New Reports Help Nail Down Myocarditis Risk With COVID-19 Vaccine

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This week’s literature features new descriptions of myocarditis linked to the two available mRNA vaccines against SARS-CoV-2. They tell a story largely consistent with experience to date, and support what might be its most useful public-health message: the associated myocarditis is usually mild and self-limiting, and is far less likely to occur than myocarditis or death in unvaccinated people with COVID-19.

In line with previous research, the new analyses suggest the myocarditis — with onset usually a few days to a week after injection — has an overall incidence that ranges from less than one to perhaps three per 100,000 people who received at least one of the full mRNA-vaccine regimen’s two injections. Also, as in earlier studies, the incidence climbed higher — sometimes sharply — in certain groups by age and sex, particularly in young men and older male teens.

The new studies “are confirmatory, in terms of the risk being low,” but underscore that clinicians still must be wary of myocarditis as a potential complication of the mRNA vaccines, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told theheart.org | Medscape Cardiology.

Bozkurt, a leading heart failure specialist and researcher, didn’t contribute to any of the new reports but does study the myocarditis of COVID-19 and was lead author on a recent review of the potential vaccine complication’s features and possible mechanisms.

In the new myocarditis reports, she observed, more than 90% of the cases were mild and “resolved on their own without a major adverse outcome.” Bozkurt emphasized the need for perspective regarding the risk. For example, the myocarditis associated with SARS-CoV-2 infection is not only more likely than the vaccine-related myocarditis, but it’s also usually far more severe.

Bozkurt pointed to a recent study in which the mRNA vaccines, compared with no vaccination, appeared to escalate the myocarditis risk by a factor of 3, whereas the risk for myocarditis in SARS-CoV-2 infection was increased 18 times.

In contrast, she observed, the new myocarditis cases reported this week feature a few that are novel or are at least very rare, including the case of a patient who developed cardiogenic shock and another with fulminant myocarditis who died.

The Centers for Disease Control and Prevention (CDC) in May publicly described the apparent link between myocarditis and the two available mRNA vaccines against SARS-CoV-2: BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). The next month, the US Food and Drug Administration added a warning about the risk to their labeling.

Less Than One Case per 100,000

Fifteen confirmed cases of myocarditis were identified among about 2.4 million members of Kaiser Permanente Southern California aged 18 or older who received at least one injection of the Pfizer or Moderna mRNA vaccines between December 2020 and July 2021, in a report published October 4 in JAMA Internal Medicine. The study counted cases up to 10 days after the first or second injection, of which there were two and 13, respectively.

All eight patients who received the Pfizer BNT162b2 vaccine and the eight given the Moderna mRNA-1273 vaccine were male with a median age of 25 years (interquartile range, 20 – 32 years).

“The main takeaway messages from our study are that the incidence of myocarditis after COVID-19 mRNA vaccinations is very low, that this condition is primarily observed in young men within a few days after the second dose, and that most patients recover quickly,” senior author Mingsum Lee, MD, PhD, Kaiser Permanente Los Angeles Medical Center, told theheart.org | Medscape Cardiology.

“The incidence of vaccine-related myocarditis was significantly lower than rates of COVID-19 hospitalization during the same period and population area,” she added.

The group saw a per-million incidence of 0.8 and 5.8 myocarditis cases in the 10 days after first and second injections, respectively. That made for an incidence of 0.58 per 100,000, or one case per 172,414 fully vaccinated adults.

The group also considered a cohort of 1,577,741 unvaccinated people with a median age of 39 years (interquartile range, 28 – 53 years) during the same period. Of the 75 cases of myocarditis, 52% were in men, they reported.

Comparing the vaccinated and unvaccinated cohorts, they saw a 10-day vaccine-associated myocarditis incidence rate ratio (IRR) of:

• 0.38 (95% CI, 0.05 – 1.40; P = .15) after the first dose

• 2.7 (95% CI, 1.4 – 4.8; P = .004) after the second dose

In a comparison of the vaccinated group with itself using data from a 10-day period in the previous year, the corresponding myocarditis IRRs were 1.0 (P > .99) and 3.3 (P = .03), respectively.

Lee said none of the 15 patients required admission to an intensive care unit. “All patients with myocarditis responded well to treatment and felt better quickly,” she noted.

Myocarditis after an mRNA vaccine injection is rare and, Lee said emphatically, and “the benefits of the COVID-19 vaccine greatly outweigh the risks.”

Sex- and Age-Stratified Rates

In a separate analysis of 5,442,696 people given a first dose of the Pfizer BNT162b2 vaccine and 5,125,635 given a second dose, there were 142 cases of myocarditis with onset 21 days after dose 1 and 30 days after dose 2. Of those cases, 136 were documented as “definite or probable” in an Israeli Ministry of Health database covering to the end of May 2021.

There were also 40 cases among vaccinated people seen after the 30-day window, which were considered not related to the vaccination, and 101 cases among unvaccinated people; of the latter, 29 had confirmed diagnoses of COVID-19.

Of the 136 people with definite or probable cases, the myocarditis was “generally mild” in 129 and usually resolved on its own, notes the report on the study, published October 6 in the New England Journal of Medicine, with lead author Dror Mevorach, MD, Hadassah-Hebrew University Medical Center, Jerusalem.

The estimated myocarditis incidence after a second such vaccine dose across the entire Israeli population, based on the current study, was about one per 26,000 males and one per 218,000 females, the group writes. Those figures compare with one case per 10,857 among “the general unvaccinated population.”

Again, the risk was concentrated among younger men and male adolescents. In an analysis limited to vaccinated people aged 16 to 19 years, myocarditis in the 21 days after a second mRNA injection was seen in about one of 6637 males and one of 99,853 females, the group reported.

The standardized incidence ratio of 5.34 (95% CI, 4.48 – 6.40) after a second injection, across all groups, “was driven mostly by the diagnosis of myocarditis in younger male recipients.” Among that male subgroup, the ratios by age group were:

• 13.60 (95% CI, 9.30 – 19.20) for 16 to 19 years

• 8.53 (95% CI, 5.57 – 12.50) for 20 to 24 years

• 6.96 (95% CI, 4.25 – 10.75) for 25 to 29 years

Among people who received a second injection. compared with unvaccinated people, the 30-day rate ratio was 2.35 (95% CI, 1.10 – 5.02). Again, the effect concentrated in males aged 16 to 19 years. Among them, the myocarditis rate ratios in the 30 days after a second mRNA vaccine injection were:

• 8.96 (95% CI, 4.50 – 17.83) for the 16 to 19 group

• 6.13 (95% CI, 3.16 – 11.88) for 20 to 24 years

• 3.58 (95% CI, 1.82 – 7.01) for 25 to 29 years

Most of the patients with myocarditis showed “significant clinical improvement,” with a mean hospitalization time of only 3 to 4 days, the report notes. Treatment consisted of nonsteroidal anti-inflammatory drugs “with or without colchicine for presumed pericardial inflammation.”

However, seven patients (4.9%) developed important complications, including left-ventricular dysfunction, ventricular arrhythmias, and heart failure. Among them was a 22-year-old patient who died of fulminant myocarditis within 24 hours of diagnosis, the group writes.

From an Israeli Healthcare Organization

Published by the same journal as the Mevorach et al. study, an analysis of a separate database showed largely consistent findings among patients in the largest of Israel’s four healthcare organizations charged by the government to administer health services.

The report, with authors led by Guy Witberg, MD, Rabin Medical Center, Petah Tikva, Israel, focused on members of the healthcare organization who were 16 years or older and had received at least one Pfizer mRNA vaccine dose by the end of May 2021.

The cohorts from the two separate reports surely overlap substantially, as the Ministry of Health analysis from Mevorach and colleagues derived from a nationwide database, and — as Witberg and associates write — the healthcare organization providing their data covers 52% of the Israeli population.

Of 2,558,421 vaccinated people in the analysis, of whom 94% received two doses, 54 developed confirmed myocarditis in the 42 days after the first dose. Their median age was 27 years (interquartile range, 21 – 35 years) and all but three (94%) were male. Of those 54 cases, 41 were considered mild and 12 intermediate in severity, and one was fulminant with the patient in cardiogenic shock, the group writes. In addition, nonsustained ventricular tachycardia and atrial fibrillation developed in 5% and 3% of cases, respectively.

The estimated myocarditis incidence in the 42 days after administration of at least one mRNA vaccine dose was 2.13 per 100,000 vaccinated people. In that group, Witberg and colleagues note, the corresponding incidences per 100,000 were 4.12 and 0.23 for males and females, respectively.

Also in the current report, incidences per 100,000 vaccinated people aged 16 to 29 years, by sex, included:

• 5.49 (95% CI, 3.59 – 7.39) overall

• 10.69 (95% CI, 6.93 – 14.46) for males (the highest rate in the report)

There was only one case in a female aged 16 to 29 years, and two cases in females 30 years or older.

Of note, some authors of the current study are also authors on the high-profile report from Barda et al., published August 25 in the New England Journal of Medicine, that used the same database to arrive at an mRNA-vaccine-related incidence of myocarditis of 2.7 per 100,000. Eligibility criteria and follow-up time were different in that report, as were case ascertainment criteria.

The myocarditis risk associated with the two mRNA vaccines is small compared with “the morbidity and mortality of COVID-19 infection, in which up to 28% of hospitalized patients showed signs of myocardial injury,” write Vinay Guduguntla, MD, University of California, San Francisco, and Mitchell H. Katz, MD, NYC Health + Hospitals, New York City, in an editorial accompanying the Lee et al. report.

“Randomized clinical trials show that COVID-19 mRNA vaccines represent a safe and effective method of preventing infection,” they state. “The identification of rare myocarditis does not change clinical decision-making.”

Bozkurt, who is immediate past-president of the Heart Failure Society of America, has disclosed consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Lee and the report’s other authors had no disclosures. Mevorach discloses consulting for Enlivex Therapeutics; disclosures for the other authors are available at NEJM.org. Witberg has “no interests to disclose”; disclosures for the other authors are available at NEJM.org. Guduguntla is an editorial fellow and Katz a deputy editor at JAMA Internal Medicine; neither had disclosures.

JAMA Intern Med. Published online October 4, 2021. Letter, Editorial

N Engl J Med. Published October 6, 2021. Mevorach et al., Witberg et al.  

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