Myocarditis and pericarditis recovery following smallpox vaccine 2002-2016: A comparative observational cohort study in the military health system

PLoS One. 2023 May 8;18(5):e0283988. doi: 10.1371/journal.pone.0283988. eCollection 2023.


Objectives: (1) Characterize the initial clinical characteristics and long-term outcomes of smallpox vaccine-associated hypersensitivity myocarditis and pericarditis (MP) in United States service members. (2) Describe the process of case identification and adjudication using the 2003 CDC nationally defined myocarditis/pericarditis epidemiologic case definitions to include consideration of case-specific diversity and evolving evidence.

Background: Between 2002 and 2016, 2.546 million service members received a smallpox Vaccinia vaccine. Acute MP is associated with vaccinia, but the long-term outcomes have not been studied.

Methods: Records of vaccinia-associated MP reported to the Vaccine Adverse Event Reporting System by vaccination date were adjudicated using the 2003 MP epidemiologic case definitions for inclusion in a retrospective observational cohort study. Descriptive statistics of clinical characteristics, presentation, cardiac complications, and time course of clinical and cardiac recovery were calculated with comparisons by gender, diagnosis and time to recovery.

Results: Out of over 5000 adverse event reports, 348 MP cases who survived the acute illness, including 276 myocarditis (99.6% probable/confirmed) and 72 pericarditis (29.2% probable/confirmed), were adjudicated for inclusion in the long-term follow-up. Demographics included a median age of 24 years (IQR 21,30) and male predominance (96%). Compared to background military population, the myocarditis and pericarditis cohort had a higher percentage of white males by 8.2% (95% CI: 5.6, 10.0) and age <40 years by 4.2% (95% CI: 1.7,5.8). Long-term follow-up documented full recovery in 267/306 (87.3%) with 74.9% recovered in less than a year (median ~3 months). Among patients with myocarditis, the percentage who had a delayed time to recovery at time of last follow-up was 12.8% (95% CI: 2.1,24.7) higher in those with an acute left ventricular ejection fraction (EF) of ≤50% and 13.5% (95% CI: 2.4,25.7) higher in those with hypokinesis. Patient complications included 6 ventricular arrhythmias (2 received implanted defibrillators) and 14 with atrial arrhythmias (2 received radiofrequency ablation). Three of 6 patients (50%) diagnosed with cardiomyopathy had clinical recovery at their last follow-up date.

Conclusions: Hypersensitivity myocarditis/pericarditis following the smallpox vaccine is associated with full clinical and functional ventricular recovery in over 87% of cases (74.9% <1 year). A minority of MP cases experienced prolonged or incomplete recovery beyond 1 year.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Female
  • Humans
  • Male
  • Military Health Services*
  • Myocarditis* / diagnosis
  • Myocarditis* / epidemiology
  • Myocarditis* / etiology
  • Pericarditis* / diagnosis
  • Pericarditis* / epidemiology
  • Pericarditis* / etiology
  • Retrospective Studies
  • Smallpox Vaccine* / adverse effects
  • Smallpox* / prevention & control
  • Stroke Volume
  • United States
  • Vaccination
  • Vaccinia virus
  • Vaccinia* / prevention & control
  • Ventricular Function, Left


  • Smallpox Vaccine

Grants and funding

The authors received no specific funding for this work.