Abstract
The use of mRNA COVID-19 vaccine can on rare occasions cause life-threatening, fulminant myopericarditis. This case report demonstrates previously reported benefit of early use of venoarterial extracorporeal membrane oxygenation mechanical assistance and supports the use of intravenous highly purified immunoglobulin pharmacotherapy to help achieve a good clinical outcome.
1. Introduction
Myopericarditis, predominantly in male adolescents and young adults, can follow the administration of mRNA COVID-19 vaccines, used to provide immunity against Coronavirus 2 (SARS-CoV-2). Most cases are mild and follow a benign course but rarely the condition is fulminant, resulting in acute heart failure requiring mechanical support. Cardiac magnetic resonance (CMR) imaging is invaluable in the diagnosis and follow-up of suspected vaccine-induced myopericarditis. We highlight a case of fulminant myopericarditis following the administration of the Pfizer BNT162b2 vaccine.
2. Presentation and clinical course
A 33-year-old male presented with pleuritic chest pain 3 days following his second dose of the Pfizer vaccine. He had an unremarkable past medical history and denied illicit drug or alcohol use. He was febrile to 38.5 °C, had a respiratory rate of 22 breaths per minute with a SaO2 of 98% in ambient air, and stable haemodynamics. Examination revealed no pericardial rub or features of heart failure. Initial electrocardiogram demonstrated sinus rhythm with concave ST elevation in leads I, V3-6, II, and aVF, and generalised PR segment depression. Transthoracic echocardiography (TTE) demonstrated normal left ventricular (LV) size, severe global LV systolic impairment, LV ejection fraction (EF) 25%, and a LV outflow tract velocity time integral of 11.6 cm. His right ventricle (RV) was mildly impaired, right ventricular systolic excursion velocity (RVS’) 7.1 cm/s, tricuspid annular plane systolic excursion (TAPSE) 1.1 cm. There was no pericardial effusion.
Blood results revealed C-reactive protein 57.8 mg/L, high-sensitivity cardiac troponin 4115 ng/L, creatinine kinase 2940 U/L, pro B-type Natriuretic Peptide 1686 pc/mL, and lactate 2.3 mmol/L. Chest roentgenography was normal. Blood cultures were negative. COVID polymerase chain reaction and viral serology results were negative. He was commenced on Colchicine 500 mg twice daily (BID).
Within 4 h of presentation, he developed acute pulmonary oedema and cardiogenic shock, systolic blood-pressure < 80 mmHg. He was transferred to the intensive care unit and commenced on Dobutamine 2.5 μg (mcg)/kg/min and Noradrenaline 0.1 mcg/kg/min. He rapidly progressed to severe respiratory failure and was intubated within 90 min of transfer. He developed progressive hypotension, systolic blood-pressure < 60 mmHg, despite compensatory sinus a tachycardia rate of 180 bpm and subsequent incrementation of Noradrenaline to 0.3 mcg/kg/min. Renal and hepatic function remained normal, but lactate rose to 3.8 mmol/L, and the decision was made to initiate early (within 2 h of intubation) femofemoral venoarterial extracorporeal membrane oxygenation (VA ECMO) mechanical support, circuit flow at 3000 revolutions per minute generating a flow rate of 3L/minute, with rapid improvement in haemodynamics. Intravenous Hydrocortisone 100 mg 6 hourly and two 90-gm infusions of Flebogamma 10% highly purified immunoglobulin (IgG) were given within a 24 h period. He was successfully weaned off VA ECMO after 33 h of mechanical support followed by rapid weaning of Dobutamine. Repeat TTE demonstrated an improved LVEF of 35% and normalisation of RV systolic function. He was successfully extubated the following day. Hydrocortisone was stopped.
CMR imaging was performed on day 6 of his admission on a 3 Tesla scanner (MagnetomSkyra, Siemens, Germany). The inferolateral LV segments were hypokinetic and LVEF was low normal (EF 53%). Right ventricular function was mildly reduced (RVEF 45%). Acute myocarditis was diagnosed on Lake Louise Criteria.1 Myocardial oedema was demonstrated in the anterior, inferoseptal, inferior, and lateral LV segments on T2-weighted short tau inversion recovery and T2-mapping images. There was extensive patchy late gadolinium enhancement (LGE) in the subepicardial to mid myocardial regions of the corresponding anterior and lateral segments. There was also subepicardial LGE of the inferior segments and mid myocardial LGE of the septum. Fig. 1.
Fig.1.
(a) Short tau inversion recovery image: Patchy oedema of the anteroseptal and inferolateral wall. (c) T2-mapping image: myocardial oedema in the anterior and inferior walls. (b) and (d) Patchy epicardial and mid myocardial late gadolinium enhancement of the anteroseptum and inferolateral wall (b), anterior and inferior walls (d).
Plasma concentrations of 38 cytokines were measured and compared to a reference range generated based on a sample population of 20 healthy, non-COVID-vaccinated individuals of varied age and gender (HCYTOMAG-60-38PX Millipore, MERCK). Twenty-five were elevated and six lowered. Six cytokines were highly elevated (>5 standard deviations above the mean): interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-9, and lymphotoxin (LT)-α. Further serological testing demonstrated an antispike IgG titre above the detection limit of 250 U/mL, consistent with two vaccine doses. Antinucleocapsid IgG was not detected, indicating no past SARS-CoV-2 infection.
Right ventricular endomyocardial biopsy performed on day 13, just prior to discharge, revealed no features of myocarditis. He was discharged on Colchicine 500mcg BID.
3. Follow-up
At the 2-month review, he complained of New York Heart Association Class I symptoms and fatigue. His CMR demonstrated normalisation of biventricular function with persistent oedema in the LV anterior and lateral walls and residual patchy subepicardial and mid myocardial LGE of the LV, with significant overall reduction in the extent of both compared to his previous study.
4. Discussion
The mRNA vaccines, BNT162b2 (Pfizer) and mRNA-1273 (Moderna), are novel in their use of RNA to encode the SARS-CoV-2 spike antigen, and in their lipid nanoparticle delivery vectors. Myopericarditis has been reported following their use.2 Data from the Vaccine Adverse Event Reporting System) showed that the majority of cases occurred after the second dose, at median age 21 years and that 82% were males. The estimated incidence among males 18–24 years was 52.4 and 56.3 cases per million doses for the Pfizer and Moderna vaccines, respectively. Almost all patients with vaccine-induced myocarditis present with chest pain, 70% have an abnormal electrocardiogram, 77% have an abnormal CMR with LGE and myocardial oedema, and 80% have normal systolic function on TTE.3
Most cases reported are mild,2 occur within a week of vaccine administration, and respond rapidly to medical treatment. Rarely, however, fulminant myocarditis develops, resulting in heart failure, requiring inotropic or mechanical support for reported periods between 5 and 7 days.4
The mechanism by which mRNA-platform vaccines induce myopericarditis is unknown. In our patient's plasma, we found a high degree of deviation of immunologic factors from healthy levels. Widespread increases in cytokine levels likely reflect significant inflammation. Cytokines IL-1α, IL-1β, IL-6, and LTα are inflammatory cytokines produced by innate immune cells in response to pathogens and damage-associated molecular patterns, including RNA, as well as by cardiac cells in response to cardiac injury. They drive the recruitment and activation of immune cells, particularly monocytes. The importance of IL-1 in cardiomyopathies is well-established, evidenced by clinical trials of the IL-R antagonist anakinra in patients with myocardial infarction and idiopathic recurrent pericarditis.5,6 Similarly, serum IL-6 levels are associated with severity of clinical course in myocarditis.7
We believe the patient developed fulminant myocarditis following administration of the Pfizer BNT 162b2 vaccine, evidenced by his CMR findings. The negative right ventricular endomyocardial biopsy results are the likely result of the predominant localisation of abnormalities to the left ventricle. The cytokine panel is unable to distinguish changes that are peculiar to myocarditis induced by vaccination or that may persist after vaccination. The markedly raised IL-6 levels in this case, however, are consistent with the severity of disease manifested. We believe that the use of mechanical support was instrumental in his recovery. Despite no randomised controlled data supporting the routine use of intravenous immunoglobulin therapy for acute myocarditis, we equally believe its use was fundamental to the patient's recovery. Observational data indicate that myocarditis is responsive to colchicine and supports its use in acute myocarditis.8 We highlight that abnormal CMR findings can persist despite normalisation of ventricular function following COVID-19–induced myocarditis.
5. Conclusion
Rarely, mRNA COVID-19 vaccination can result in fulminant myocarditis. This case highlights the benefit of prompt mechanical support with ECMO, and corticosteroid and intravenous (IV) gamma globulin pharmacotherapy.
CRediT authorship contribution statement
Natalie L. Montarello: Conceptualization, Investigation, Writing of manuscript, Review and editing. Hao Zheng Wong: Writing, Review and editing. Ashlee Jeffries: Review and editing. Griffith B. Perkins: Review and editing. Pravin Hissaria: Review and editing. Michael B. Stokes: Review and editing. Eamon Raith: Review and editing. Karen Teo: Review and editing. Julie Bradley: Supervision, Review and editing.
References
- 1.Ferreira V.M., Schulz-Menger J., Holmvang G., Kramer C.M., Carbone I., Sechtem U., et al. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol. 2018;72(24):3158–3176. doi: 10.1016/j.jacc.2018.09.072. [DOI] [PubMed] [Google Scholar]
- 2.Gargano J.W., Wallace M., Hadler S.C., Langley G., Su J.R., Oster M.E., et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the advisory committee on immunization practices - United States, june 2021. MMWR Morb Mortal Wkly Rep. 2021;70(27):977–982. doi: 10.15585/mmwr.mm7027e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Truong D.T., Dionne A., Muniz J.C., McHugh K.E., Portman M.A., Lambert L.M., et al. Clinically suspected myocarditis temporally related to COVID-19 vaccination in adolescents and young adults: suspected myocarditis after COVID-19 vaccination. Circulation. 2022;145(5):345–356. doi: 10.1161/CIRCULATIONAHA.121.056583. [DOI] [PubMed] [Google Scholar]
- 4.Verma A.K., Lavine K.J., Lin C.Y. Myocarditis after covid-19 mRNA vaccination. N Engl J Med. 2021;385(14):1332–1334. doi: 10.1056/NEJMc2109975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Brucato A., Imazio M., Gattorno M., Lazaros G., Maestroni S., Carraro M., et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA. 2016;316(18):1906–1912. doi: 10.1001/jama.2016.15826. [DOI] [PubMed] [Google Scholar]
- 6.Abbate A., Kontos M.C., Grizzard J.D., Biondi-Zoccai G.G., Van Tassell B.W., Robati R., et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study) Am J Cardiol. 2010;105(10):1371–1377. e1. doi: 10.1016/j.amjcard.2009.12.059. [DOI] [PubMed] [Google Scholar]
- 7.Amioka N., Nakamura K., Kimura T., Ohta-Ogo K., Tanaka T., Toji T., et al. Pathological and clinical effects of interleukin-6 on human myocarditis. J Cardiol. 2021;78(2):157–165. doi: 10.1016/j.jjcc.2021.03.003. [DOI] [PubMed] [Google Scholar]
- 8.Behbahani-Nejad O., Mikolich B., Morgenstern D., Mikolich J.R. Myocarditis response to colchicine therapy based on cardiac MRI diagnostic criteria. J Am Coll Cardiol. 2021;77(18_Supplement_1):1432. [Google Scholar]