Cardiac Complications After SARS-CoV-2 Infection and mRNA COVID-19 .. – cdc.gov

Cardiac complications, particularly myocarditis and pericarditis, have been associated with SARS-CoV-2 (the virus that causes COVID-19) infection (1–3) and mRNA COVID-19 vaccination (2–5). Multisystem inflammatory syndrome (MIS) is a rare but serious complication of SARS-CoV-2 infection with frequent cardiac involvement (6). Using electronic health record (EHR) data from 40 U.S. health care systems during January 1, 2021–January 31, 2022, investigators calculated incidences of cardiac outcomes (myocarditis; myocarditis or pericarditis; and myocarditis, pericarditis, or MIS) among persons aged ≥5 years who had SARS-CoV-2 infection, stratified by sex (male or female) and age group (5–11, 12–17, 18–29, and ≥30 years). Incidences of myocarditis and myocarditis or pericarditis were calculated after first, second, unspecified, or any (first, second, or unspecified) dose of mRNA COVID-19 (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) vaccines, stratified by sex and age group. Risk ratios (RR) were calculated to compare risk for cardiac outcomes after SARS-CoV-2 infection to that after mRNA COVID-19 vaccination. The incidence of cardiac outcomes after mRNA COVID-19 vaccination was highest for males aged 12–17 years after the second vaccine dose; however, within this demographic group, the risk for cardiac outcomes was 1.8–5.6 times as high after SARS-CoV-2 infection than after the second vaccine dose. The risk for cardiac outcomes was likewise significantly higher after SARS-CoV-2 infection than after first, second, or unspecified dose of mRNA COVID-19 vaccination for all other groups by sex and age (RR 2.2–115.2). These findings support continued use of mRNA COVID-19 vaccines among all eligible persons aged ≥5 years.

This study used EHR data from 40 health care systems* participating in PCORnet, the National Patient-Centered Clinical Research Network (7), during January 1, 2021–January 31, 2022. PCORnet is a national network of networks that facilitates access to health care data and interoperability through use of a common data model across participating health care systems (https://pcornet.org/dataexternal icon). The PCORnet Common Data Model contains information captured from EHRs and other health care data sources (e.g., health insurance claims), including demographic characteristics, diagnoses, prescriptions, procedures, and laboratory test results, among other elements. The study population included persons with documented SARS-CoV-2 testing, viral illness diagnostic codes, or COVID-19 vaccination during the study period. Data were obtained through a single query that was executed by participating health care systems to generate aggregated results.

Five cohorts were created using coded EHR data among persons aged ≥5 years: 1) an infection cohort (persons who received ≥1 positive SARS-CoV-2 molecular or antigen test result); 2) a first dose cohort (persons who received a first dose of an mRNA COVID-19 vaccine); 3) a second dose cohort (persons who received a second dose of an mRNA COVID-19 vaccine); 4) an unspecified dose cohort (persons who received an mRNA COVID-19 vaccine dose not specified as a first or second dose); and 5) an any dose cohort (persons who received any mRNA COVID-19 vaccine dose). The any dose cohort is a combination of the other three vaccination cohorts; persons who received 2 doses were included twice in this cohort, once for each dose.^† Vaccine doses specifically coded as booster or extra doses were excluded. Persons with a positive SARS-CoV-2 test result ≤30 days before receipt of an mRNA COVID-19 vaccine were excluded from the vaccine cohorts; persons who had received an mRNA COVID-19 vaccine dose ≤30 days before a positive SARS-CoV-2 test result were excluded from the infection cohort. In the infection cohort, there were no other exclusions based on vaccination status. The following index dates were used for cohort entrance: first positive SARS-CoV-2 test result for the infection cohort; first vaccination for the first dose cohort; second vaccination for the second dose cohort; the single vaccination for the unspecific dose cohort; and the first, second, and unspecified vaccination for the any dose cohort. Persons could be represented twice in the any dose cohort if they received a first and second dose; they would have a different index date for each of the doses.

Incidence of three cardiac outcomes (myocarditis; myocarditis or pericarditis; and myocarditis, pericarditis, or MIS) were defined using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes^§ within 7-day or 21-day risk windows after the index date; persons who had received any of these diagnoses during the year preceding the index date were excluded. The outcome including MIS was only assessed for the infection cohort because the rare reports of MIS after mRNA COVID-19 vaccination typically had evidence of previous SARS-CoV-2 infection (8); a 42-day risk window also was used for this outcome to allow for a possible long latency between infection and diagnosis of MIS (6).^¶ Because persons with MIS who have cardiac involvement might only receive an ICD-10-CM code for MIS, rather than myocarditis or pericarditis, this combined outcome allowed for a comprehensive capture of potential cardiac complications after infection. Nearly 80% of cases of MIS have cardiac involvement (9). Cohorts were stratified by sex and age group.

The sex- and age-stratified incidences of the cardiac outcomes (cases per 100,000 persons) were calculated within 7-, 21-, or 42-day risk windows. Unadjusted RRs and 95% CIs were calculated as the incidences of the outcomes within the infection cohort divided by the incidences in the first, second, unspecified, and any dose cohorts separately for each sex and age stratum. RRs whose CIs did not include 1.0 were considered statistically significant; RRs were not compared across outcomes, risk windows, vaccine dose, or sex and age stratum. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.**

The study population consisted of 15,215,178 persons aged ≥5 years, including 814,524 in the infection cohort; 2,548,334 in the first dose cohort; 2,483,597 in the second dose cohort; 1,681,169 in the unspecified dose cohort; and 6,713,100 in the any dose cohort (Table 1).^†† Among the four COVID-19 vaccination cohorts, 77%–79% of persons were aged ≥30 years; within the SARS-CoV-2 infection cohort, 63% were aged ≥30 years.

Among males aged 5–11 years, the incidences of myocarditis and myocarditis or pericarditis were 12.6–17.6 cases per 100,000 after infection, 0–4 after the first vaccine dose, and 0 after the second dose; incidences of myocarditis, pericarditis, or MIS were 93.0–133.2 after infection (Table 2). Because there were no or few cases of myocarditis or pericarditis after vaccination, the RRs for several comparisons could not be calculated or were not statistically significant. The RRs were significant when comparing myocarditis, pericarditis, or MIS in the 42 days after infection (133.2 cases per 100,000) with myocarditis or pericarditis after the first (4.0 cases per 100,000; RR 33.3) or second (4.7 cases per 100,000; RR 28.2) vaccine dose.

Among males aged 12–17 years, the incidences of myocarditis and myocarditis or pericarditis were 50.1–64.9 cases per 100,000 after infection, 2.2–3.3 after the first vaccine dose, and 22.0–35.9 after the second dose; incidences of myocarditis, pericarditis, or MIS were 150.5–180.0 after infection. RRs for cardiac outcomes comparing infected persons with first dose recipients were 4.9–69.0, and with second dose recipients, were 1.8–5.6; all RRs were statistically significant.

Among males aged 18–29 years, the incidences of myocarditis and myocarditis or pericarditis were 55.3–100.6 cases per 100,000 after infection, 0.9–8.1 after the first vaccine dose, and 6.5–15.0 after the second dose; incidences of myocarditis, pericarditis, or MIS were 97.2–140.8 after infection. RRs for cardiac outcomes comparing infected persons with first dose recipients were 7.2–61.8, and with second dose recipients, were 6.7–8.5; all RRs were statistically significant.

Among males aged ≥30 years, the incidences of myocarditis and myocarditis or pericarditis were 57.2–114.0 cases per 100,000 after infection, 0.9–7.3 after the first vaccine dose, and 0.5–7.3 after the second dose; incidences of myocarditis, pericarditis, or MIS were 109.1–136.8 after infection. RRs for cardiac outcomes among infected persons compared with first dose recipients were 10.7–67.2, and compared with second dose recipients, were 10.8–115.2; all RRs were statistically significant.

Among females aged 5–11 years, incidences of myocarditis and myocarditis or pericarditis were 5.4–10.8 cases per 100,000 after infection, and incidences of myocarditis, pericarditis, or MIS were 67.3–94.2 after infection (Table 3). No cases of myocarditis or pericarditis after vaccination were identified. The incidences of cardiac outcomes did not vary by age among females aged ≥12 years. In this group, the incidences of myocarditis and myocarditis or pericarditis were 11.9–61.7 cases per 100,000 after infection, 0.5–6.2 after the first vaccine dose, and 0.5–5.4 after the second dose; incidences of myocarditis, pericarditis, or MIS were 27.1–93.3 after infection. Among females aged ≥12 years, RRs for cardiac outcomes comparing infected persons with first dose recipients were 7.4–42.6, and with second dose recipients, were 6.4–62.9; all RRs were statistically significant.

Acknowledgments

All institutions participating in this study; PCORnet, the National Patient-Centered Clinical Research Network, developed with funding from the Patient-Centered Outcomes Research Institute (PCORI); Karen R. Broder, Samantha Chao, Joshua Denson, Julia Fearrington, Bridget Nolan, Sonja A. Rasmussen, Tom Shimabukuro, William E. Trick, leadership of the Data, Analytics, and Visualization Task Force, CDC COVID-19 Emergency Response Team.

¹Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts; ²CDC COVID-19 Emergency Response Team; ³Applied Clinical Research Center, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁴Louisiana Public Health Institute, New Orleans, Louisiana; ⁵Department of Pediatrics, Stanford University School of Medicine, Stanford, California; ⁶Center for Child Health, Behavior and Development, Seattle Children’s Research Institute, Seattle Children’s Hospital, Seattle, Washington; ⁷Department of Population and Data Sciences and Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas; ⁸Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, North Carolina; ⁹The Fenway Institute, Fenway Health, Harvard Medical School, Boston, Massachusetts; ¹⁰Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia; ¹¹Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania; ¹²OCHIN, Inc., Portland, Oregon; ¹³Nemours Cardiac Center, Nemours Children’s Health System, Wilmington, Delaware.

References

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* In the first and second dose cohorts, 27% of persons received mRNA-1273 (Moderna) vaccine and 73% received BNT162b2 (Pfizer-BioNTech) vaccine. In the unspecified dose cohort, 36% received Moderna and 64% Pfizer-BioNTech. In the any dose cohort, 29% received Moderna and 71% Pfizer-BioNTech.
^† Persons in the infection cohort included those who received ≥1 positive SARS-CoV-2 molecular or antigen test result.
^§ The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code for a first dose; the second dose cohort included persons who had either the second of 2 doses ≥20 days after a first dose or a specific code for a second dose.
^¶ The unspecified dose cohort included persons who had a single dose that was not specified as a first or second dose; doses specified as booster doses were excluded.
** The any dose cohort is the first, second, and unspecified dose cohorts combined; persons who had 2 doses are represented twice in the cohort but had different index dates for their first and second doses.
^†† Persons of Hispanic origin could be of any race; Asian, Black or African American, White, or other (which includes American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, multiple race, and other race) persons are not Hispanic.
^§§ Missing race category includes no information, refused to answer, unknown, or missing.

Abbreviations: MIS = multisystem inflammatory syndrome; NC = not calculated.
* Cases per 100,000 persons.
^† Persons in the infection cohort included those who received ≥1 positive SARS-CoV-2 molecular or antigen test result.
^§ The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code for a first dose; the second dose cohort included persons who had either the second of 2 doses ≥20 days after a first dose or a specific code for a second dose.
^¶ The unspecified dose cohort included persons who had a single dose that was not specified as a first or second dose; doses specified as booster doses were excluded.
** The any dose cohort is the first, second, and unspecified dose cohorts combined; persons who had 2 doses are represented twice in the cohort but had different index dates for their first and second doses.
^†† BNT162b2 (Pfizer-BioNTech) is the only mRNA COVID-19 vaccine approved for persons aged 5–17 years.
^§§ Diagnoses of myocarditis, pericarditis, or MIS after a positive SARS-CoV-2 test result compared with diagnoses of myocarditis or pericarditis after vaccination. The 42-day risk ratios were only calculated for this outcome and comparison. The incidence of myocarditis or pericarditis in this risk window was 4.0, 37.1, 19.7, and 12.8 cases per 100,000 for males aged 5–11, 12–17, 18–29, and ≥30 years after a first dose of an mRNA COVID-19 vaccine; 4.7, 39.4, 16.8, and 12.7 cases per 100,000 after a second dose; 12.9, 33.4, 31.3, and 25.3 cases per 100,000 after an unspecified dose; and 6.5, 37.1, 22.0, and 15.8 cases per 100,000 after any dose.
^¶¶ Dashes indicate the incidence for vaccination cohorts was not applicable because the comparison for incidence of myocarditis, pericarditis, or MIS after infection was to myocarditis or pericarditis after vaccination.

Abbreviations: MIS = multisystem inflammatory syndrome; NC = not calculated.
* Cases per 100,000 persons.
^† Persons in the infection cohort included those who received ≥1 positive SARS-CoV-2 molecular or antigen test result.
^§ The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code for a first dose; the second dose cohort included persons who had either the second of 2 doses ≥20 days after a first dose or a specific code for a second dose.
^¶ The unspecified dose cohort included persons who had a single dose that was not specified as a first or second dose; doses specified as booster doses were excluded.
** The any dose cohort is the first, second, and unspecified dose cohorts combined; persons who had 2 doses are represented twice in the cohort but had different index dates for their first and second doses.
^†† BNT162b2 (Pfizer-BioNTech) is the only mRNA COVID-19 vaccine approved for persons aged 5–17 years.
^§§ Diagnoses of myocarditis, pericarditis, or MIS after a positive SARS-CoV-2 test result compared with diagnoses of myocarditis or pericarditis after vaccination. The 42-day risk ratios were only calculated for this outcome and comparison. The incidence of myocarditis or pericarditis in this risk window was 0, 8.1, 8.1, 9.5 cases per 100,000 for females 5-11, 12-17, 18-29, and ≥30 years after a first dose of an mRNA COVID-19 vaccine; 0, 7.5, 5.8, and 8.0 cases per 100,000 after a second dose; 0, 6.7, 12.9, and 14.2 cases per 100,000 after an unspecified dose; and 0, 7.5, 8.7, and 10.1 cases per 100,000 after any dose.
^¶¶ Dashes indicate the incidence for vaccination cohorts was not applicable because the comparison for incidence of myocarditis, pericarditis, or MIS after infection was to myocarditis or pericarditis after vaccination.