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202 J. Oft and P. Zakowski
successfully transplanted using this approach
and have outcomes similar to the general heart
transplant population.
The parasite is trophic to muscle and heart
cells as well as the neurologic system. While
proactive monitoring with PCR may detect reactivation infection prior to onset of symptoms,
clinical presentations include fever, malaise,
myocarditis or decreased cardiac function, and
may mimic acute rejection [47]. Additional
presentations include hepatosplenomegaly, skin
lesions, and less commonly CNS infection.
These symptoms should prompt additional PCR
testing if beyond six months post-transplant or
following an increase in immunosuppression.
Clinical Approach to Infectious Features
Many of the infections described above present
with similar clinical syndromes in the immunocompromised population. A precise and timely
diagnosis of infection in the HTx recipient is
both more difficult and vital for successful treatment, preservation of graft function, and protection from morbidity and mortality. A general
approach to these clinical aspects is summarized
below.
Fever
After the initial post-operative period, a new
fever generally indicates an underlying infection
and is frequently the first symptom. A systematic approach to fever requires consideration of
risk factors for specific infections to identify the
causative pathogen and guide appropriate empirical therapy. The timing of the fever in relation
to the transplant is one of the first factors considered. Many bacterial infections occur in the
first month after transplantation, often related
to invasive devices or surgical complications. In
the first six months, induction of immunosuppression increases susceptibility to opportunistic
infections and reactivation of latent viral infections. After six months, infections are likely to
be community-acquired and overlap with the
non-transplant population, along with an accumulated risk for opportunistic infections as time
goes on. Next, the total immunosuppression of
the patient is considered, with attention to any
recent history of rejection or augmented immunosuppression. Leukocyte differentials, immunoglobulin levels, and T-cell assays also help
quantify the net immune status to some degree.
The infectious history of both the donor and
recipient is important, particularly for fever
occurring within the first three months after
transplant. Both donor and recipient serologies
prior to transplant should be reviewed, as well
as the patient’s occupational, recreational, and
travel history. Overall, these principles can be
used to aid in the evaluation of not just fever but
many of the other clinical features of infection
after transplant.
Pulmonary Inltrates
Pulmonary infiltrates in HTx patients occur due
to bacterial, viral, fungal, or protozoal infections
and may also be due to non-infectious causes,
including pulmonary edema and neoplasm. Like
fever, timing of onset is important. The nature
of pulmonary symptoms may also offer a clue:
generally speaking, bacterial and viral infections tend to present acutely, whereas fungal and
parasitic infections are more insidious in onset.
Sputum cultures should be performed along with
chest X-rays or CT. Judicious use of microbial
cell-free DNA testing may aid in non-invasive
diagnosis. Lastly, definitive diagnosis can often
be obtained via histology from BAL and/or
transbronchial lung biopsy. Empiric treatment is
warranted while awaiting the testing results.
Wound Infections
Wound infections generally occur within the first
month after transplantation and may lead to mediastinitis. Mediastinitis typically presents with
fever, wound drainage, and sternal instability.
Wound cultures should be collected to optimize
20316 Managing Infections After Heart Transplantation
antibiotic therapy. The most common causative
pathogens are Staphylococci, and debridement
should be performed if possible [48].
Urinary Tract Infections
Urinary tract infections (UTIs) are common
after HTx due to perioperative catheterization.
The incidence and treatment are the same as the
non-transplant surgical population. Treatment
should be adjusted based on urine culture.
Colonized catheters should be replaced, and
treatment is not indicated to eradicate colonizing
organisms. In the later post-transplant stages (>
6 months), in sexually active transplant recipients, a complaint of genitourinary symptoms or
disclosure of high-risk behavior should trigger
an appropriate evaluation for sexually transmitted infections [2].
CNS Infection
While CNS infections after HTx are relatively
rare, they are potentially fatal if left untreated.
Common CNS syndromes include meningitis, focal deficits, and/or encephalitis. Typical
symptoms are headache, altered mental state,
fever, seizures, or focal symptoms. The timing of the onset of symptoms may offer clues
to the potential pathogen. A useful principle
is that early onset symptoms are likely due to
bacteria, Aspergillus, or Candida (due to their
capacity for hematogenous spread), whereas
later symptoms tend to be due to opportunistic
infections. Focal disease presenting within the
first month may be due to a brain abscess. Later
disease may be due to progressive multifocal
leukoencephalopathy from JC virus, Nocardia or
Rhizopus abscesses or meningoencephalitis from
listeria, cryptococcus, VZV, HHV-6, or even
CMV [49]. Brain imaging with CT and MRI
should be performed, along with lumbar puncture for CSF analysis.
GI and Liver Infections
Many of the opportunistic infections described
may disseminate to the gastrointestinal (GI)
and hepatobiliary systems. Symptoms such as
abdominal pain, bleeding, and diarrhea are nonspecific and may also be caused by peptic ulceration, pancreatitis, or drug toxicities. There is a
low threshold for performing endoscopy/colonoscopy with biopsy to aid in the identification
of the responsible pathogen.
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COVID-19 Considerations in Heart Transplantation
Yael Peled
17
Abstract
While much of the knowledge accumulated
for COVID-19 is relevant to the general
population and immunosuppressed patients
alike, some of the particular characteristics of
heart transplant (HTx) recipients warrant tailored approaches to patient management and
to prevention and treatment. Although there
are several pharmacologic therapies available
for HTx recipients, it should be remembered
that this is a rapidly evolving field, further
emphasizing the crucial roles of transplant
team in managing the patients according to
the most up-to-date guidelines. Particularly
important in the crystallization of a vaccination policy was to encourage vaccination
as soon as vaccines became available. The
impact of the accumulated data on SARSCoV-2 will extend beyond protection from
COVID-19 into the implementation of new
vaccine technologies for various other infectious disease targets, improving preparedness
for future health crises, and into applications
Y. Peled (*)
Leviev Heart and Vascular Center, Sheba Medical
Center, Tel Hashomer, Ramat Gan, Israel
e-mail: yael.peled-potashnik@sheba.health.gov.il
Y. Peled
Faculty of Medical and Health Sciences, Tel Aviv
University, Tel Aviv, Israel
for oncology, metabolic diseases, gene
therapy, and gene editing. This chapter will
explore the management of COVID-19 in
HTx patients and vaccination strategies.
Keywords
Heart transplant · COVID-19 ·
Immunosuppression · Pharmacotherapy ·
Immunocompromised · Cytokine storm ·
Vaccines
Clinical Pearls
• Heart transplant recipients are at risk for
more severe COVID-19 and mortality compared with the general population.
Medical comorbidities that have been asso-
•
ciated with more severe COVID-19 and a
greater risk of mortality include older age,
chronic kidney disease, cardiac allograft vasculopathy/graft dysfunction, diabetes mellitus, obesity, frailty, and chronic lung disease.
• Heart transplant recipients, characterized by a
failure to mount a sufficient recall response,
are at risk for prolonged infection with
SARS-CoV-2 and could constitute a reservoir
of divergent escape variants that can spread
in the general community.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_17
207
208 Y. Peled
• Pharmacotherapy targeted against the virus
holds the greatest promise when administered
early in the course of the illness (be aware
of potential drug-drug interactions), whereas
immunomodulatory agents to reduce systemic inflammation may be considered in the
advanced inflammatory response phase.
• The relevant professional bodies encourage
COVID-19 vaccination due to real-world data
on the efficacy and safety of mRNA-based
vaccines in transplant recipients.
Introduction
On December 31, 2019, a cluster of pneumonia cases of unknown etiology was reported in
Wuhan, China. On January 9, 2020, the novel
Severe Acute Respiratory Coronavirus 2 (SARSCoV-2) was identified as the causative agent of
this outbreak. This was the start of what would
become the coronavirus disease 2019 (COVID-
19) pandemic, with over 774 million confirmed
cases and over 7 million deaths reported globally as of March 3, 2024 [1, 2]. The global
response to the COVID-19 pandemic has been
a complex and multifaceted effort, leading to
the introduction of a wide range of non-pharmaceutical interventions and the rapid development of pharmaceuticals (antivirals, monoclonal
antibodies, and, most importantly, COVID-19
vaccines) to control the outbreak. The COVID19 pandemic has constituted a particular challenge for heart transplant (HTx) recipients:
Immunocompromised people, in general, have
been over-represented in breakthrough infections, corresponding to 44% of post-vaccination
infections despite accounting for only 2.7% of
the population (in the pre-delta era) [3, 4]. For
solid organ transplant recipients (SOTRs), the
risk of contracting COVID-19 infection was
80-fold higher, and the risk of hospitalization
and death was 485-fold higher compared to the
general population [5]. SOTRs, being characterized by a failure to mount a sufficient recall
response, are at risk for prolonged infection with
SARS-CoV-2 and could constitute a reservoir
of divergent escape variants that could spread
in the general community. Prolonged viral replication in the context of an inadequate immune
response facilitates viral evolution, which could
lead to the evolution of new variants of concern
(VOCs) [6, 7].
COVID-19 in Heart Transplant Recipients
The specific characteristics of the SARS-CoV-2
virus pose a significant challenge in the care
of HTx patients with COVID-19: The zoonotic
origin of the virus limits pre-existing human
immunity to SARS-CoV-2. In addition, the high
affinity of the spike protein for the angiotensinconverting enzyme 2 (ACE2) receptor and the
novel 4 amino acid insertion facilitate facile
entry of the virus into host cells, and the ensuing replication in the host leads to high viral
loads and efficient spread [8, 9]. SARS-CoV-2
undergoes a high degree of genomic mutation,
and variants with more extensive mutations have
been shown to be associated with higher transmissibility, higher viral infectivity, and greater
immune evasion potential [10]. For HTx recipients, the consequences are more severe COVID19 and a greater risk of mortality [11, 12] since
the above challenges are exacerbated by coexisting medical comorbidities, increased exposure
to SARS-CoV-2 (given their frequent contact
with the health-care system), reduced immune
responses following vaccination and, paradoxically, exclusion from clinical trials (calling into
question the effectiveness of vaccination). Early
in the pandemic [13–15], mortality of HTx
recipients from COVID-19 was shown to be
between 20 and 40%, which was significantly
higher than the percentage mortality in the
general population [16–18]. Transplant recipients with COVID-19 had a 30% increased risk
of death or mechanical ventilation compared
with matched controls (Table 17.1) [19–31].
From the onset of the pandemic to May 2021,
the odds of being diagnosed with COVID-19
were more than five times higher in HTx recipients versus the general population, and the
chances of hospitalization in HTx recipients
17 COVID-19 Considerations in Heart Transplantation
RV dysfunction
↑ Pulmonary artery pressure
Tricuspid valve regurgitation
Thromboembolic events
Severe COVID-19
↑ Older age
↑ LDH, troponin-T,
NT-proBNP,
D-dimer
↓ absolute lymphocyte count
NA
In-hospital mortality rate: 36%
Hospitalized: 90%
Reduced RV function: 28%
Elevated pulmonary artery pressure:
28%
Moderate-to-severe tricuspid regurgi-
tation: 19%
ECG abnormalities: 19%
New thromboembolic events: 19%
Severe COVID-19: 38%
In-hospital mortality rate: 32%
Hospitalized: 79%
Evidence of myocardial injury: 77%
NA
Severe COVID-19: 25%
In-hospital mortality rate: 25%
Hospitalized: 61.5%
Acute kidney injury: 84%
Dialysis: 38%
Severe COVID-19: 46%
CRP
(continued)
Age (>65)
Higher incidence of CKD and
diabetes
Higher respiratory rate and
lower oxygen saturation at the
first clinical evaluation
↑Procalcitonin.↑
In-hospital mortality rate: 41%
Hospitalized: 65%
Severe COVID-19: 31%
New thromboembolic events: 7%
209
1
Study/Country Organ (# recipients) Time from HTx to COVID-19 Reported clinical events Predictors of adverse outcome
Table 17.1 Clinical outcomes of heart transplant recipients with COVID-19
Rivinius et al. [19]/Germany Heart (#21) 95 months (median) Mortality rate: 33%
Latif et al. [20]/USA Heart (#28) 8.6 years (4.2–14.5) Mortality rate: 25%
Ketcham et al. [21]/USA Heart (#13) 9.6 years (median) Mortality rate: 15%
Iacovoni et al. [22]/Italy Heart (#26) 6 years (median) Mortality rate: 27%
210 Y. Peled
↑age, diabetes mellitus,
extracardiac arteriopathy,
previous PCI, CAV score, ↓
GFR, and ↑ NYHA functional
classes were all significantly
associated with in-hospital
CNI + PSI > CNI + antimeta-
bolite
PSI use was associated with
a 6.8-fold risk of severe
COVID-19
Prednisone use associated
with a 7.3-fold risk of severe
COVID-19 and17.8-fold
increased risk of death
In-hospital mortality rate: 25%
Hospitalized: 67%
Severe COVID-19: 25%
Mortality rate: 29.7%
Hospitalized: 17%
In-hospital stay: 17.8 days
ICU stay: 4(9) days
mortality
NA
Severe COVID-19: 25%
NA
In-hospital mortality rate:0
Hospitalized: 100%
Hospitalized: 100%
20% Vasopressors and mechanical
ventilation
ICU length of stay 4–21days
Mild-moderate COVID-19: 100%
NA
In-hospital mortality rate:
Hospitalized: 86.4%
NA
Moderate-severe RV dysfunction:
27.3%
zation)
Hospitalized:100%
Moderate-severe COVID-19: 80%
(continued)
5.6 years (2.0–13.7) Mortality rate: 15%
centers)
Study/Country Organ (# recipients) Time from HTx to COVID-19 Reported clinical events Predictors of adverse outcome
Genuardi et al. [23]/USA Heart (#99 recipients at 11
Table 17.1 (continued)
10.5 ± 8.7 years
Heart (#47)
Bottio et al. [24]/7 HTx centers in
Northern Italy
6.5 years (4.25–12.5) Mortality rate: 0%
Soriano et al. [25]/Brazil Heart (#5) 3–264 months Mortality rate: 40%
Waleed Al-Darzi et al. [26]/USA 5 Heart (#5)
Heart and Lung (#1)
Taghavi et al. [27]/Iran Heart (#22) 3.1 years Mortality rate: 13.6%
Ahluwalia et al. [28]/USA Heart (#5) 21 years (6–25) Mortality rate: 20% (prior hospitali-
17 COVID-19 Considerations in Heart Transplantation
211
NA
In-hospital mortality rate: 0
NA
Hospitalized: 100%
Mild-moderate COVID-19:100%
In-hospital mortality rate: 40%
Hospitalized: 83%
ARDS: 17%
2.2 years Mortality rate: 0
NA
Mortality rate within 30 days of
ICU hospitalization: 33%
ICU stay: 18 days
Mechanical ventilation: 17%
Stroke: 17%
Moderate-severe RV dysfunction:
27.3%
admission: 0
post-HTx)
Hospitalized: 100%
Moderate COVID-19: 60%
Severe COVID-19: 40%
Mechanical ventilation: 40%
Study/Country Organ (# recipients) Time from HTx to COVID-19 Reported clinical events Predictors of adverse outcome
Ballout et al. [29]/USA Heart (#3)
Table 17.1 (continued)
Heart and kidney (#1)
Carraffa et al. [30]/Italy Heart (#6) 12 years (4.0–17.5) Mortality rate: 33%
Lima et al. [31]/USA Heart (#5) 7.9 months (3 within 2 months
Studies are pre-vaccination; not included are studies reporting SOTRs other than heart; also not included are single case reports.
1
Abbreviations ARDS, acute respiratory distress syndrome; BNP, B-type natriuretic peptide; CAV, cardiac allograft vasculopathy; CKD, chronic kidney disease; CNI, calcineu-
rin inhibitor; CRP, C-reactive protein; GFR, glomerular filtration rate; LDH, lactate dehydrogenase; NA, not available; PCI, percutaneous coronary intervention; PSI, prolife-
ration signal inhibitor; RV, right ventricular
212 Y. Peled
with COVID-19 were approximately 80% [14].
Immunosuppressive therapy and the high burden
of comorbidities in HTx patients were—and still
are—major contributors to the poor COVID19 prognosis. Factors associated with higher
COVID-19 mortality include older age, diabetes
mellitus, obesity, frailty, and chronic heart, kidney, and lung disease. In terms of laboratory values, lymphopenia and higher levels of C-reactive
protein, ferritin, procalcitonin, IL-6, D-dimer,
and lactate dehydrogenase have been reported
to be predictors for mortality. Mortality was also
higher among patients with lower incomes and
those who live in more densely populated areas
[32]. Social disparities may negatively affect
outcomes, even in the highly selected population of HTx recipients, characterized by access
to specialized care and close follow-up [33]. As
the pandemic progressed, ongoing excess deaths
of SOTRs were reported despite the advent of
vaccinations and new therapeutics. COVID-19
likely caused over 5000 excess deaths among
SOTRs in the USA in the 13-month period
from March 2020 to March 2021 (representing
1 in 75 SOTRs) and a substantial proportion of
all deaths among SOTRs during that time [34].
Thereafter, the susceptibility of HTx recipients
to COVID-19 did not change, even for less virulent variants; for example, among hospitalized
adult HTx recipients with omicron infection in
two French transplant centers, there were 56%
ICU admissions and 44% deaths versus 47%
ICU admissions and 26% deaths among delta
cases [12].
Management of COVID-19-Positive Heart Transplant Patients
The viral evasion of immune responses and
cytokine storm play essential roles in the pathogenesis, clinical manifestation, and outcomes of
COVID-19 [35]. When determining therapy for
COVID-19 in HTx recipients, clinicians must
consider patient, vaccination, and virus characteristics (Table 17.2). Optimal timing of the
therapeutic intervention in relation to the disease
phase may maximize the therapeutic benefit
(Fig. 17.1) [36]. Thus, involvement of the transplant team in treating COVID-19 and in keeping
up to date with novel targeted therapies and vaccinations are of crucial value.
Adjusting Chronic Immunosuppressive Therapies
Immunosuppressive medications have opposite
effects in the early viral response phase versus the advanced host inflammatory response
phase of COVID-19 progression [36]. In the
early stage of COVID-19, immunosuppressive drugs reduce the innate/adaptive immune
response needed to suppress SARS-CoV-2 viral
replication. At advanced stages, immunosuppressive agents have been successfully used
to prevent and treat the cytokine storm triggered by the virus and have been effective in
reducing mortality and the need for mechanical ventilation in patients with COVID-19
[54–57]. Thus, a tailored phase-specific therapy
approach should be pursued according to the
potential benefit versus the risk of reducing
immunosuppression (Fig. 17.1). Standard prac-
tice in most centers is to discontinue the antiproliferative agent, mycophenolate, promptly
after the diagnosis of COVID-19, the rationale being the possibilities of causing the viral
infection to worsen, the development of leukopenia, or increasing the risk of secondary bacterial infection. Nevertheless, the actual effect
of antirejection drugs on viral diseases is a
complex issue that has not yet been fully elucidated. Mycophenolate is an anti-proliferative
agent that impairs the synthesis of guanosine,
which is essential for DNA and RNA synthesis during the replication of immune cells
and viruses [58]. In-vitro studies have demonstrated that mycophenolate has antiviral activity against different viruses, such as dengue
virus, coxsackievirus, and West Nile virus,
and against coronaviruses, including MERSCoV, and human coronaviruses HCoV-OC43
and HCoV-NL63 [56, 59, 60]. Clinical observations that mycophenolate was well tolerated in patients who were already being treated