Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study

Nordic myocarditis cohort

We conducted a population based multi-country study of nationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), as defined in a prespecified common protocol (online supplemental material 1). Our Nordic myocarditis cohort included all individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis (defined by ICD-10 (international classification of diseases and related health problems, 10th revision) codes I40.0, I40.1, I40.8, I40.9, I41.1, I41.8, or I51.4) at discharge (alive or dead) from inpatient hospital care, from 1 January 2018 to the latest date of follow-up in 2022, which was specific for each country (online supplemental table S1).

In Denmark, inpatient hospital care was defined as a hospital stay of ≥24 hours because duration of hospital contacts coding has replaced inpatient hospital care coding in current Danish patient registries. Patients with a pre-existing diagnosis of myocarditis (defined by ICD-10 codes) or heart failure (ICD-10 codes defined in online supplemental table S2) were excluded from the study. Online supplemental table S1 describes the washout periods for pre-existing diagnoses in the different countries. Only patients with a potential 90 days of follow-up in the register data were included in the study. Information on clinical diagnoses and length of hospital stay was sourced from national registries (online supplemental table S3).

Individuals admitted to hospital for myocarditis within 28 days of vaccination with a SARS-CoV-2 mRNA vaccine (any dose) were categorised as having myocarditis associated with vaccination; individuals admitted to hospital for myocarditis within 28 days of a positive polymerase chain reaction (PCR) test result for the SARS-CoV-2 virus were categorised as having myocarditis associated with covid-19 disease. The remaining patients who were admitted to hospital for myocarditis were categorised as conventional myocarditis. If an individual had received an mRNA vaccine and had a positive PCR test result for SARS-CoV-2 infection within 28 days, the latest exposure defined the type of myocarditis. Information on mRNA vaccinations for the SARS-CoV-2 virus were obtained from national vaccination registries in each country, and information on positive PCR test results were taken from national infectious disease surveillance registries (online supplemental table S3).

Length of stay after admission to hospital for new onset myocarditis was calculated as day of discharge minus day of admission + 1. If a patient with incident myocarditis had a subsequent admission to hospital within 24 hours of discharge, the subsequent admission to hospital was counted as part of the original admission to hospital for new onset myocarditis.

Cohort stratification

To evaluate the role of predisposing comorbidity, we included information on pre-existing diagnoses (in the two years before admission to hospital for new onset myocarditis) of malignancy, cardiovascular disease, or autoimmune diseases (ICD-10 codes defined in online supplemental table S2), from main or secondary diagnoses recorded in inpatient or specialist outpatient care. Also, we recorded whether the admission for new onset myocarditis was on or after 1 January 2020, to separate patients with myocarditis occurring before or during the covid-19 pandemic.

Outcomes

The clinical outcomes investigated were a new onset diagnosis of heart failure within 90 days of admission to hospital for new onset myocarditis; death from any cause within 90 days of admission to hospital for new onset myocarditis; and readmission to inpatient hospital care for any cause within 90 days of discharge from hospital for new onset myocarditis. If new onset heart failure was diagnosed in the same admission period as new onset myocarditis, new onset heart failure was categorised as occurring on the day after admission to hospital for myocarditis.

Statistical analysis

Cumulative 90 day relative risks of heart failure and death by type of myocarditis type for all four countries were estimated, with conventional myocarditis as the reference category. In subgroup analyses, we used a combined outcome of heart failure or death within 90 days of myocarditis, to preserve the statistical power to describe differences between the myocarditis groups. Subgroup analyses were performed by age group (12-39 years and ≥40 years), sex, and in those admitted to hospital for new onset myocarditis on or after 1 January 2020 (reference was those admitted to hospital for new onset myocarditis before the pandemic). To investigate outcomes in healthy younger individuals with myocarditis, we conducted another analysis in those aged <40 years with no pre-existing diagnoses of malignancy, cardiovascular disease, or autoimmune disease. Similarly, subgroup analyses of cumulative 90 day relative risks of readmission after discharge from hospital for new onset myocarditis were performed by age group, sex, and in those admitted to hospital for new onset myocarditis on or after 1 January 2020 (reference was those admitted to hospital for new onset myocarditis before the pandemic), in these younger individuals with no pre-existing diagnoses of malignancy, cardiovascular disease, or autoimmune disease.

Cumulative incidences of heart failure and death by country for conventional myocarditis and myocarditis associated with vaccination, as a function of time from admission to hospital for myocarditis, were estimated with the Kaplan-Meier estimator (calculated as 1−Kaplan-Meier estimates). Cumulative incidence of readmission by country was also estimated with the Kaplan-Meier estimator but with time from discharge from hospital as the underlying time scale. Also, Kaplan-Meier estimates in multiples of 10 days of follow-up, by country, were combined with a random effects meta-analysis implemented with the mixmeta package12 of R.13 As input to the meta-analyses, log odds of estimates specific to each country were used as estimates, and the difference between log odds of confidence limits specific to each country were divided by 2×1.96 as standard errors. If at least one of the country estimates was zero, then the sum of events divided by the total number of patients with myocarditis was used to obtain results combined across countries. Cumulative incidences by country were not estimated for myocarditis associated with covid-19 disease because of limited statistical power.

Patient and public involvement

No patients or members of the public were directly involved in the design, analysis, or writing up of the study, owing to insufficient funds and time. The study was conducted by national public health institutions in Denmark, Finland, Norway, and Sweden, who have a legal obligation to investigate potential health hazards to the public.

Characteristics of the Nordic myocarditis cohort

Our cohort included 7292 patients with a diagnosis of myocarditis; 530 (7.3%) were categorised as having myocarditis associated with vaccination, 109 (1.5%) were associated with covid-19 disease, and 6653 (91.2%) had conventional myocarditis (table 1). Patients were predominantly men (5304 (72.7%) overall) and 3715 (50.9%) were aged <40 years. Online supplemental table S4 shows median (interquartile range) age by type of myocarditis, age group, and country. Eighty five (16.0%), 54 (49.5%), and 1893 (28.5%) patients were admitted to hospital for ≥7 days in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. Only 11 of 639 patients with non-conventional myocarditis had received a SARS-CoV-2 mRNA vaccine and had covid-19 disease within 28 days of admission to hospital for myocarditis.

Absolute and relative risk of heart failure and death

At 90 days of follow-up for new onset myocarditis, heart failure was diagnosed in 22 (4.5 %), 12 (11.0 %), and 496 (7.5 %) patients with myocarditis associated with vaccination, myocarditis associated with covid-19 disease, and conventional myocarditis, respectively. We found that patients with myocarditis after vaccination had a significantly decreased risk of heart failure at 90 days after admission to hospital for myocarditis (relative risk 0.56, 95% confidence interval 0.37 to 0.85, P=0.006) compared with those with conventional myocarditis (table 2). Conversely, we found a non-significant increased risk of heart failure at 90 days in patients with myocarditis associated with covid-19 disease (1.48, 0.86 to 2.54) compared with conventional myocarditis. Death was rare during the 90 days of follow-up, with six (1.1%), six (5.5%), and 156 (2.3%) patients dying of any cause within 90 days of admission to hospital in the vaccination, covid-19, and conventional myocarditis groups, respectively. The relative risk of death over 90 days of follow-up was 0.48 (0.21 to 1.09) for patients with myocarditis associated with vaccination and 2.35 (1.06 to 5.19) for patients with myocarditis associated with covid-19 disease, compared with conventional myocarditis (table 2).

For estimates of the risk of heart failure in individual countries, we found similar patterns for myocarditis associated with vaccination and conventional myocarditis across the Nordics countries (online supplemental figure S1); limited statistical power did not allow calculation of risk estimates for myocarditis associated with covid-19 disease. We found no indication of differences between the Nordic countries for the risk of death for patients with vaccination type myocarditis within 90 days of follow-up, although statistical power was limited because of few deaths (online supplemental figure S2). In combined meta-analyses, we found that estimates of risk for both heart failure and death were lower for patients with myocarditis associated with vaccination compared with conventional myocarditis for all time points during follow-up (figure 1).

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Absolute and relative risk of readmission

At 90 days of follow-up from discharge for new onset myocarditis, 62 (11.7%), nine (8.3%), and 988 (14.9%) patients were readmitted to hospital in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of readmission between types of myocarditis within 90 days of discharge from hospital, with conventional myocarditis as the reference, was 0.79 (95% confidence interval 0.62 to 1.00) for patients with myocarditis associated with vaccination and 0.55 (0.30 to 1.04) for patients with myocarditis associated with covid-19 disease (table 3). Online supplemental figure S3 presents the risk of readmission in the vaccination and conventional myocarditis groups in 10 day periods for each country. In a combined Nordic analysis, we found that the estimated risk of readmission to hospital was numerically lower for patients with myocarditis associated with vaccination compared with those with conventional myocarditis at all periods during follow-up (online supplemental figure S4).

Subgroup analyses

In subgroup analyses, we found similar patterns to the main analyses in younger patients, older patients, and in men and women, with a lower risk of the combined outcome of heart failure and death by 90 days of follow-up for patients with myocarditis associated with vaccination compared with those with conventional myocarditis or myocarditis associated with covid-19 disease (online supplemental table S4). Among men and when the analysis was restricted to patients admitted on or after 1 January 2020, we found a significantly lower risk of heart failure or death for patients with myocarditis associated with SARS-CoV-2 mRNA vaccination compared with the two other types of myocarditis (P=0.005 and P=0.002, compared with convential myocarditis, respectively, and both P<0.001 compared with covid-19 type myocarditis, respectively; online supplemental table S5). We found no significant differences in the risk of readmission in younger patients and in women for the three myocarditis groups (online supplemental table S6), but a significantly reduced risk of readmission was found for men and those admitted on or after 1 January 2020 in the vaccination type myocarditis group compared with the conventional myocarditis group (P=0.03 and P=0.03, respectively). We also found a significantly reduced risk of readmission among older patients in the covid-19 type myocarditis group compared with the conventional myocarditis group (P=0.02, online supplemental table S6). Sensitivity analyses of patients with conventional myocarditis admitted to hospital before 1 January 2020 (ie, before the pandemic) as reference were comparable with the results of the main analyses (online supplemental table S7).

Finally, we performed an analysis restricted to patients aged 12-39 years with no pre-existing registered diagnoses of malignancy, heart disease, or autoimmune disease (table 4). We found that myocarditis after SARS-CoV-2 mRNA vaccination was associated with a non-significant reduced relative risk of heart failure or death at 90 days of follow-up compared with conventional myocarditis (relative risk 0.50, 95% confidence interval 0.22 to 1.12). In this subgroup, we also found that myocarditis after covid-19 disease was associated with an increased risk of heart failure or death within 90 days of admission (relative risk 5.78, 1.84 to 18.20) compared with myocarditis associated with vaccination. We found no differences in the risk of readmission between the types of myocarditis for patients aged <40 years with no diagnoses of malignancy, heart disease, or autoimmune disease (online supplemental table S6).

Principal findings

In a population based study of 23 million individuals in Denmark, Finland, Norway, and Sweden, we found that myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with a significantly lower risk of heart failure within 90 days of admission compared with conventional myocarditis and myocarditis after covid-19 disease (P=0.006 and P=0.005, respectively). Also, among younger patients with no potentially predisposing comorbidities for developing myocarditis, we found that myocarditis after covid-19 disease was associated with a substantially higher risk of heart failure or death at 90 days of follow-up compared with myocarditis after vaccination. Taken together, our findings suggested that the outcomes of myocarditis after vaccination were less severe than other types of myocarditis during the first 90 days after the onset of myocarditis.

Strengths and limitations

Our study was based on nationwide health registers in four Nordic countries, covering all patients with myocarditis admitted to hospital aged ≥12 years. Also, the register data on SARS-CoV-2 mRNA vaccination, PCR test results for SARS-CoV-2 infection, admissions to hospital for myocarditis, and outcomes after myocarditis were collected prospectively as part of routine clinical and administrative practices, thereby eliminating potential recall bias.

A limitation of our study was that we did not have information on paraclinical evaluations of the severity of myocarditis (eg, electrocardiography, echocardiography, or cardiac magnetic resonance imaging (MRI)). Our prespecified outcome of a diagnosis of heart failure by a hospital physician, however, has previously been associated with high validity in the non-geriatric population.14 Also, compared with only radiographic findings, a diagnosis of heart failure is likely to reflect clinically relevant impairment. A second limitation of the study was that patients with myocarditis not related to vaccination or covid-19 disease were combined into one category, with some incidences of myocarditis caused by drug treatment for an underlying condition (eg, myocarditis induced by cancer chemotherapy), which inherently could result in a higher risk of readmission to hospital, heart failure, and death. In our sensitivity analysis restricted to younger individuals without predisposing comorbidities, however, our findings were similar to the main analysis.

A third limitation of the study was the potential for misclassification of the cause of myocarditis for patients with myocarditis associated with vaccination and covid-19 disease. This potential bias is difficult to avoid in large scale studies, however, and most likely is non-differential. Furthermore, in our sensitivity analyses with those admitted to hospital for new onset myocarditis before the pandemic as reference, we found similar findings to our main analyses, suggesting no strong bias from misdiagnosed cases during the pandemic period. A fourth limitation was the slight heterogeneity in the definition of myocarditis, because for patients in Denmark, admission to hospital was defined as ≥24 hours because of a current lack of distinction between inpatents and outpatients in Danish registries. A fifth limitation was no examination of medical prescriptions before diagnosis, which could have indicated the cause of myocarditis for a small subset of patients. Finally, because of current regulations on data privacy, we could not adjust the combined Nordic cohort for individual level covariates, and therefore we conducted subgroups analyses.

Comparison with other studies

Our results are compatible with the findings of smaller cohort studies in individual clinical centres,15 16 which found that myocarditis associated with SARS-CoV-2 mRNA vaccination was associated mainly with mild clinical outcomes. Nevertheless, six patients with myocarditis after vaccination died within 90 days of admission to hospital. Establishing causality given the rarity of death is difficult (1.1% of patients with myocarditis associated with vaccination), however, because these deaths could have been from other causes or from conventional myocarditis occurring by chance within 28 days of vaccination. Schauer et al, in their study covering three to eight months after the first admission to hospital for myocarditis associated with vaccination, reported that resolution of cardiac MRI abnormalities were not complete in all patients.15 Because the clinical significance of these abnormalities is not yet known, continued surveillance of this patient group to detect possible developing cardiomuscular disease is warranted. The overall findings on outcomes of myocarditis associated with vaccination by us and others are reassuring, however, and should be considered when weighing the benefits and potential risks of mRNA vaccines against the SARS-CoV-2 virus at the individual and population levels.

Although our study consistently suggested that the outcomes of myocarditis after vaccination were less severe than for other types of myocarditis, we found only minimal differences in the relative risk of readmission to hospital within 90 days by type of myocarditis. This finding could reflect increased clinical interest in patients with myocarditis associated with vaccination, however, which could have resulted in increased rates of readmission for further clinical evaluation. Also, the higher risk of death among patients with myocarditis after covid-19 disease could potentially bias the risk of readmission downward for this patient group.

Compared with myocarditis associated with vaccination, myocarditis after covid-19 disease had substantially worse clinical outcomes, with a longer stay for the initial admission to hospital and increased risk of heart failure or death among younger individuals with no predisposing comorbidities. The difference in clinical outcomes for the two types of myocarditis could indicate differences in cause rather than a similar exposure to the SARS-CoV-2 spike protein, which is expressed during both mRNA vaccination and SARS-CoV-2 infection. The absolute risk of covid-19 myocarditis in the four Nordic countries was low during the study period,7 however, despite high testing rates for the SARS-CoV-2 virus and high seroprevalence of SARS-CoV-2 nucleocapsid antibodies.17

Our population based study provides new prognostic information on myocarditis associated with vaccination. The low cumulative incidence of heart failure or death by 90 days for patients developing myocarditis after vaccination is reassuring. We previously found that the incidence of myocarditis after a second dose of mRNA vaccine was higher than after a positive test result for SARS-CoV-2 infection among younger patients.7 In this study, however, our findings strongly suggested that the clinical outcomes were substantially worse for myocarditis associated with covid-19 disease. Among younger patients with no predisposing comorbidities, we found that the risk of heart failure or death within 90 days of new onset myocarditis was about six times higher for patients with myocarditis associated with covid-19 disease than for those with myocarditis after vaccination. Also, comparing the incidence of myocarditis after vaccination versus after covid-19 disease might not be meaningful when determining recommendations for the use of mRNA vaccines against the SARS-CoV-2 virus. Vaccination with mRNA vaccines has many well described beneficial properties, including protection against severe forms of covid-19 disease18 19 and death.18 20

Future studies of patients who developed myocarditis after SARS-CoV-2 mRNA vaccination should aim for an extended follow-up period of at least one year. Also, longitudinal evaluation of changes in paraclinical parameters, such as measurement of systolic and diastolic cardiac dysfunction, scarring on cardiac MRI, assessment of heart arrhythmia, and biological markers will be valuable for determining the natural history of myocarditis after vaccination with mRNA vaccines.

Conclusions

We found that myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with a lower risk of heart failure within 90 days of admission to hospital compared with conventional myocarditis and myocarditis after covid-19 disease. Less severe outcomes of myocarditis after vaccination were found in different subgroups, including younger patients with no predisposing comorbidities, and in both men and women. Our results suggested that the outcome of myocarditis associated with SARS-CoV-2 mRNA vaccination was less severe than for other types of myocarditis.