liver
transplantation, indicative of the hospital's proficiency in complex
surgical interventions. With an average of approximately three cases per
year.{}

~~~~~~~~IPA was a significant cause of morbidity and mortality among
heart and other solid organ transplant recipients. {[}4{]} The active
infection raised concerns about the transplant timing.

In this case, the timeline is demonstrated in Figure 6. The decision to
proceed with orthotopic heart transplant in the presence of active
infection required careful consideration by a multidisciplinary team.
During the perioperative and postoperative periods, the team had to
weigh the risks and benefits of the transplant simultaneously with an
ongoing infection. The decision was well made to minimize the risk of
exacerbating the infection or compromising the patient's post-transplant
outcome and the potential consequences of delaying the transplant.

\textbf{Follow-up}

The chest's CT scans were performed on the 2\textsuperscript{nd} and
6\textsuperscript{th} week after initiating voriconazole treatment,
which revealed a gradual improvement in the consolidation observed in
the right lower lobe (Figure 7). To monitor for rejection, serial
endomyocardial biopsies were performed and all pathological results did
not show any significant concerns.

\textbf{Conclusion}

We demonstrated that controlled infection within a 24-hour period and
the presence of probable IPA may not necessarily be a contraindication
for orthotopic heart transplant. However, the decision should be
carefully weighed on an individual basis and should not be extended to
general practice.

\textbf{Learning Objectives}

To recognize the appropriate timing of orthotopic heart transplant in
the setting of active infection.

To understand the appropriate preoperative and postoperative management
of invasive pulmonary aspergillosis in orthotopic heart transplant
patient.

\textbf{Author contributions}

All authors contributed to editing of the manuscript and provided direct
patient care.

\textbf{References}

1.~~~~~Macdonald P. Heart transplantation: who should be considered and
when?.~\emph{Intern Med J}. 2008;38(12):911-917.
doi:10.1111/j.1445-5994.2008.01833.x

2.~~~~~Montoya JG, Giraldo LF, Efron B, et al. Infectious complications
among 620 consecutive heart transplant patients at Stanford University
Medical Center.~\emph{Clin Infect Dis}. 2001;33(5):629-640.
doi:10.1086/322733

3.~~~~~Pons S, Sonneville R, Bouadma L,~et al. Infectious complications
following heart transplantation in the era of high-priority allocation
and extracorporeal membrane oxygenation. Ann Intensive Care. 2019 Jan
25;9(1):17. doi: 10.1186/s13613-019-0490-2.~{}

4.~~~~~Singh N, Husain S; AST Infectious Diseases Community of Practice.
Invasive aspergillosis in solid organ transplant recipients.~\emph{Am J
Transplant}. 2009 Dec;9 Suppl 4:S180-91. doi:
10.1111/j.1600-6143.2009.02910.x.

5.~~~~~Malinis M, Boucher HW; AST Infectious Diseases Community of
Practice. Screening of donor and candidate prior to solid organ
transplantation-Guidelines from the American Society of Transplantation
Infectious Diseases Community of Practice.~\emph{Clin
Transplant}.~2019;33(9):e13548. doi:10.1111/ctr.13548{}

6.~~~~~Mu\selectlanguage{ngerman}ñoz P, Cerón I, Valerio M, et al. Invasive aspergillosis among
heart transplant recipients: a 24-year perspective.~\emph{J Heart Lung
Transplant}. 2014;33(3):278-288. doi:10.1016/j.healun.2013.11.003{}

7.~~~~~Tone K, Umeda Y, Makimura K. Cross-reactivity in Cryptococcus
antigen latex agglutination test in two commercial kits. Med Mycol. 2016
May;54(4):439-43. doi: 10.1093/mmy/myv115.{}

\par\null

\textbf{Figure Legends{}}

\textbf{Figure 1: {[}Comparison of chest X ray finding on the
1}\textsuperscript{\textbf{st}} \textbf{day and
9}\textsuperscript{\textbf{th}} \textbf{day of admission.}

(A) and (B) On the 9\textsuperscript{th} day of admission, after
adequate decongestion, the follow up chest X-ray revealed persistent
pulmonary infiltration right middle lung zone (yellow
arrow).\textbf{{]}} ~\textbf{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1-Post-BiVAD/Figure1-Post-BiVAD}

\end{center}
\end{figure}

\textbf{Figure 2: {[}Biventricular assist device configuration.~}A
visualization of a biventricular assist device (BiVAD) with a
configuration where the left ventricular assist device (LVAD) inflow
cannula is connected via the left atrium (LA), and the outflow cannula
is connected via the ascending aorta (Ao). The right ventricular assist
device (RVAD) inflow cannula is connected via the right atrium (RA), and
the outflow cannula is connected via the pulmonary artery (PA).~Created
with BioRender.com.\textbf{{]}}{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=1.00\columnwidth]{figures/RVAD/RVAD}

\end{center}
\end{figure}

\par\null

\textbf{Figure 3: {[}Pathological findings from endomyocardial biopsy on
the 9}\textsuperscript{\textbf{th}} \textbf{day of admission.~}(A) The
black arrows indicate mild interstitial fibrosis. (B) The yellow arrow
indicates vacuolar degeneration.\textbf{{]}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2-EMB/Figure2-EMB}

\end{center}
\end{figure}

\textbf{Figure 4: {[}Plain AP and lateral chest X ray and bronchoscopic
finding.} (A) and (B) Comparison of chest X ray views indicating a
suspected superior segment of right lower lobe lesion (yellow arrows).
(C) Bronchoscopic finding reveal blood streak on bronchus intermedius
(red arrow).\textbf{{]}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure3-FOB/Figure3-FOB}

\end{center}
\end{figure}

\textbf{Figure 5: {[}Pathology of the explanted heart.~}(A) Gross
pathology showed biventricular dilatation with no significant ischemia
or fibrosis that are consistent with dilated cardiomyopathy. (B)
Microscopic finding revealed myocyte hypertrophy (yellow arrows) and
vacuolar degeneration (black arrows).\textbf{{]}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure4-Explant-heart/Figure4-Explant-heart}

\end{center}
\end{figure}

\textbf{Figure 6: {[}Timeline of admission.} Created with
BioRender.com.{]}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure5-Timeline/Figure5-Timeline}

\end{center}
\end{figure}

\textbf{Figure 7: {[}Comparison of computed tomography scan of the chest
showed improvement at~}

\textbf{6th week after voriconazole treatment.{]}}{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure6-CT-chest/Figure6-CT-chest}

\end{center}
\end{figure}

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