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ArticlesVolume 76102809October 2024Open access
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Cardiac manifestations and outcomes of COVID-19 vaccine-associated myocarditis in the young in the USA: longitudinal results from the Myocarditis After COVID Vaccination (MACiV) multicenter study
Supriya S. Jaina Sjain7@nymc.edu ∙ Steven A. Andersonb ∙ Jeremy M. Steelec ∙ Hunter C. Wilsond ∙ Juan Carlos Munize ∙ Jonathan H. Soslowf∙ et al. Show more
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Summary
Background
We aimed to study the clinical characteristics, myocardial injury, and longitudinal outcomes of COVID-19 vaccine-associated myocarditis (C-VAM).
Methods
In this longitudinal retrospective observational cohort multicenter study across 38 hospitals in the United States, 333 patients with C-VAM were compared with 100 patients with multisystem inflammatory syndrome in children (MIS-C). We included patients ≤30 years of age with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers and/or cardiovascular imaging findings. Demographics, past medical history, hospital course, biochemistry results, cardiovascular imaging, and follow-up information from April 2021 to November 2022 were collected. The primary outcome was presence of myocardial injury as evidenced by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging.
Findings
Patients with C-VAM were predominantly white (67%) adolescent males (91%, 15.7 ± 2.8 years). Their initial clinical course was more likely to be mild (80% vs. 23%, p < 0.001) and cardiac dysfunction was less common (17% vs. 68%, p < 0.0001), compared to MIS-C. In contrast, LGE on CMR was more prevalent in C-VAM (82% vs. 16%, p < 0.001). The probability of LGE was higher in males (OR 3.28 [95% CI: 0.99, 10.6, p = 0.052]), in older patients (>15 years, OR 2.74 [95% CI: 1.28, 5.83, p = 0.009]) and when C-VAM occurred after the first or second dose as compared to the third dose of mRNA vaccine. Mid-term clinical outcomes of C-VAM at a median follow-up of 178 days (IQR 114–285 days) were reassuring. No cardiac deaths or heart transplantations were reported until the time of submission of this report. LGE persisted in 60% of the patients at follow up.
Interpretation
Myocardial injury at initial presentation and its persistence at follow up, despite a mild initial course and favorable mid-term clinical outcome, warrants continued clinical surveillance and long-term studies in affected patients with C-VAM.
Funding
The U.S. Food and Drug Administration.
Keywords
- Myocarditis
- COVID-19 vaccine-associated myocarditis
- Cardiac MRI
- Myocardial injury
- LGE late gadolinium enhancement
- MIS-C multisystem inflammatory syndrome in children
Research in context
Evidence before this study
In August 2021, we published the first report of a robust pediatric cohort with COVID-19 vaccine-associated myocarditis (C-VAM), systematically studied by cardiac magnetic resonance imaging (CMR) and demonstrating myocardial injury as evidenced by late gadolinium enhancement (LGE). A PubMed search from 03/01/2021 to 9/30/2021, using the terms “COVID-19 vaccine myocarditis” AND “late gadolinium enhancement” AND “outcome” produced only two results, including our study above. No literature existed on the sequelae of C-VAM or the prognosis of LGE in these patients. We thus embarked on a larger multicenter longitudinal study to comprehensively evaluate the cardiac manifestations and outcomes of C-VAM, especially the evolution of myocardial damage in children, adolescents, and young adults.
Added value of this study
This study not only provides a detailed phenotypic clinical characterization of C-VAM in 333 children, adolescents, and young adults, but also includes important longitudinal myocardial tissue information in vaccine-associated myocarditis and provides data on the cardiovascular outcomes of this complication in a large cohort of patients across 38 sites in the United States. This constitutes the hitherto largest longitudinal study in C-VAM that includes information on myocardial injury and scarring, along with its possible risk factors. The study contrasts C-VAM to multisystem inflammatory syndrome in children (MIS-C), a complication related to COVID-19 with cardiac manifestations.
Implications of all the available evidence
Myocardial injury as evidenced by LGE on CMR imaging is common in patients with myocarditis after mRNA COVID-19 vaccination who present to the hospital, especially in adolescent males. As the long-term significance of this myocardial damage is unclear, continued clinical surveillance of affected patients is warranted.
Introduction
Vaccination has been a public health cornerstone in the mitigation of the SARS-CoV-2 pandemic. Myocarditis is a rare complication of mRNA vaccines.1–3 Late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) imaging is increasingly used to characterize acute myocardial injury and chronic scarring in childhood myocarditis.4 We previously reported a high rate of myocardial injury with COVID-19 vaccine-associated myocarditis (C-VAM) in a pediatric pilot cohort.3 The natural history, implications of myocardial injury, and overall prognosis for young patients with C-VAM are insufficiently studied. In other conditions, including viral myocarditis, LGE can be a harbinger of heart failure, dilated cardiomyopathy, arrhythmias, and sudden cardiac death in the future.5–9 The objectives of this study were to describe the initial clinical and cardiac imaging characteristics of C-VAM, explore possible risk factors for myocardial injury as evidenced by LGE on CMR imaging and evaluate cardiovascular outcomes, in a large cohort of children, adolescents and young adults diagnosed with C-VAM.
Methods
Study design and participants
This was a longitudinal multicenter retrospective observational study across 38 U.S. member institutions of the Myocarditis After COVID Vaccination (MACiV) study network of pediatric cardiologists and CMR experts. We included patients ≤30 years of age with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers and/or cardiovascular imaging findings, as per the Centers for Disease Control and Prevention (CDC) criteria1 (Appendix A). Patients with a plausible alternative etiology for their acute myocarditis, including a recent infectious cause, were excluded. Institutional research ethics boards approved the study at every participating site and waived informed consent requirements. Demographics, past medical history, hospital course, biochemistry results, cardiovascular imaging, and follow-up information from April 2021 to November 2022 were collected. Sex and race/ethnicity as reported by patients/parents were retrieved from the medical records. Patients were stratified into younger (5–15 years) and older (16–30 years) age groups, reflecting the sequential vaccine roll-out of the U.S Food and Drug Administration’s Emergency Use Authorizations of mRNA vaccines. To gain a better perspective of the cardiac involvement in myocarditis associated with COVID-19 vaccination, we compared these patients with those who had multisystem inflammatory syndrome in children (MIS-C), based on CDC criteria10 (Appendix B), an important complication of COVID-19 in the pediatric population with frequent cardiac manifestations that the vaccine seeks to prevent. Patients with MIS-C, who had CMR for myocarditis during the acute or subacute illness were included.
Clinical information and cardiovascular testing
Biomarkers of myocardial injury (troponin), heart failure (brain-natriuretic peptide BNP or NT-pro-BNP) and systemic inflammation (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) were collected. Troponin levels were standardized by dividing them by their respective upper limits of normal to account for assay variability across different institutions and to allow for comparison of different types of troponins (high sensitivity vs. regular). To compare clinical courses, greater than mild clinical severity was defined as ≥1 of the following: presence of ventricular arrhythmias, including ventricular tachy-arrhythmias and higher-grade atrioventricular conduction block, left ventricular (LV) systolic dysfunction on echocardiogram as defined by left ventricular ejection fraction (LVEF) <55%, need for inotropic medications, mechanical ventilation or invasive cardiac support, heart transplantation, or death.
Results from electrocardiograms (ECGs), telemetry, Holter monitoring, echocardiography, and CMR were collected. The CMR findings were verified by site co-investigators with expertise with this modality. CMR information about myocardial edema, hyperemia, myocardial injury and scarring along with ventricular volumes were recorded. Myocardial edema was identified by prolonged T2 time on mapping or high T2 signal intensity visually or by a myocardial/skeletal muscle signal intensity ratio ≥2. Hyperemia was diagnosed by early gadolinium enhancement. The presence of LGE in the myocardium or elevated native T1 times or extracellular volume fraction (ECV) were regarded as markers of myocardial injury.11–14 T2 and native T1 times as well as ECV values were compared to local or reported pediatric normal ranges.15,16 To assess the severity of myocardial injury, patients were stratified based on LGE severity. Greater than mild LGE severity was defined as multifocal and/or transmural LGE or ≥4 American Heart Association (AHA) myocardial segments with LGE.17
Outcomes
The primary outcome was presence of myocardial LGE at initial presentation. Secondary outcomes included the following variables during follow-up: presence of myocardial LGE; presence of cardiovascular symptoms including chest pain, palpitations, shortness of breath, syncope; ventricular or supra-ventricular tachycardias; frequent premature ventricular contractions; second- or third-degree atrioventricular conduction block; LVEF <55% on echocardiogram; listing for heart transplantation; re-hospitalization and/or death attributable to cardiac causes.
Statistical analysis
Continuous data are reported as means and standard deviations, if normally distributed; otherwise as medians and interquartile ranges (IQR). Categorical results are displayed as frequencies and percentages, as appropriate. Only complete data were included for analyses. Pearson’s correlation and Spearman’s rank correlation were used to assess the strength and direction of the relationship between parametric and non-parametric data, respectively. Fisher’s exact test was used for categorical variables; the student’s t-test or the Mann–Whitney U test was used for continuous variables. Tukey’s post-hoc testing was used to adjust for multiplicity. Candidate demographic characteristics were assessed for association with baseline LGE using simple logistic regression and tested for multicollinearity and interaction before being included in multivariable analyses using stepwise forward logistic regression. Relationships with LGE are reported as odds ratios (OR) with 95% Confidence Intervals (CI). The Likelihood ratio test, Hosmer–Lemeshow test, Link test, and receiver operating curves were used to assess model fit, linearity, and discriminatory power, respectively. p-values <0.05 were regarded as significant. All analyses were performed with Stata, v.18 statistical software (StataCorp. 2023. Stata Statistical Software: Release 18. TX: StataCorp LLC).
Role of the funding source
The funder of the study did not have any role in study design, data collection, data analysis, or writing of the report except for its interpretation, review, edit and decision to submit for publication.
Results
Four hundred and thirty-three patients were enrolled, including 333 with C-VAM and 100 with MIS-C. Baseline demographic, clinical characteristics and cardiac imaging findings are summarized in Table 1.