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• Providing comments on methods, analyses & conclusions. Seeking additional information & response from the authors.
  John J Jones
  Published on: 16 April 2023
• Seeking more information on risk factors and vaccination status of those w/myocarditis post-SARS-CoV-2
  Tracy Beth Høeg, Miloš Miljković and Vinay Prasad
  Published on: 11 April 2023

• Published on: 16 April 2023

  Providing comments on methods, analyses & conclusions. Seeking additional information & response from the authors.

  • John J Jones, Physician John J Jones MD

  I read with interest the Nordic myocarditis cohort study by Husby et al (1) on clinical outcomes of three different types of myocarditis: COVID-19 mRNA vaccination-associated (“vaccine-associated”), COVID-19 infection-associated (“infection-associated”) and “conventional” myocarditis. I would like to make several comments and request response from the authors.

  A significant limitation of the Nordic and other similar studies is the under-diagnosis of COVID-19 vaccine-associated myocarditis and possibly COVID-19 infection-associated myocarditis. To be included in the Nordic myocarditis cohort study, an individual had to develop symptom(s) with myocarditis, present to a medical provider with such symptom(s), and the medical provider had to consider myocarditis and then order at least ECG or cardiac enzyme(s), and the individual had to be admitted to the hospital as an inpatient. Individuals with myocarditis who did not satisfy all the above conditions would not have been included in the Nordic study. Only a prospective study with continuous screening for myocardial injury/inflammation would be able to provide complete information on the incidence and outcomes of myocarditis associated with COVID-19 vaccine or infection. Limited prospective data on myocardial injury post-vaccine is currently available, suggesting significantly more common occurrence (2,3) than proclaimed but with unknown long-term prognosis.

  During the COVID-19 pandemic, there were many more pat...

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  I read with interest the Nordic myocarditis cohort study by Husby et al (1) on clinical outcomes of three different types of myocarditis: COVID-19 mRNA vaccination-associated (“vaccine-associated”), COVID-19 infection-associated (“infection-associated”) and “conventional” myocarditis. I would like to make several comments and request response from the authors.

  A significant limitation of the Nordic and other similar studies is the under-diagnosis of COVID-19 vaccine-associated myocarditis and possibly COVID-19 infection-associated myocarditis. To be included in the Nordic myocarditis cohort study, an individual had to develop symptom(s) with myocarditis, present to a medical provider with such symptom(s), and the medical provider had to consider myocarditis and then order at least ECG or cardiac enzyme(s), and the individual had to be admitted to the hospital as an inpatient. Individuals with myocarditis who did not satisfy all the above conditions would not have been included in the Nordic study. Only a prospective study with continuous screening for myocardial injury/inflammation would be able to provide complete information on the incidence and outcomes of myocarditis associated with COVID-19 vaccine or infection. Limited prospective data on myocardial injury post-vaccine is currently available, suggesting significantly more common occurrence (2,3) than proclaimed but with unknown long-term prognosis.

  During the COVID-19 pandemic, there were many more patients in the Nordic study with myocarditis post-vaccine than post-infection (530 vs 109, ratio 4.9), especially among individuals 12-39 years old (340 vs 48, ratio 7.1). Regrettably, unlike their earlier study (4), the authors in the current study did not provide the population denominators to allow calculation of incidences of diagnosed post-vaccine vs post-infection myocarditis. It would be useful to know if in the current Nordic study, the incidence of post-vaccine myocarditis was higher than that of post-infection myocarditis at least in some subgroups, as clearly shown for males aged 13-39 years in a UK National Database study (5) and suggested in the same authors’ previous study (4).

  In their analyses, the authors presented data on only 3 comorbidities: malignancy, cardiovascular disease, or autoimmune diseases. They recognized age difference, with the infection-associated myocarditis group being significantly older (median age 17-20 years older, except for Finland) than the vaccine-associated myocarditis group (Table S4). They then presented data on individuals aged 12-39 years (mean not available, to exclude persistent effect of age difference) without the above 3 comorbidities, but ignoring other significant comorbidities (Table 4). It is unclear why the authors did not report on other comorbidities that they had presented in their previous paper (4), including chronic pulmonary disease, diabetes, and renal disease, and on body mass index (6), especially knowing that outcomes after COVID-19 infection are affected by multiple comorbidities other than the 3 they selected. Their finding of nearly similar percentage of “any” predisposing comorbidity in post-vaccination vs post-infection myocarditis (Table 1) may, therefore, be misleading, since that comparison does not account for all known comorbidities, which may be more prevalent in hospitalized COVID-19 infected individuals (compared to vaccine-associated myocarditis patients) and which, if present, would result in worse clinical outcomes in these infected patients, including the subgroup aged 12-39 years.

  When comparing outcomes of heart failure and death in post-vaccine vs post-infection myocarditis patients, it is important to recognize that the post-infection patients may be “sicker” patients, like other hospitalized COVID-19 infected patients. Additionally, clinical outcomes of post-infection patients including heart failure or/and death and hospital length of stay are influenced by COVID-19 infection with all its manifestations, not just by COVID-19 infection-associated myocarditis. In other words, COVID-19 infection-associated myocarditis may not be inherently/alone accountable for worse clinical outcomes compared to COVID-19 mRNA vaccine-associated myocarditis.

  The authors found significantly more hospital readmissions among vaccine-associated myocarditis patients vs infection-associated myocarditis patients, 62 vs 9 (relative risk 0.76 vs 0.49, admitted Jan 1, 2020 or later). The authors attempt to explain this finding, which is not consistent with their other observations, as follows: “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.” The authors do not provide evidence to support their speculation on the clinical interest being higher for vaccine-associated myocarditis vs infection-associated myocarditis. Furthermore, since the absolute number of deaths in both groups was very small & the same, i.e., 6, that would not be expected to have significant effect on relative risk in the 2 groups.

  In the Discussion section, the authors state that: “The overall findings on outcomes of myocarditis associated with vaccination by us and others are reassuring …” That statement is not evidently supported by the available data. Even without considering the multiple limitations in the study detailed above, a greater number of vaccine-associated myocarditis patients developed heart failure (22 vs 12) and underwent hospital readmission (62 vs 9) than infection-associated myocarditis patients, in the 1st 90 days after myocarditis onset. More importantly, among the many more patients with vaccine-associated myocarditis (compared to those with infection-associated myocarditis), the majority would be expected to demonstrate persistent cardiac MRI abnormalities (7, 8, 9), as the authors partly acknowledge. Most practicing physicians would not find it reassuring that there are significantly higher numbers of vaccine-associated myocarditis and numerically higher numbers of vaccine-associated myocarditis-related heart failure and hospital readmissions, compared to infection-associated numbers.

  The above discussion is particularly relevant for decisions on COVID-19 vaccination in healthy adolescents and healthy young adults, where the occurrence of vaccine-associated myocarditis would likely result in late gadolinium enhancement with its potential adverse prognosis (10), namely increased risk of combined end point comprised of all-cause mortality, cardiac mortality, and major adverse cardiovascular events. Vaccine-associated myocarditis would effectively scar, for life, healthy young individuals who are at minimal to low risk of mortality* (and other serious adverse outcomes) from COVID-19 infection itself. Decisions on COVID-19 vaccination should utilize individual risk-benefit assessment, which is the cornerstone of individualized evidence-based healthcare.

  * Age-based analysis of COVID-19 infection mortality risk in children & young individuals (irrespective of individual state of health):
  US Census age statistics (11):
  Children, age 0-17 years: Population: 72,777,000 = 22.31% of total population (326,195,000), as of 2021 US Census.
  Young individuals, age 0-39 years: = 51.66% of total population (326,195,000), as of 2021 US Census.
  CDC COVID-19 infection statistics (12):
  Age 0-17 years: COVID-19 deaths: 1,582 = 0.14% of all deaths (1,125,044), as of Apr 12, 2023 CDC data.
  Therefore, children, age 0-17 years, are 159 times less likely to die from COVID-19 infection, than would be expected based on their % of the US population.
  Age 0-39 years: COVID-19 deaths: 44,516 = 3.96% of all deaths (1,125,044), as of Apr 12, 2023 CDC data.
  Therefore, young individuals, age 0-39 years, are 13 times less likely to die from COVID-19 infection, than would be expected based on their % of the US population.

  References:
  1. Husby A, Gulseth H, Hovi P, et al. Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study. BMJ Med. 2023;2(1):e000373. doi: 10.1136/bmjmed-2022-000373.
  2. Mansanguan S, Charunwatthana P, Piyaphanee W, et al. Cardiovascular Manifestation of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents. Trop Med Infect Dis. 2022;7(8):196. doi: 10.3390/tropicalmed7080196.
  3. Chiu S, Chen Y, Hsu C, et al. Changes of ECG parameters after BNT162b2 vaccine in the senior high school students. Eur J Pediatr. 2023;182(3):1155-1162. doi: 10.1007/s00431-022-04786-0.
  4. Karlstad O, Hovi P, Husby A, et al. SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents. JAMA Cardiol. 2022;7(6):600-612. doi: 10.1001/jamacardio.2022.0583.
  5. Patone M, Mei X, Handunnetthi L, et al. Risk of Myocarditis After Sequential Doses of
  COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex. Circulation. 2022;146:743–754. doi: 10.1161/CIRCULATIONAHA.122.059970.
  6. Gao M, Piernas C, Astbury N, et al. Lancet Diabetes Endocrinol. 2021;9(6):350-359. doi: 10.1016/S2213-8587(21)00089-9. Associations between body-mass index and COVID-19 severity in 6·9 million people in England: a prospective, community-based, cohort study.
  7. Schauer J, Buddhe S, Gulhane A, et al. Persistent Cardiac Magnetic Resonance Imaging Findings in a Cohort of Adolescents with Post-Coronavirus Disease 2019 mRNA Vaccine Myopericarditis. J Pediatr. 2022;245:233-237. doi: 10.1016/j.jpeds.2022.03.032.
  8. Kracalik I, Oster M, Broder K, et al. Lancet Child Adolesc Health. 2022;6(11):788-798. Outcomes at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults in the USA: a follow-up surveillance study. doi: 10.1016/S2352-4642(22)00244-9.
  9. Amir G, Rotstein A, Razon Y, et al. CMR Imaging 6 Months After Myocarditis Associated with the BNT162b2 mRNA COVID-19 Vaccine. Pediatr Cardiol. 2022;43(7):1522-1529. doi: 10.1007/s00246-022-02878-0.
  10. Georgiopoulos G, Figliozzi S, Sanguineti F, et al. Prognostic Impact of Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance in Myocarditis: A Systematic Review and Meta-Analysis. Circ Cardiovasc Imaging. 2021 Jan;14(1):e011492. doi: 10.1161/CIRCIMAGING.120.011492.
  11. US Census. Age and Sex Composition in the United States 2021. https://www.census.gov/data/tables/2021/demo/age-and-sex/2021-age-sex-co.... Accessed April 16, 2023.
  12. CDC. Provisional COVID-19 Deaths by Sex and Age. https://data.cdc.gov/NCHS/Provisional-COVID-19-Deaths-by-Sex-and-Age/9bh.... Accessed April 16, 2023.

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  Conflict of Interest:
  None declared.

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• Published on: 11 April 2023

  Seeking more information on risk factors and vaccination status of those w/myocarditis post-SARS-CoV-2

  • Tracy Beth Høeg, MD, PhD Physician Epidemiologist Department of Epidemiology and Biostatistics, University of California-San Francisco
  • Other Contributors:
    • Miloš Miljković, MD, Chief Medical Officer
    • Vinay Prasad, MD, MPH Professor of Epidemiology and Biostatistics

  To the Editor:

  We read with interest the Nordic registry study by Husby et al on clinical outcomes of three different types of myocarditis: SARS-CoV-2 mRNA vaccination-associated, COVID-19 associated and “conventional” myocarditis. We appreciate the information the authors provided on patient characteristics by myocarditis type. We note >50% patients with COVID-19-associated and conventional myocarditis were over 40, those with vaccine-associated myocarditis were younger on average and 38% were 12-24 years v.s <25% for the other two types. Further, the proportion of men was higher in all three categories, and the proportion of patients with underlying comorbidities similar; however, we wonder, given the relatively small number of patients, if the authors could disclose which comorbidities and how many were present (in total) among the patients with COVID-19 vs. vaccination-associated myocarditis, perhaps as a summary table.

  Second, do the authors have any information on the vaccination status (number of doses and dates given in relation to the myocarditis diagnosis) among those categorized as having COVID-associated myocarditis? If so, could this information be broken down by age group?
  Related, the most recent exposure defined the type of myocarditis in patients who received both an mRNA vaccine and had a positive test for SARS-CoV-2 in the last 28 days. We therefore wonder if the authors could provide the number of times both were diagnosed with...

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  To the Editor:

  We read with interest the Nordic registry study by Husby et al on clinical outcomes of three different types of myocarditis: SARS-CoV-2 mRNA vaccination-associated, COVID-19 associated and “conventional” myocarditis. We appreciate the information the authors provided on patient characteristics by myocarditis type. We note >50% patients with COVID-19-associated and conventional myocarditis were over 40, those with vaccine-associated myocarditis were younger on average and 38% were 12-24 years v.s <25% for the other two types. Further, the proportion of men was higher in all three categories, and the proportion of patients with underlying comorbidities similar; however, we wonder, given the relatively small number of patients, if the authors could disclose which comorbidities and how many were present (in total) among the patients with COVID-19 vs. vaccination-associated myocarditis, perhaps as a summary table.

  Second, do the authors have any information on the vaccination status (number of doses and dates given in relation to the myocarditis diagnosis) among those categorized as having COVID-associated myocarditis? If so, could this information be broken down by age group?
  Related, the most recent exposure defined the type of myocarditis in patients who received both an mRNA vaccine and had a positive test for SARS-CoV-2 in the last 28 days. We therefore wonder if the authors could provide the number of times both were diagnosed within the last 28 days and the proportion of attributions to SARS-CoV-2 versus vaccination for these occurrences.

  Finally, was there any evidence of genetic predisposition to vaccine-associated myocarditis with twins, siblings or related family members being disproportionately affected?

  We thank the authors for this study and for their responses to the above questions, which we feel could both help inform vaccination recommendations and provide insights into underlying pathophysiology of mRNA vaccine- and COVID-19-associated myocarditis.

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  Conflict of Interest:
  None declared.

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