Case report: Electrocardiographic changes in pembrolizumab-induced fatal myocarditis

Abstract

Immune checkpoint inhibitor (ICI)-induced myocarditis is rare but fatal. Because of the rapid course of ICI-induced myocarditis, understanding of clinical course is only possible through information from case reports. We report a case of pembrolizumab-induced myocarditis in which we were able to document the course of electrocardiographic changes from onset to death. A 58-year-old woman with stage IV lung adenocarcinoma, who had completed her first cycle of pembrolizumab, carboplatin, and pemetrexed, was admitted with pericardial effusion. She underwent pericardiocentesis after admission. A second cycle of chemotherapy was administered 3 weeks after the first cycle. Twenty-two days after admission, she developed a mild sore throat and tested positive for SARS-CoV-2 antigen. She was diagnosed with mild coronavirus disease 2019 (COVID-19), isolated, and treated with sotrovimab. Thirty-two days after admission, an electrocardiogram showed monomorphic ventricular tachycardia (VT). Suspecting myocarditis caused by pembrolizumab, the patient was started on daily methylprednisolone after coronary angiography and endocardial biopsy. Eight days after the start of methylprednisolone administration, she was considered to have passed the acute stage. However, four days later, R-on-T phenomenon triggered polymorphic VT and she died. The impact of viral infections such as COVID-19 on patients be treated with immune checkpoint inhibitors is still unknown and we need to be careful with systemic management after viral infections.

Full text

Case report:
Electrocardiographic changes
in pembrolizumab-induced
fatal myocarditis
Kazuhiro Nishiyama
1
*, Kei Morikawa
1
, Yusuke Shinozaki
1
,
Junko Ueno
1
, Satoshi Tanaka
1
, Hajime Tsuruoka
1
,
Shinya Azagami
1
, Atsuko Ishida
1
, Nobuyuki Yanagisawa
2
,
Yoshihiro J. Akashi
3
and Masamichi Mineshita
1
1
Division of Respiratory Medicine, Department of Internal Medicine, St Marianna University School of
Medicine, Kawasaki, Kanagawa, Japan,
2
Department of Pathology, St. Marianna University School of
Medicine, Kawasaki, Kanagawa, Japan,
3
Division of Cardiology, Department of Internal Medicine, St.
Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
Immune checkpoint inhibitor (ICI)-induced myocarditis is rare but fatal. Because
of the rapid course of ICI-induced myocarditis, understanding of clinical course
is only possible through information from case reports. We report a case of
pembrolizumab-induced myocarditis in which we were able to document the
course of electrocardiographic changes from onset to death. A 58-year-old
woman with stage IV lung adenocarcinoma, who had completed her first cycle of
pembrolizumab, carboplatin, and pemetrexed, was admitted with pericardial
effusion. She underwent pericardiocentesis after admission. A second cycle of
chemotherapy was administered 3 weeks after the first cycle. Twenty-two days
after admission, she developed a mild sore throat and tested positive for SARS-
CoV-2 antigen. She was diagnosed with mild coronavirus disease 2019 (COVID-
19), isolated, and treated with sotrovimab. Thirty-two days after admission, an
electrocardiogram showed monomorphic ventricular tachycardia (VT).
Suspecting myocarditis caused by pembrolizumab, the patient was started on
daily methylprednisolone after coronary angiography and endocardial biopsy.
Eight days after the start of methylprednisolone administration, she was
considered to have passed the acute stage. However, four days later, R-on-T
phenomenon triggered polymorphic VT and she died. The impact of viral
infections such as COVID-19 on patients be treated with immune checkpoint
inhibitors is still unknown and we need to be careful with systemic management
after viral infections.
KEYWORDS
irAE, lung cancer, myocarditis, pembrolizumab, COVID-19
Frontiers in Immunology frontiersin.org01
OPEN ACCESS
EDITED BY
Emanuele Bobbio,
Sahlgrenska University Hospital, Sweden
REVIEWED BY
Piero Gentile,
Niguarda Ca’Granda Hospital,
Italy
Gopal Chandra Ghosh,
Rabindranath Thakur Diagnostic and
Medical Care Center, India
Entela Bollano,
Sahlgrenska University Hospital, Sweden
*CORRESPONDENCE
Kazuhiro Nishiyama
kazuhiro.nishiyama@marianna-u.ac.jp
SPECIALTY SECTION
This article was submitted to
Cancer Immunity
and Immunotherapy,
a section of the journal
Frontiers in Immunology
RECEIVED 24 October 2022
ACCEPTED 06 February 2023
PUBLISHED 16 February 2023
CITATION
Nishiyama K, Morikawa K, Shinozaki Y,
Ueno J, Tanaka S, Tsuruoka H, Azagami S,
Ishida A, Yanagisawa N, Akashi YJ and
Mineshita M (2023) Case report:
Electrocardiographic changes in
pembrolizumab-induced fatal myocarditis.
Front. Immunol. 14:1078838.
doi: 10.3389/fimmu.2023.1078838
COPYRIGHT
© 2023 Nishiyama, Morikawa, Shinozaki,
Ueno, Tanaka, Tsuruoka, Azagami, Ishida,
Yanagisawa, Akashi and Mineshita. This is an
open-access article distributed under the
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that
the original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
TYPE Case Report
PUBLISHED 16 February 2023
DOI 10.3389/fimmu.2023.1078838

Introduction
The advent of immune checkpoint inhibitors (ICIs) has
revolutionized cancer treatment. ICIs sustain T-cell activation and
exert the anti-tumor effects by blocking immunosuppressive
signaling from antigen-presenting cells and tumor cells (1).
Currently, seven ICIs are approved for the treatment of cancer.
Specifically, they are pembrolizumab, nivolumab (PD-1 inhibitors),
atezolizumab, durvalumab, avelumab (PD-L1 inhibitors),
ipilimumab, and tremelimumab (CTLA-4 inhibitors). ICIs have
shown efficacy in the treatment of lung cancer, but they also cause
various immune-related adverse events (irAEs). Among them,
myocarditis is rare but has the highest mortality rate among all
irAEs (2). In cancer therapy, the incidence of myocarditis has been
reported to be 1.14% for all ICIs, 0.5% for PD-1 inhibitors, 2.4% for
PD-L1 inhibitors, and 3.3% for CTLA-4 inhibitors (3). In the
KEYNOTE-189 trial, which evaluated the efficacy and safety of
platinum doublet and pembrolizumab combination chemotherapy
in patients with non-squamous non-small cell lung cancer,
myocarditis was reported in only one case (0.2%) (4).
Recently, the coronavirus disease 2019 (COVID-19) pandemic
has had a major impact on healthcare. COVID-19 is an acute
respiratory illness caused by infection with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2). It is known that some
COVID-19 patients develop cytokine release syndrome (CRS), in
which inflammation-inducing cytokines are increased and the
immune system is activated (5-7). Theoretically, COVID-19
infection could further activate the immune system of cancer
patients being treated with ICI, resulting in severe irAEs. We report
a case of pembrolizumab-induced myocarditis that developed after
COVID-19 infection, in which we were able to document the course
of electrocardiographic changes from onset to death.
Case presentation
A 58-year-old female with a smoking history of at least 35 pack
years had no medical history of dyslipidemia, diabetes mellitus,
hypertension or other medical conditions, and no family history of
coronary artery disease. She received her second COVID-19
vaccination 6 manths ago and no other vaccinations. She was
diagnosed with left lower lobular adenocarcinoma of the lung that
had metastasized to the left hilar and right mediastinal lymph
nodes, invading the pericardium. The tumor was negative for
epidermal growth factor receptor (EGFR), anaplastic lymphoma
kinase (ALK), with a programmed death ligand 1 (PD-L1) tumor
proportion score (TPS) of 25%. She visited her previous physician
complaining of dyspnea after completing her first cycle of
pembrolizumab, carboplatin, and pemetrexed 9 days earlier.
Subsequently, she was referred to our hospital due to a worsening
pericardial effusion on computed tomography (CT) scan (Figure 1).
On initial examination, she was afebrile with a blood
pressure of 125/78 mm Hg, a heart rate of 124 beats/min, and an
oxygen saturation of 97% on 3 liters per minute of oxygen
administration. Blood tests showed no elevation of creatine kinase
(CK), creatine kinase–myocardial band (CK-MB) or troponin T.
Electrocardiogram showed sinus tachycardia and low-voltage QRS
complexes (Figure 2A), while transthoracic echocardiography (TTE)
revealed pericardial effusion. We diagnosed her with cardiac
tamponade, and she underwent pericardiocentesis, removing
500 ml of bloody fluid by drainage tube. Subsequently, her
symptoms and tachycardia improved, and her oxygen saturation
was 96% without oxygen administration. Cytology from the
pericardial fluid revealed class V and neoplastic cells consistent
with metastatic lung adenocarcinoma but no genetic mutation was
detected by highly sensitive next-generation sequencing gene panel
assay. The pericardial fluid drainage tube was removed 6 days later
since there was no re-accumulation of pericardial fluid.
A second cycle of chemotherapy was administered 3 weeks after
the first cycle since her blood tests revealed declining tumor markers,
and no regrowth of the primary tumor on CT scan. Twenty-two days
after admission, she developed a mild sore throat and tested positive
for SARS-CoV-2 antigen. She was diagnosed with mild COVID-19,
isolated, and treated with sotrovimab. Twenty-seven days after
admission, blood tests showed elevated CK, CK-MB and troponin
T, and a negative T wave appeared on electrocardiogram (Figure 2B).
AB
FIGURE 1
Chest computed tomography on admission. (A) Lung window shows a mass shadow in the lower lobe of the left lung. (B) Mediastinal window shows
pericardial effusion.
Nishiyama et al. 10.3389/fimmu.2023.1078838
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She did not complain of palpitations or chest pain. TTE showed a left
ventricular ejection fraction of about 70%, with no re-accumulation
of pericardial fluid, ventricular wall thickening, or ventricular
hypokinesis. However, CK and CK-MB continued to rise on blood
tests, and palpitations appeared 5 days later. She was afebrile with a
blood pressure of 118/82 mm Hg, a heart rate of 111 beats/min, and
an oxygen saturation of 93% on 3 liters per minute of oxygen
administration. Differential diagnoses were considered, with
myocarditis most concerning, followed by acute coronary
syndrome, takotsubo cardiomyopathy, pericardial effusion, and
pulmonary embolism. An electrocardiogram showed monomorphic
VT (Figure 2C). Blood tests revealed CK 5906 U/l, CK-MB 141.7 ng/
ml, troponin T 0.721 ng/ml, and N-terminal prohormone of
brain natriuretic peptide (NT-proBNP) 1368 pg/ml. Pulmonary
embolism was subsequently ruled out with computed tomography–
angiography of the chest. Her hemodynamics had been stable, and
she was started on continuous intravenous amiodarone. The next
day, coronary angiography and endomyocardial biopsy (EMB)
were performed. Her coronary arteries were found to be normal.
Cardiac magnetic resonance (CMR) was not performed due to
infection control.
We suspected pembrolizumab-induced myocarditis and
initiated daily methylprednisolone (1 mg/kg/day) immediately
after EMB. The following day, CK and CK-MB decreased on
blood test (Figure 3) and ventricular tachycardia disappeared on
electrocardiogram. Eight days after the start of methylprednisolone
administration, negative T waves remained on electrocardiogram,
but ST-segment elevation was no longer present (Figure 2D);
therefore, she was considered to have passed the acute stage and
amiodarone administration was terminated. Nine days after EMB,
she was diagnosed histologically as having acute lymphocytic
myocarditis. Myocardial tissue collected at the EMB showed an
infiltrate of inflammatory cells predominantly composed of
lymphocytes (Figure 4A) and granulation fibrosis of the stroma
(Figure 4B). Immunostaining of the tissue showed an inflammatory
cell infiltrate predominantly composed of CD8-positive T
lymphocytes (Figure 4C). A viral genome study of the tissue was
not available at our institution. Twelve days after the start of
methylprednisolone administration, R-on-T phenomenon
triggered polymorphic VT (Figure 2E). It immediately
degenerated into ventricular fibrillation and cardiopulmonary
resuscitation was attempted, but she died.
AB
D
E
C
FIGURE 2
Changes in electrocardiographic waveforms during hospitalization. The admission electrocardiogram showed (A) sinus tachycardia and low-voltage
QRS complexes. (B) Negative T waves appeared on electrocardiogram 27 days after admission, and (C) monomorphic VT appeared 5 days later.
Eight days after the start of methylprednisolone administration, (D) negative T waves remained but ST-segment elevation was no longer present.
Pre-death electrocardiogram showed (E) R-on-T phenomenon triggered polymorphic VT. QT/QTc intervals: (A) 313/443 ms, (B) 395/507 ms,
(C) 433/572 ms, (D) 408/482 ms, (E) 400/408 ms.
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Discussion
This is the first report of pembrolizumab-induced myocarditis
after COVID-19 infection and is also a valuable case in which
electrocardiographic changes of myocarditis could be recorded in
detail. Although the patient died as a result of arrhythmia, we were
able to confirm that corticosteroids are markedly effective in the
acute phase of pembrolizumab-induced myocarditis.
Myocarditis is an inflammatory disease of the myocardium
caused by viral infection, autoimmunity, or drugs (8). The definitive
diagnosis of myocarditis is made by EMB. Myocarditis is classified
as eosinophilic, lymphocytic, giant cell, granulomatous or
pleomorphic based on the type of cells infiltrating the
myocardium. In recent years, ICI-induced myocarditis has been
reported with the spread of ICI, and COVID-19-associated
myocarditis with the COVID-19 pandemic.
ICI-induced myocarditis occurs when ICIs maintain T
lymphocyte activity, T lymphocytes infiltrate the myocardium,
and the immune response is excessive (9). The median time of
onset was reported to be 34 days after the first ICI administration
(3). Histological findings of EMB have been reported to show
myocardial infiltration of CD4- positive lymphocytes, CD8-
positive lymphocytes, and CD68-positive macrophages (10–12).
Corticosteroids are often used in the initial treatment of ICI-
induced myocarditis, and other immunosuppressive agents are
also considered in corticosteroid-resistant patients (11,12,13).
Guidelines published in 2018 by the American Society of Clinical
Oncology and the National Comprehensive Cancer Center Network
recommend treatment with 1 to 2 mg/kg of prednisone for ICI-
induced myocarditis (15).
On the other hand, COVID-19-associated myocarditis is
thought to result from direct damage to the myocardium by the
virus and myocardial damage by the host’s immune response (16).
The exact incidence of COVID-19-associated myocarditis is
unknown because of diagnostic difficulties; some reports indicate
that 5.0% of COVID-19 patients developed new onset myocarditis
(17). Fulminant myocarditis caused by COVID-19 has been
reported to produce ventricular dysfunction and heart failure
within 2 to 3 weeks after infection with SARS-CoV-2 (18,19).
Histological findings of EMB shows infiltration of CD4- and CD8-
positive lymphocytes in myocardial tissue, as well as CD68-positive
macrophages in patients with severe clinical symptoms, such as
fulminant myocarditis (20,21). There are reports that the SARS-
CoV-2 genome was detected in myocardial tissue from some
COVID-19 patients (22–25). However, there have been reports of
virus-negative COVID-19-associated myocarditis, and the
authenticity of the SARS-CoV-2 genome remains uncertain (26).
Although the treatment of COVID-19-associated myocarditis has
not yet been established, corticosteroids are not recommended in
viral myocarditis (27).
This patient developed myocarditis 41 days after the first dose
of pembrolizumab and 11 days after SARS-CoV-2 infection.
Myocardial tissue showed histological findings of acute lymphocytic
myocarditis. The timing of onset and histological findings of
myocarditis were consistent with both pembrolizumab-induced
myocarditis and COVID-19-associated myocarditis. We considered
pembrolizumab-induced myocarditis most likely since that
myocarditis improved markedly after corticosteroid administration.
However, COVID-19-associated myocarditis also causes myocardial
damage due to the immune response, so it cannot be completely ruled
out. COVID-19 infection has been reported to increase the risk of
serious irAEs and may have triggered the development of
pembrolizumab-induced myocarditis in this case (28).
An electrocardiogram is a simple test that records the heart’s
electrical signals and is often used to detect arrhythmias and
myocardial disorders. In this case, symptoms of myocarditis, such
as palpitations and chest pain, were not present at first, and it was
difficult to suspect myocarditis from the symptoms alone. However,
we were able to suspect myocarditis at an early stage based on
elevated CK and electrocardiographic changes. In addition, frequent
ECG testing after the onset of myocarditis made it possible to
document ECG changes during the course of treatment for
myocarditis. Poor prognostic factors in electrocardiograms of
acute myocarditis have been reported as pathological Q wave,
wide QRS complex, QRS/T angle ≥100°, prolonged QT interval,
high-degree atrioventricular block and malignant ventricular
tachyarrhythmia (29–32). There are also reports of a high
incidence of heart block, such as complete atrioventricular block
and right bundle branch block, in electrocardiograms of patients
with ICI-induced myocarditis (33). Her ECG showed no heart
block, but a wide QRS complex, QRS/T angle ≥100°, prolonged
QT interval and malignant ventricular tachyarrhythmia, which
predicted a poor prognosis.
There have been several case reports of successful treatment of
pembrolizumab-induced myocarditis (34–36). However, in this
case, she survived the acute stage of myocarditis without the use
of an extracorporeal circulatory device, but the resulting arrhythmia
FIGURE 3
Cardiac biomarkers and electrolytes in blood tests after admission.
CK and CK-MB decreased initially after methylprednisolone
administration, and troponin T and NT-proBNP decreased later.
Electrolytes values at the first occurrence of VT were K 4.1 mEq/L,
Ca 9.1 mg/dL, Mg 1.8 mg/dL, and at the second occurrence of VT
were K 4.7 mEq/L, Ca 8.9 mg/dL, Mg 2.0 mg/dL. Drugs that induce
VT are not used.
Nishiyama et al. 10.3389/fimmu.2023.1078838
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in the post-acute stage resulted in her death. It is suggested that the
arrhythmia was caused by severe myocardial damage due to acute
myocarditis. The reason for the severe myocardial damage may be
related to COVID-19 infection and pericardial invasion of lung
cancer. This patient had been infected with COVID-19 prior to the
onset of myocarditis, so infection control measures were necessary.
This limited the types of tests that could be performed and delayed
the diagnosis of myocarditis. It also took longer to respond to
emergencies, making it difficult to deal with fatal arrhythmias. In
addition, the possibility of COVID-19-associated myocarditis was
considered at the pre-treatment stage, which caused a delay in the
initiation of corticosteroid administration. There is a report of
pembrolizumab-induced myocarditis in a patient with pericardial
infiltration of lung cancer (37). Thus, the administration of ICI to
patients with pericardial infiltration of tumor may have resulted in
excessive lymphocyte infiltration into the myocardium.
There are several limitations in the present case report. First, it
was difficult to perform an CMR on COVID-19-infected patients at
our institution, and second, we were unable to perform a viral
genome study of myocardial tissue. A viral genome study of
myocardial tissue might have brought us closer to identifying the
cause of myocarditis.
AB
C
FIGURE 4
Histological findings of endocardial biopsy. Histological findings of the myocardium showed (A) an infiltrate of inflammatory cells predominantly
composed of lymphocytes by hematoxylin-eosin (HE) staining and (B) granulation fibrosis of the stroma by Masson’s trichrome (MT) staining.
Immunostaining of the tissue showed (C) CD3-positive T cells infiltrated more than CD20-positive B cells. CD8-positive T lymphocytes infiltrated
more than CD4-positive T lymphocytes. Infiltration of CD68-positive macrophages and CD138-positive plasma cells was also observed. (HE ×200,
MT ×200 and CD3/CD4/CD8/CD20/CD68/CD138 immunostaining ×200).
Nishiyama et al. 10.3389/fimmu.2023.1078838
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Conclusion
We report a case of pembrolizumab-induced myocarditis that
developed after COVID-19 infection, in which we were able to
document the course of electrocardiographic changes from onset
to death. In myocarditis, elevated myocardial markers
and electrocardiographic changes may precede clinical
symptoms, so regular myocardial marker measurements and
electrocardiographic testing are important. In addition, ECG
examination is useful even after the start of treatment, since the
prognosis may be inferred from ECG changes. Early diagnosis of
pembrolizumab-induced myocarditis is important because early
administration of corticosteroids may improve the prognosis. The
impact of viral infections such as COVID-19 on patients with ICIs
is unknown, and the appearance of irAEs after infection should
be noted.
Data availability statement
The original contributions presented in the study are
included in the article. Further inquiries can be directed to the
corresponding author.
Author contributions
The manuscript was drafted by KN and KM. KN, KM, YS, JU,
ST, HT, SA, AI, and MM examined and treated the patient. NY
performed the histopathological assessment. YA gave clinical
advice. All authors contributed to the article and approved the
submitted version.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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