Journal of Pediatric Cardiology and Cardiac Surgery 8(2): 82‒86 (2024)

Case Report

Cytokine Storm Originating from the Intrapericardial Cavity
in a Child With Pericardial Effusion Following COVID-19
Shusei Ebihara, MD, Yoshihiko Kodama, MD, PhD, Kazunari Takamura, MD,
Masako Harada, MD, and Hiroshi Moritake, MD, PhD
Division of Pediatrics, Developmental and Urological-Reproductive Medicine,
Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

Symptoms of coronavirus infectious disease 2019 (COVID-19) are usually mild in young patients. Some children, however, present with a significant degree of complications which may be associated with an excessive
reaction by the immune system. Herein, we report an analysis of cytokine and chemokine in an 11-year-old girldiagnosed with left ventricular dysfunction and cardiac tamponade complicated with COVID-19. She recovered
without complications after intravenous immunoglobulin, dexamethasone, remdesivir, and surgical pericardialdrainage. Cytokine concentrations had markedly increased in the pericardial fluid specimen; especially for interleukin-6 being disproportionate to its serum concentration. Cytokine storm originating from the pericardial
cavity was considered an underlying mechanism of her condition.

Keywords: cardiac tamponade, COVID-19, multisystem inflammatory syndrome in children, cytokine
profile, left ventricular dysfunction

Introduction
Symptoms of coronavirus infectious disease 2019
(COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tend to be mild inyoung patients. Some individuals, however, may experience an overactive immune response to SARS-CoV-2
infection; this is mainly associated with multisystem
inflammatory syndrome in children (MIS-C), andshares the mechanism with Kawasaki disease.1, 2)
COVID-19 has also been reported to cause a different
form of excessive immune reaction in adults.3) Still,
it is not fully understood whether the site of origin of
immune hyperactivity is localized to a particular partof the body. Herein, we present a case of an 11-year-oldgirl with COVID-19 and cardiac involvement possibly
caused by hyperactive immune response, although her
symptoms were atypical for MIS-C. Cytokine analysisof her pericardial effusion and serum suggested that theorigin of her immune hyperactivity was the intrapericardial cavity.

Case Presentation
An 11-year-old girl presented with fever, sore throat,and cough. Polymerase Chain Reacton (PCR) analysis
using a specimen obtained from a nasal swab confirmeda diagnosis of COVID-19. SARS-CoV-2 sequencing was
not performed, but the Omicron species was likely thevariant because the patient presented in the early phaseof the prevalence of this variant. Fever disappeared on
the second day after the onset, while she started to feelmild chest pain on the third day which became worse
over the following days. On the fifth day, she visited anemergency clinic with severe chest pain. On echocardiography, she had severe left ventricular (LV) dysfunction
with an ejection fraction of 33.5% and moderate pericardial effusion. She was admitted to the intensive care unitof our hospital.

Received: May 15, 2023; Accepted: November 1, 2023
J-STAGE Advance Published Online: July 5, 2024
Corresponding author: Yoshihiko Kodama, MD, PhD, Division of Pediatrics, Developmental and Urological-Reproductive Medicine,
Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki 889‒1601, Japan
E-mail: yoshihiko_kodama@med.miyazaki-u.ac.jp
Yoshihiko Kodama ( https://orcid.org/0000-0002-4836-7077)
doi: 10.24509/jpccs.23-012© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery
This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/)

83

Her body temperature was 36.5°C, blood pressure
90/54 mmHg, heart rate 120/min, respiratory rate
28/min, and SpO2 100% in room air. A gallop rhythm
was audible on auscultation of the heart, and extremities were cold. There was no hepatomegaly. A chest

X-ray revealed no pneumonia or prominent cardiac
enlargement (Fig. 1a). A blood test showed: white blood
cell count 7,500/µL (neutrophil 78.5%, lymphocyte
18.6%, monocyte 2.8%), C-reactive protein 0.15 mg/dL,
creatinine 1.02 mg/mL, creatine kinase (CK) 121 U/L,

Fig. 1 (a) Chest X-ray showing no evidence of pneumonia nor prominent enlargement of cardiac silhouette.
(b) Echocardiography detected considerable pericardial eﬀusion.
Table 1 Cytokine levels in serum and in pericardial ﬂuid
Cytokine (pg/mL)
IL-1β
IL-1ra
IL-2
IL-4
IL-5
IL-6
IL-7
IL-8
IL-9
IL-10
IL-12
IL-13
IL-15
IL-17
Eotaxin
FGF basic
G-CSF
GM-CSF
IFN-γ
IP-10
MCP-1
MIP-1αPDGF-bb
MIP-1βRANTES
TNF-α
VEGF

Serum (reference)
0.67 (0.52±0.27)
7657.75 (398.97±171.51)
3.07 (6.68±2.83)
1.82 (2.61±0.6)7.53 (8.23±1.71)
6.13 (5.56±2.47)
46.88 (51.25±4.06)
171.95 (75.99±45.12)
198.45 (262.16±26.63)
4.1 (5.44±0.73)
1.6 (0.56±0.23)
1.26 (2.13±0.51)
129.34 (170.05±45.73)
5.35 (21.31±9.76)
27.54 (50.04±7.68)
13.5 (17.01±2.6)
105.6 (796.77±438.52)
0.86 (1.97±0.72)
17.01 (3.6±0.94)
2131.5 (1251.72±1254.61)
24.71 (39.53±12.85)
4.62 (56.26±34.61)
3182.37 (5276.75±2230.68)
134.8 (209.77±39.33)
6891.99 (14598.71±2442.89)
34.36 (96.85±43.29)
6.92 (128.05±58.77)

Pericardial ﬂuid

Ratio (Pericardial/plasma)1.62
725.11
13.41
16.19
69.13
2344.09304.88312.89
81.78
27.3
2.72
6.91
276.6747.23
432.46
43.38
296.3
7.21
90.89
39626.02
1431.32
2.04
OOR below
27.43
108.1650.53
207.53

2.41
0.09
4.37
8.90
9.18
382
6.50
1.82
0.41
6.7
1.70
5.48
2.14
8.83
15.7
3.21
2.81
8.38
5.34
18.6
57.9
0.44
̶

0.20
0.02
1.47
30.0

These were sampled on the ﬁfth day. Serum reference values indicate a mean±a standard deviation in ﬁve healthy subjects in ourinstitution as a control. FGF, ﬁbroblast growth factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; IP, interferon-γ-inducible protein; MCP, monocyte chemoattractant
protein; MIP, macrophage inﬂammatory protein; OOR, out of range; PDGF, platelet-derived growth factor; RANTES, regulated onactivation, normal T-cell expressed and secreted; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery

84

CK-myocardial band (MB) 4 U/L, and troponin-T0.03 ng/mL, these suggesting myocardial damage andmild renal dysfunction.
Dopamine (3 µg/kg/min) and milrinone (0.3 µg/kg/min)were introduced for LV dysfunction, and intravenous
immunoglobulin (1.5 g/kg in total over 4 days), dexamethasone (0.1 mg/kg/day for 4 days), and remdesivir(100 mg/day for 4 days) were also administered. Sixhours after admission, her blood pressure decreased to
80/60 mmHg. Echocardiography showed a considerable
increase in pericardial effusion (Fig. 1b). Surgical drainage of the effusion was performed, and biochemical analysis revealed total protein of 5.9 g/dL, albumin of 3.8 g/dL,
and lactate dehydrogenase of 226 U/L, suggesting that thefluid was of an exudative nature. No cellular components
were found in the pericardial fluid. On the sixth day, herbody temperature rose to 39.0°C, and C-reactive protein(0.95 mg/dL), CK (1768 U/L), and CK-MB (37 U/L) had
peaked to their highest levels of the illness course. Afterthe seventh day, no febrile episodes were noted, and theLV ejection fraction gradually improved to 57.1% by theninth day. The patient returned home in a healthy condition on the 20th day.
Table 1 shows the data of 27 cytokines and chemokines analyzed using the Bio-Plex suspension arraysystem (Bio-Rad Laboratories, Hercules, CA). Cytokine
concentrations in the pericardial fluid were markedlyelevated compared with those in the serum, especiallyinterleukin (IL)-6. IL-6 was 2344.1 pg/mL in the pericardial fluid and 6.13 pg/mL in the serum; the latter being
within the reference range.

Discussion
This report presents the results of cytokine profile
analysis in a patient with cardiac tamponade and severe
LV dysfunction following COVID-19. The results wereconsistent with cytokine storm originating from theintrapericardial cavity. To the best of our knowledge, thisis the first report to describe the cytokine profile of pericardial effusion in a pediatric patient with COVID-19.
COVD-19 can lead to an excessive immune response,
which may be described as MIS-C in children, a condition similar to Kawasaki disease.2) This case met thedefinition of MIS-C,4, 5) but its timing and symptoms
were not typical. The symptoms and signs could also bediagnosed as myocarditis associated with COVID-19.
Even in the setting of myocarditis, however, direct
J Pediatr Cardiol Card Surg Vol. 8, No. 2 (2024)

damage to the myocardial cells is not always the solitarymechanism of the disease.6) Other possible mechanisms
have been nominated, such as damage to vascularendothelial cells and immune system hyperactivity,and previous reports regarding the myocardial tissue of
COVID-19-associated LV dysfunction suggested that
etiology of the disorder is more related to immunological hyperactivity than direct damage to the myocardium.6) Therefore, the underlying mechanism appears
to be closely associated with excessive activation of theimmune system, regardless of classification of the clinical condition in this patient.
Only a limited number of cytokine types increased theirserum levels in this patient, including IL-1ra, IL-8, IL-12,
and interferon (IFN)-γ. In the previous report of cytokine
analysis in fulminant myocarditis, elevated levels weredocumented in IL-10, IL-17, IL-12, vascular endothelial
growth factor (VEGF), IL-4, IFN-γ, and IL-13.7) The factthat characteristics in serum analysis in our patient weredissimilar to those in fulminant myocarditis may indicate
different pathogenesis of illness. Another possibility isthat serum cytokines were in the process of elevation
being transferred from the intrapericardial space. The
elevated serum levels of IL-12 and IFN-γ may support thisassumption, while it is unknown why the serum levels of
many others were within their normal ranges.
Most cytokines in our patient showed a marked
increase in concentration in the pericardial fluid compared with the serum, suggestive of cytokine storm
originating from the intrapericardial region. The IL-6
level was the most prominent parameter; its value inthe pericardium being 382 times higher than that in theserum. A previous report on pericardial fluid in viral
pericarditis showed a limited increase in IL-6 in pericardial effusion8); therefore, we consider that the disproportionally high IL-6 concentration in our case was atypicalfor simple viral pericarditis.
IL-6 plays an important role in the excessive immunoreaction to SARS-CoV-2. Reportedly, signaling fromthe angiotensin II and angiotensin I receptors induced
by SARS-CoV-2 activates the IL-6 amplifier, which is apossible mechanism underlying cytokine storm throughthe activation of nuclear factor kappa B and transcription factor 3.3, 9) Interestingly, a case report of an adultwith cardiac tamponade caused by COVID-19 showed asimilar cytokine profile in which the IL-6 concentrationin the pericardial effusion was disproportionately high85

compared to that in the serum.10) In the same report,
the authors concluded that the COVID-19-related
cytokine storm was limited to the pericardium. In linewith this, we suggest that immune system hyperactivity
following COVID-19 in children can also originate fromand be exclusively localized in the intrapericardial area.
Another study in patients with idiopathic pericarditis
described markedly increased IL-6 levels in the pericardial effusion.11) Although the cause of pericarditis in
those patients was unclear, they may share immunological processes similar to our own patient.
We also detected great differences between serum andintrapericardial levels of IFN-γ-induced protein (IP)-10,monocyte chemoattractant protein (MCP)-1, VEGF, andeotaxin in our patient. Some previous studies reported
elevated serum concentration of these cytokines andchemokines in severe COVID-19,12‒14) whereas suchincreases were limited in our patient. IP-10, MCP-1,and eotaxin do activate lymphocytes, monocytes, andeosinophils, but no cellular components were found in
the pericardial fluid of our patient. This may reflect thatthe large volume of pericardial fluid made it difficult todetect them.
The present case appears to demonstrate an excessive immunoreaction after COVID-19, but its patterndoes not seem to be common in hyperactive immune
responses following COVID-19, especially for MIS-C.
The symptoms and complications of MIS-C are notalways identical among patients15); still, they can besimilar to those of Kawasaki disease and can appear
systemically throughout the body. In such occasions, theserum cytokine profile can resemble Kawasaki disease,even with some differences.1) Obtaining multiple samples from bodily fluid would be unrealistic. Often, whereand how cytokines are localized is not evident fromsystemic symptoms and signs. Further study is therefore
warranted to clarify the variety of excessive immune
responses following COVID-19 in children.
Acknowledgments
We are grateful to Dr. Kazuko Uno from the Louis Pasteur Medical Research Center for measuring the cytokine
concentrations. We also thank Ellen Knapp, PhD, and Sarah
Williams, PhD, from Edanz (https://jp.edanz.com/ac) for
editing a draft of this manuscript.

FundingNone.
Conﬂicts of Interest
The authors declare no conflict of interest.
Consent to Publish
Informed consent was obtained from the parents and thepatient for publication of this case report and accompanying images, while preserving the patientʼs anonymity.
Author Contribution
SE and YK drafted the manuscript. KT, MH, and HM
critically reviewed the manuscript and supervised the study.
All authors read and approved the final manuscript.

References
1) Yilmaz Ciftdogan D, Ekemen Keles Y, Cetin BS, et al:
COVID-19 associated multisystemic inflammatory syndrome in 614 children with and without overlap with
Kawasaki disease-Turk MIS-C study group. Eur J Pediatr
2022; 181: 2031‒2043
2) Consiglio CR, Cotugno N, Sardh F, et al: CACTUS Study
Team: The immunology of multisystem inflammatory
syndrome in children with COVID-19. Cell 2020; 183:968‒981.e73) Hojyo S, Uchida M, Tanaka K, et al: How COVID-19
induces cytokine storm with high mortality. Inflamm
Regen 2020; 40: 37
4) Centers for Disease Control and Prevention Health Alert
Network (HAN): Multisystem Inflammatory Syndrome inChildren (MIS-C) Associated with Coronavirus Disease2019 (COVID-19). Available at: https://emergency.cdc.
gov/han/2020/han00432.asp (Accessed on May 15, 2020)
5) World Health Organization: Multisystem inflammatory
syndrome in children and adolescents with COVID-19:
Scientific Brief. 2020. Available at: https://www.who.
int/publications-detail/multisystem-inflammatorysyndrome-in-children-and-adolescents-with-covid-19(Accessed on May 17, 2020)
6) Kawakami R, Sakamoto A, Kawai K, et al: Pathologicalevidence for SARS-CoV-2 as a cause of myocarditis: JACC
Review Topic of the Week. J Am Coll Cardiol 2021; 77:314‒325
7) Wang J, He M, Li H, et al: Soluble ST2 is a sensitive andspecific biomarker for fulminant myocarditis. J Am Heart
Assoc 2022; 11: e0244178) Ristić AD, Pankuweit S, Maksimović R, et al: Pericardialcytokines in neoplastic, autoreactive, and viral pericarditis. Heart Fail Rev 2013; 18: 345‒3539) Hirano T, Murakami M: COVID-19: A new virus, but afamiliar receptor and cytokine release syndrome. Immunity 2020; 52: 731‒73310) Deana C, Vetrugno L, Fabris M, et al: Pericardial cytokine“Storm” in a COVID-19 patient: The confirmation of a© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery

86hypothesis. Inflammation 2022; 45: 1‒511) Motonaga T, Furuta T, Okada S, et al: Responses to treatment according to the cytokine profiles of pericardial
effusion in two children with idiopathic pericarditis. Int
Heart J 2020; 61: 1307‒131012) Chen Y, Wang J, Liu C, et al: IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19. Mol
Med 2020; 26: 9713) Patterson BK, Guevara-Coto J, Yogendra R, et al:
Immune-based prediction of COVID-19 severity and chro-J Pediatr Cardiol Card Surg Vol. 8, No. 2 (2024)

nicity decoded using machine learning. Front Immunol
2021; 12: 700782
14) Zhang Z, Ai G, Chen L, et al: Associations of immunological features with COVID-19 severity: A systematic review
and meta-analysis. BMC Infect Dis 2021; 21: 738
15) Godfred-Cato S, Bryant B, Leung J, et al: California
MIS-C Response Team: COVID-19-Associated multisystem inflammatory syndrome in children: United States,March-July 2020. MMWR Morb Mortal Wkly Rep 2020;
69: 1074‒1080