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\begin{document}

\title{A case of takotsubo cardiomyopathy triggered by asthma exacerbation
after mRNA-based vaccination for coronavirus disease 2019}



\author[1]{Yusuke Tachibana}%
\author[1]{Tadaaki Yamada}%
\author[2]{Taisuke Tsuji}%
\author[2]{Junji Murai}%
\author[2]{Kazuki Jinno}%
\author[2]{Shoki Matsumoto}%
\author[1]{Aosa Sasada}%
\author[2]{Shiho Goda}%
\author[2]{Ayaka Omura}%
\author[2]{Shinsuke Shiotsu}%
\author[2]{Tatsuya Yuba}%
\author[2]{Chieko Takumi}%
\author[2]{Noriya Hiraoka}%
\author[1]{Koichi Takayama}%
\affil[1]{Kyoto Prefectural University of Medicine}%
\affil[2]{Japanese Red Cross Kyoto Daiichi Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Recent studies have reported that coronavirus disease-2019 (COVID-19)
vaccination can exacerbate asthma. Status asthmaticus sometimes induces
takotsubo cardiomyopathy. We present a case of takotsubo cardiomyopathy
triggered by asthma exacerbation after the mRNA-based vaccination.
Therapies for status asthmaticus resulted in prompt improvement of
respiratory failure and cardiac-apex ballooning.%
\end{abstract}%



\sloppy


Case report

\textbf{A case of takotsubo cardiomyopathy triggered by asthma
exacerbation after mRNA-based vaccination for coronavirus disease 2019}

Yusuke Tachibana\textsuperscript{a,b}, Tadaaki
Yamada\textsuperscript{a*}, Taisuke Tsuji\textsuperscript{b}, Junji
Murai\textsuperscript{b}, Kazuki Jinno\textsuperscript{b}, Shoki
Matsumoto\textsuperscript{b}, Aosa Sasada\textsuperscript{a,b}, Shiho
Goda\textsuperscript{b}, Ayaka Omura\textsuperscript{b}, Shinsuke
Shiotsu\textsuperscript{b}, Tatsuya Yuba\textsuperscript{b}, Chieko
Takumi\textsuperscript{b}, Noriya Hiraoka\textsuperscript{b}, Koichi
Takayama\textsuperscript{a}

\textsuperscript{a}Department of Pulmonary Medicine, Graduate School of
Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho
Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

\textsuperscript{b}Department of Respiratory Medicine, Japanese Red
Cross Kyoto Daiichi Hospital, 15-749 Higashiyama Ward, Honmachi, Kyoto,
605-0981, Japan

\textbf{Email addresses of all authors}

Yusuke Tachibana:\emph{yutachib@koto.kpu-m.ac.jp}

Taisuke Tsuji:\emph{tsujitaisuk1027@gmail.com}

Junji Murai: hanasaka@koto.kpu-m.ac.jp

Kazuki Jinno: kazu.0706.jin@gmail.com

Shoki Matsumoto: kyokui130102@gmail.com

Aosa Sasada: sasada@koto.kpu-m.ac.jp

Shiho Goda: oomtsh25kgs@yahoo.co.jp

Ayaka Omura: a.kitani.1021@gmail.com

Shinsuke Shiotsu: sshiotsu@gmail.com

Tatsuya Yuba: tyb2001@gmail.com

Chieko Takumi: chieko-takumi@kyoto1.jrc.or.jp

Noriya Hiraoka: noriya-hiraoka@kyoto1.jrc.or.jp

Koichi Takayama: takayama@koto.kpu-m.ac.jp

\textbf{* Correspondence:}

Tadaaki Yamada

Department of Pulmonary Medicine, Graduate School of Medical Science,
Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto,
Japan

E-mail: \emph{tayamada@koto.kpu-m.ac.jp}

\textbf{ABSTRACT}

Recent studies have reported that coronavirus disease-2019 (COVID-19)
vaccination can exacerbate asthma. Status asthmaticus sometimes induces
takotsubo cardiomyopathy. We present a case of takotsubo cardiomyopathy
triggered by asthma exacerbation after the mRNA-based vaccination.
Therapies for status asthmaticus resulted in prompt improvement of
respiratory failure and cardiac-apex ballooning.

\textbf{Key Clinical Message}

In patients with asthma, mRNA-based COVID-19 vaccination can trigger
asthma exacerbation and takotsubo cardiomyopathy; therefore, adequate
asthma control is essential for asthma patients receiving the
vaccination.

\textbf{KEYWORDS:} COVID-19 vaccine, asthma exacerbation, takotsubo
cardiomyopathy, mRNA-based vaccination

\textbf{1 INTRODUCTION}

The coronavirus disease 2019 (COVID-19) pandemic has affected people's
lifestyles, and vaccines have been administered worldwide.

Most COVID-19 vaccines are mRNA-based and are highly effective; however,
their adverse reactions have not been entirely clarified. Common side
effects include fever, fatigue, headache, or local pain. However, some
studies have reported that COVID-19 vaccination exacerbates asthma
{[}1{]}. In addition, anaphylaxis, takotsubo cardiomyopathy (TTC),
myocarditis, and pericarditis have been reported to occur rarely
{[}2{]}. Therefore, attention should be paid to the emergence of severe
side effects after COVID-19 vaccination.

TTC is an acute, reversible myocardial injury induced by emotional or
physical stress. Risk factors for TTC include female sex, menopause, and
psychiatric disorders. While natural disasters and negative and positive
emotions are mental causes, physical causes include trauma, surgery,
medications, or intoxication. Respiratory disorders including
pneumothorax, chronic obstructive pulmonary disease exacerbation, and
bacterial or viral infections; chemotherapy for cancer; and invasive
procedures such as bronchoscopy or intubation have been reported as
triggers of TTC in patients with respiratory diseases. Moreover, asthma
exacerbation and its therapies, such as short- acting \selectlanguage{greek}β\selectlanguage{english}2 agonists
(SABAs), adrenaline, or intubation are known to cause TTC {[}3,4,5{]}.
Fatal complications of TTC include cardiogenic shock, systemic embolism,
and heart rupture; hence, TTC should not be missed. However, because
respiratory problems often cause dyspnea or chest pain, TTC is difficult
to diagnose {[}6,7{]}.

Here, we report our experience of COVID-19 vaccine-induced asthma
exacerbation and TTC in a patient with bronchial asthma.

\textbf{2 CASE PRESENTATION}

\textbf{2.1 Case history / examination}

A 70-year-old Japanese woman with a medical history of bronchial asthma,
rheumatoid arthritis, and hypertension had been prescribed a
fluticasone-vilanterol combination inhaler for asthma and tacrolimus,
iguratimod, and golimumab for rheumatoid arthritis. She had not
experienced asthma exacerbation during the previous decade. She was a
never-smoker with pollen allergy and had no history of drug allergies.
Although she had a slight cough and dyspnea for a few days, she received
the second dose of the mRNA-based COVID-19 vaccine BNT162b2
(Pfizer-BioNTech) and took acetaminophen to prevent fever. Approximately
12 h after vaccination, her respiratory symptoms worsened, and the
patient was transported to our emergency room by ambulance. The
percutaneous oxygen saturation (SpO\textsubscript{2}) was 86\%
(reservoir mask O\textsubscript{2,} 15 L/min). Physical examination
revealed decreased respiratory sounds and a silent chest. Wheezing
emerged after nebulization with the SABA procaterol. The patient had no
edema, rash, or aggravation of joint symptoms.

The initial blood test showed an increased white blood cell count with
eosinophilia, a negative C-reactive protein test, and increased total
immunoglobulin (Ig)E. Arterial blood gas analysis before intubation
revealed acute hypercapnic respiratory failure \textbf{(Table 1).} A
12-lead electrocardiogram demonstrated sinus rhythm with ST elevation
(V2-V5, \textbf{Figure 1} ), but the creatine kinase MB and troponin I
levels were not elevated. Chest radiography and thoracoabdominal
contrast-enhanced computed tomography revealed no acute pulmonary
abnormalities. Bronchial wall thickening and a calcified nodule were
detected in the lower lobe of the right lung. Severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test results were
negative. In the emergency department, she had a depressed level of
consciousness; therefore, endotracheal intubation was performed, and
intravenous corticosteroids were administered. To rule out cardiogenic
disease, coronary angiography was performed, which revealed no
significant coronary artery disease. However, left ventriculography and
ultrasonic cardiography revealed apical akinetic expansion (apical
ballooning) and severe hypokinesia of the mid-ventricular segments, with
slightly reduced systolic function (ejection fraction,
47\%,\textbf{Figure 2,3} ).

\textbf{2.2 Differential diagnosis}

Otolaryngological examination to investigate other comorbidities related
to asthma exacerbation revealed that the patient had no eosinophilic
sinusitis but had bilateral chronic sinusitis and right secretory otitis
media, which were treated with antibiotics. Other infections were
excluded, and there were no significant bacterial findings. Serum
aspergillus/cryptococcal/candida-mannan antigen and \selectlanguage{greek}β-\selectlanguage{english}D-glucan tests
were negative. Although the patient had oral candidiasis, it was not a
cause of asthma exacerbation. The SARS-CoV-2 nucleic acid test results
were negative.

Computed tomography showed no signs of pneumonia, exacerbation of
interstitial pneumonitis, pulmonary embolism, or acute respiratory
distress syndrome.

She had acetaminophen after COVID-19 vaccination; however, she did not
have a history of allergy to drugs, including nonsteroidal
anti-inflammatory drugs (NSAIDs). In addition, the patient did not have
any obvious contact with potential allergens. Anaphylaxis was considered
in the differential diagnosis, but other cutaneous and mucosal symptoms
were absent.

She had not experienced asthma exacerbation during the previous decade.
Accordingly, her adherence was not the cause of the asthmatic crisis. In
this case, we did not administer adrenaline before the diagnosis of TTC;
hence, adrenaline use was not involved in the onset of TTC.

Therefore, we consider that her status asthmaticus was enhanced by the
COVID-19 vaccination and not by infection, allergic reactions, or
medication.

\textbf{2.3 Outcome and follow-up}

The patient was treated with procaterol, systemic corticosteroids,
leukotriene receptor antagonists, and aminophylline for status
asthmaticus and with heparin for TTC. Adrenaline was used after the
diagnosis of TTC. The respiratory status improved promptly, and she was
extubated on day 2 and discharged on day 10. During hospitalization, ST
changes in the electrocardiogram were typical for TTC; ST elevation
normalized within few days and a deep negative T wave developed in a
week. After asthma therapy and extubation, the fractional exhaled nitric
oxide level was 10 ppb, and spirometry showed an almost normal pattern.

The patient was discharged with instructions to follow up as an
outpatient and was prescribed an inhaled corticosteroids/long-acting \selectlanguage{greek}β
\selectlanguage{english}agonists/long-acting muscarinic antagonist combination, leukotriene
receptor antagonists, and the therapeutic anti-IgE antibody omalizumab.
Her outpatient course was stable.

\textbf{3 DISCUSSION}

TTC is an acute reversible myocardial injury first reported by Sato et
al. in 1990. The term ``takotsubo'' means an octopus fishing pot in
Japanese that has a round bottom and a narrow neck, and it is similar to
the shape of the heart in TTC. TTC is triggered by emotional (negative
and positive) or physical stress, including asthma exacerbation.
Symptoms similar to those of myocardial infarction have been observed in
patients with TTC, without coronary artery stenosis {[}3,8,9{]}.

The pathophysiology of stress cardiomyopathy is unclear and may involve
several mechanisms. One pathway involves high circulating catecholamines
released by the sympathetic nerves under stress, including respiratory
diseases. Sato et al. showed that microvascular dysfunction and coronary
artery spasms cause TTC.

As most patients with TTC are postmenopausal women, estrogen deprivation
has been proposed as a cause in several hypotheses {[}20{]}, whereas
some studies have reported abnormalities in the central autonomic
nervous system {[}10{]}.

Although TTC has a good prognosis, patients with TTC sometimes develop
heart failure, arrhythmia, systemic embolism, cardiogenic shock, and
cardiac rupture, which might be fatal. Underlying diseases triggering
TTC increase mortality (12.2\% vs. 1.1\% in patients without preexisting
diseases) {[}6{]}. Our patient did not have cardiac complications;
however, adequate treatment for asthma was required.

Dyspnea is a common symptom in respiratory illnesses and TTC; therefore,
electrocardiography and echocardiography should be performed before the
use of SABAs or adrenaline.

Infection with SARS-CoV-2, a novel virus that was first reported in
Wuhan, China in 2019, might trigger asthma flare-up; however, the
SARS-CoV-2 polymerase chain reaction test of the patient was negative,
indicating that she was not infected with SARS-CoV-2. COVID-19
aggravates many diseases; therefore, vaccines have been developed and
implemented rapidly worldwide to reduce the risk of progression and
death. mRNA-based COVID-19 vaccines are effective and safe. Nonetheless,
adverse events associated with the vaccines are not completely
understood. Almost all COVID-19 vaccines used in Japan are mRNA-based.

TTC has been reportedly triggered by mRNA-based COVID-19 vaccines
{[}11,12,13{]} or the influenza vaccine {[}12,14{]}. However, our
patient had status asthmaticus, and the vaccination did not seem
directly of TTC, despite her symptoms being common to both diseases.

Colaneri et al. reported a case of asthma exacerbation triggered by an
mRNA-based COVID-19 vaccine {[}1{]}. mRNA-based vaccines promote
secretion of type I interferons and that increased interferon-I
production is associated with asthma exacerbation {[}15,16{]}. Nappi et
al. reported a case in which two doses of the adenovirus-vectored
vaccine ChAdOx1 (Astra Zeneca) progressively worsened asthma and a
subsequent dose of the COVID-19 vaccine mRNA-1273 (Moderna) triggered
eosinophilic granulomatosis with polyangiitis {[}17{]}. Regardless of
the type of vaccine, COVID-19 vaccination itself may exacerbate asthma.

Hence, we concluded that the mRNA-based vaccine enhanced asthma
exacerbation and TTC onset in our patient. However, our study was
limited because the relationship between asthma exacerbation and
mRNA-based COVID-19 vaccines is currently difficult to demonstrate
directly. Thus, more reports and further studies are required.

Between February 17, 2021, and July 25, 2021, 74,137,348 patients
received the BNT162b2 vaccine in Japan. Among these, 219 (0.0003\%)
cases of asthma attacks were reported to the Japanese Ministry of
Health, Labour, and Welfare, which indicates a low incidence {[}18{]}.

Pfaar et al. reported that patients taking biologicals for asthma do not
have an increased risk of allergic reactions following COVID-19
vaccination {[}19{]}.

\textbf{4 CONCLUSION}

The mRNA-based COVID-19 vaccination can trigger asthma exacerbation and
TTC in patients with asthma control. The combination of COVID-19
vaccination and adequate asthma control is essential for patients with
bronchial asthma during the SARS-CoV-2 pandemic.

\textbf{AUTHOR CONTRIBUTIONS}

Y. Tachibana, T. Yamada, and T. Tsuji conceived and presented the idea.
Y. Tachibana wrote the manuscript in consultation with T. Tsuji, T.
Yamada and K. Takayama. J. Murai collected the data. K. Jinno, S.
Matsumoto, A. Sasada, S. Goda, A. Omura, S. Shiotsu, T. Yuba, C. Takumi,
and N. Hiraoka contributed to the interpretation. All authors provided
critical feedback and helped to complete the manuscript.

\textbf{ACKNOWLEDGMENTS}

We thank Dr D. Itoh (Japanese Red Cross Kyoto Daiichi Hospital, Kyoto,
Japan) for cardiovascular examinations, advises, and interpretation.

\textbf{FUNDING}

This research was conducted without any funding.

\textbf{DECLARATION OF INTEREST}

None.

\textbf{CONSENT}

Written informed consent for publication of clinical data was obtained
from the patient.

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