The Incidence of Myocarditis and Pericarditis in Post COVID-19 Unvaccinated Patients-A Large Population-Based Study
The Incidence of Myocarditis and Pericarditis in Post COVID-19 Unvaccinated Patients-A Large Population-Based Study
Clinical Medicine
Article
The Incidence of Myocarditis and Pericarditis in Post COVID-19
Unvaccinated Patients—A Large Population-Based Study
Ortal Tuvali 1,† , Sagi Tshori 2,† , Estela Derazne 3 , Rebecca Regina Hannuna 2 , Arnon Afek 3,4 , Dan Haberman 1 ,
Gal Sella 1 and Jacob George 1, *
1 Heart Center, Kaplan Medical Center, Rehovot, Hebrew University of Jerusalem, Jerusalem 91905, Israel;
[email protected] (O.T.); [email protected] (D.H.); [email protected] (G.S.)
2 Research Authority, Rehovot, Hebrew University of Jerusalem, Jerusalem 91905, Israel;
[email protected] (S.T.); [email protected] (R.R.H.)
3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; [email protected] (E.D.);
[email protected] (A.A.)
4 General Management, The Chaim Sheba Medical Centre, Tel Hashomer, Ramat-Gan 52621, Israel
* Correspondence: [email protected]; Tel.: +972-8-944-1335; Fax: +972-8-944-1598
† These authors contributed equally to this work.
Abstract: Myocarditis and pericarditis are potential post-acute cardiac sequelae of COVID-19 in-
fection, arising from adaptive immune responses. We aimed to study the incidence of post-acute
COVID-19 myocarditis and pericarditis. Retrospective cohort study of 196,992 adults after COVID-19
infection in Clalit Health Services members in Israel between March 2020 and January 2021. Inpatient
myocarditis and pericarditis diagnoses were retrieved from day 10 after positive PCR. Follow-up
was censored on 28 February 2021, with minimum observation of 18 days. The control cohort of
590,976 adults with at least one negative PCR and no positive PCR were age- and sex-matched. Since
the Israeli vaccination program was initiated on 20 December 2020, the time-period matching of
Citation: Tuvali, O.; Tshori, S.;
the control cohort was calculated backward from 15 December 2020. Nine post-COVID-19 patients
Derazne, E.; Hannuna, R.R.; Afek, A.;
developed myocarditis (0.0046%), and eleven patients were diagnosed with pericarditis (0.0056%).
Haberman, D.; Sella, G.; George, J.
The Incidence of Myocarditis and
In the control cohort, 27 patients had myocarditis (0.0046%) and 52 had pericarditis (0.0088%). Age
Pericarditis in Post COVID-19 (adjusted hazard ratio [aHR] 0.96, 95% confidence interval [CI]; 0.93 to 1.00) and male sex (aHR 4.42;
Unvaccinated Patients—A Large 95% CI, 1.64 to 11.96) were associated with myocarditis. Male sex (aHR 1.93; 95% CI 1.09 to 3.41) and
Population-Based Study. J. Clin. Med. peripheral vascular disease (aHR 4.20; 95% CI 1.50 to 11.72) were associated with pericarditis. Post
2022, 11, 2219. https://doi.org/ COVID-19 infection was not associated with either myocarditis (aHR 1.08; 95% CI 0.45 to 2.56) or
10.3390/jcm11082219 pericarditis (aHR 0.53; 95% CI 0.25 to 1.13). We did not observe an increased incidence of neither
Academic Editor: Andrea Frustaci pericarditis nor myocarditis in adult patients recovering from COVID-19 infection.
2. Methods
2.1. Study Setting
We retrieved observational data from Clalit Health Services (CHS). CHS is the largest
of four health maintenance organizations that offer mandatory health care coverage in Israel.
CHS insures over 50% of the Israeli population (>4.4 million persons), and the CHS-insured
population is approximately representative of the Israeli population at large [12,13]. CHS
provides outpatient care, and inpatient care is divided between CHS and other hospitals.
Research data can be retrieved from the central data warehouse using the CHS Secure
Data Sharing Platform powered by MDClone (https://www.mdclone.com, accessed on
5 September 2021).
This study was approved by the institutional review board, and was exempt from the
requirement for informed consent.
days after COVID-19 infection and earliest between 6 months from infection or 28 Feb
ary 2021. This was done to ensure a minimum follow-up period of 18 days and a m
infection and earliest between 6 months from infection or 28 February 2021. This was done
mum follow-up period of six months. Since data was retrieved during October 2021,
to ensure a minimum follow-up period of 18 days and a maximum follow-up period of
allowed
six months.forSince
overdata
6 months delay during
was retrieved in dataOctober
transfer between
2021, hospitals
we allowed that
for over do not belon
6 months
the CHS
delay andtransfer
in data the CHS data hospitals
between warehouse. The
that do notpost-COVID
belong to the timeframe
CHS and thewas CHSdefined
data from
least ten days
warehouse. Theafter the datetimeframe
post-COVID of positivewasPCR test from
defined contingent upon
at least ten lack
days of the
after symptoms
date rela
of positive PCR test contingent upon lack of symptoms related to COVID-19
to COVID-19 infection, according to the definitions of the Israeli Ministry of Health. infection,
according
tients withto the definitions
a first of the Israeli
vaccination receivedMinistry of Health.
before Patients
COVID-19 with a first
infection vaccina-
were excluded
tion received before COVID-19 infection were excluded (n = 16,632), resulting in the final
16,632), resulting in the final COVID-19 cohort (n = 196,992).
COVID-19 cohort (n = 196,992).
Figure 1. Study profile, design and timelines. ‘clalit’ = Clalit Health Services. Vaccination = COVID-19
Figure 1. Study
vaccination. PCR profile, design and timelines.
−/+ = negative/positive COVID-19‘clalit’
PCR. = (A).
Clalit Health Services.
Flowchart Vaccination
of patient selection in = COV
19
COVID and control cohorts. (B). Research timeline from first PCR in 7 March 2020 to the end of study selectio
vaccination. PCR −/+ = negative/positive COVID-19 PCR. (A). Flowchart of patient
COVID andThe
(lower part). control
COVIDcohorts.
cohort is(B). Research
depicted timeline
in the upper part,from first
and the PCR in
matching 7 March
period of the 2020
controlto the en
study
cohort (lower part).
is depicted The
in the COVID cohort is depicted in the upper part, and the matching period o
middle.
control cohort is depicted in the middle.
J. Clin. Med. 2022, 11, 2219 4 of 10
A control group was created from a cohort of adult patients with at least one negative
COVID-19 PCR between 7 March 2020 and 15 December 2020, and with no prior positive
COVID-19 PCR before retrieval of data in August 2021 (n = 935,976). 15 December 2020
was selected as the stop date, since the massive Israeli vaccination campaign was initiated
on 20 December 2020. Still, five patients were excluded due to a previous COVID-19
vaccination. From this pool of patients (n = 935,971), the control cohort was created by
3:1 matching of age (±2 years) and sex (n = 590,976). The follow-up period of each of
the three control patients was set to the exact same length of follow-up of the matched
COVID-19 patient. The follow-up period was calculated backwards from 15 December 2020
(Figure 1B), in order to avoid the potential impact of COVID-19 vaccination on myocarditis
and pericarditis. Although the COVID-19 patients’ drafting period was from March 2020
to January 2021, almost all COVID-19 cases occurred between July 2020 and January
2021 (Figure S1).
3. Results
A total of 787,968 Clalit Health Services adult members (age ≥ 18) were included
in the study (Figure 1), comprising of COVID-19 cohort (n = 196,992) and a sex and age
3:1 matched control cohort (n = 590,976). Total follow-up was 700,040 person-months in
the COVID-19 cohort, and 2,100,077 person-months in the control cohort, with a median
follow-up of 4.1 months [IQR 1.3–5.6 months]. The mean standard deviation (SD) age in
both groups was 42.4 (17.7) years, and 45.7% were males (Table 1). There was a slightly
higher BMI (mean (SD) 27.1 (7.1) vs. 26.1 (6.7) kg/m2 ) with higher prevalence of obesity
(29.9% vs. 24.6%), diabetes mellitus (13% vs. 10.5%), essential hypertension (18.5% vs. 17%),
cerebrovascular accidents (4% vs. 3.7%) and heart failure (2.6% vs. 2.2%) in the COVID-19
cohort. There was a lower prevalence of current and past smoking (11.3% vs. 18.4% and
10.8% vs. 12.3%) and peripheral vascular disease (1.2% vs. 1.4%) in the COVID-19 cohort.
During the study period, nine cases of myocarditis and 11 cases of pericarditis were
detected in the COVID-19 cohort (Table 2). Twenty-seven cases of myocarditis and 52 cases
of pericarditis were detected in the control cohort. Two out of the nine myocarditis pa-
tients were hospitalized due to severe COVID-19 infection with the need for mechanical
ventilation, and myocarditis was diagnosed during the COVID-19 hospitalization at days
19 and 37 after infection, respectively. None of the patients who were diagnosed with
pericarditis were hospitalized due to COVID-19 infection. The median (IQR) duration
of hospitalization following myocarditis in the COVID-19 cohort was 5 (2–25) days vs.
3 (3–5) days in the control cohort (p = 0.291). The median (IQR) duration of hospitalization
following pericarditis was 2 (2–3.5) days in the COVID-19 cohort and 3 (1.8–5.3) days in the
control cohort (p = 0.272).
No statistical difference in the incidence rate of both myocarditis (p =1) and pericarditis
(p =0.17) was observed between the COVID-19 cohort and the control cohort (Figure 2).
J. Clin. Med. 2022, 11, 2219 5 of 10
Control COVID-19
(n = 590,976) (n = 196,992)
Age (year) 42.4 (17.7) 42.4 (17.7)
Sex
Male 270,210 (45.7) 90,070 (45.7)
Female 320,766 (54.3) 106,922 (54.3)
BMI (kg/m2) 26.1 (7.1) 27.1 (6.7)
Sector
Arab 109,759 (18.6) 58,841 (29.9)
Bedouin 19,956 (3.4) 5306 (2.7)
Jewish 436,986 (74.1) 108,360 (55.0)
Other 23,285 (3.9) 24,475 (12.4)
Smoking
Never 383,002 (69.3) 137,079 (78.0)
Current 101,475 (18.4) 19,824 (11.3)
Past 67,992 (12.3) 18,917 (10.8)
Obesity 145,537 (24.6) 58,807 (29.9)
Diabetes 61,978 (10.5) 25,583 (13.0)
Hyperlipidemia 183,704 (31.1) 60,629 (30.8)
CKD 18,593 (3.1) 6725 (3.4)
PVD 8016 (1.4) 2448 (1.2)
Hypertension 100,736 (17.0) 36,502 (18.5)
ACS 32,987 (5.6) 11,027 (5.6)
CVA 22,032 (3.7) 7833 (4.0)
Heart failure 13,228 (2.2) 5132 (2.6)
Variables were expressed as no. (%) or as mean (SD). CKD = chronic kidney disease. PVD = peripheral vascular
disease, CVA = Cerebrovascular Accident. ACS = acute coronary syndrome.
Table 2. Baseline characteristics of patients with myocarditis and pericarditis patients in the COVID
and no COVID cohorts.
Myocarditis Pericarditis
No COVID COVID No COVID COVID
(n = 27) (n = 9) p-Value (n = 52) (n = 11) p-Value
No statistical difference in the incidence rate of both myocarditis (p =1) and pericar-
J. Clin. Med. 2022, 11, 2219 ditis (p =0.17) was observed between the COVID-19 cohort and the control cohort (Figure
6 of 10
2).
Figure 2. Kaplan-Meier estimates of cumulative probability of myocarditis (A) and pericarditis (B) in
Figure 2. Kaplan-Meier estimates of cumulative probability of myocarditis (A) and pericarditis (B)
COVID-19 and control cohorts during 6 months.
in COVID-19 and control cohorts during 6 months.
In the multivariable Cox proportional hazards regression model (Table 3, Tables S2 and S3),
age (aHR 0.96; 95% CI 0.93 to 1.00, p =0.045) and the male sex (aHR 4.42; 95% CI 1.64 to
11.96, p = 0.003) were independently associated with myocarditis. Obesity was borderline
associated with myocarditis (aHR 2.31; 95% CI 0.99 to 5.41, p = 0.053). Post COVID-19
infection was not associated with myocarditis (aHR 1.08; 95% CI 0.45 to 2.56, p = 0.869).
J. Clin. Med. 2022, 11, 2219 7 of 10
Myocarditis Pericarditis
aHR (95% CI) p-Value aHR (95% CI) p-Value
COVID-19 1.08 (0.45–2.56) 0.869 0.53 (0.25–1.13) 0.100
Age 0.96 (0.93–1.00) 0.045 * 1.01 (0.99–1.03) 0.537
Sex (male) 4.42 (1.64–11.96) 0.003 * 1.93 (1.09–3.41) 0.025 *
BMI 1.00 (0.97–1.04) 0.935 1.00 (0.94–1.06) 0.897
Diabetes 1.15 (0.26–5.00) 0.856 0.97 (0.43–2.21) 0.950
Hyperlipidemia 0.33 (0.08–1.43) 0.139 1.13 (0.54–2.38) 0.749
Obesity 2.31 (0.99–5.41) 0.053 1.32 (0.64–2.71) 0.448
CKD 3.80 (0.82–17.66) 0.088 1.91 (0.72–5.05) 0.191
Smoking (Now) 1.62 (0.65–4.06) 0.304 0.85 (0.42–1.74) 0.661
Smoking (Past) 1.85 (0.61–5.64) 0.277 0.73 (0.33–1.63) 0.439
PVD 1.35 (0.14–12.84) 0.793 4.20 (1.50–11.72) 0.006 *
ACS 3.93 (0.76–20.40) 0.104 1.52 (0.61–3.80) 0.366
Hypertension 1.46 (0.36–5.87) 0.592 0.88 (0.38–2.06) 0.770
CKD = chronic kidney disease. PVD = peripheral vascular disease. ACS = acute coronary syndrome. * Statistically
significant results are highlighted in bold.
Male sex (aHR 1.93; 95% CI 1.09 to 3.41, p = 0.025) and peripheral vascular disease
(aHR 4.20; 95% CI 1.50 to 11.72, p = 0.006) were associated with pericarditis (Table 3). Post
COVID-19 infection was not associated with pericarditis (aHR 0.53; 95% CI 0.25 to 1.13, p = 0.1).
4. Discussion
In the current large population study of subjects, who were not vaccinated against
SARS-CoV-2, we observed no increase in the incidence of myocarditis or pericarditis from
day 10 after positive SARS-CoV-2.
Multivariable analysis did show male sex as associated with a higher risk of developing
myocarditis or pericarditis, regardless of previous COVID-19 infection.
COVID-19 infection is responsible for considerable morbidity and mortality at an
unprecedented scale globally. Cumulative scientific and clinical data is evolving on the
sub-acute and long-term effects of COVID-19 infection, which can affect multiple organ
systems. Recent studies suggest several mechanisms for the pathogenesis of the persistent
and prolonged signs and symptoms associated with the cardiovascular system.
Several earlier studies on SARS-CoV infections have highlighted the possible link
between types of coronavirus infections and immune-mediated responses [14,15].
Antibodies to Coronavirus-OC43 and 229E were found in patients diagnosed with
multiple sclerosis [16]. High and sustained levels of anti-erythrocyte autoantibodies were
found in mice infected with murine hepatitis Coronavirus [17].
Given the clinical similarities between SARS-CoV-2 and other coronaviruses [18,19],
it is conceivable that immune-mediated tissue damage is also potentially induced by
SARS-CoV-2 infection. Molecular mimicry, activation of specific T cells to virus altered
self-proteins, and activation of B cells constitute a few examples of mechanisms mediating
the potential occurrence of myocarditis and pericarditis that could play a role in triggering
delayed cardiac inflammation [9]. Furthermore, in a recent study 309 COVID-19 patients
were tested for the presence of six different autoantibodies, such as anti-nuclear antibodies
and anti-Interferon-α2 antibodies, at least two months after the initial illness. In this study,
autoantibodies were associated with a higher risk of developing post-acute sequelae of
COVID-19 [20].
Early in the COVID-19 pandemic, it was evident that COVID-19 patients with car-
diovascular comorbidities have worse prognosis and higher in-hospital mortality [21].
Individuals with underlying autoimmune diseases appear to be particularly vulnerable to
severe sequelae resulting from COVID-19 infection [22]. Other studies demonstrated that
severe COVID-19 disease is associated with robust inflammatory responses including type
two and hyper four hypersensitivity responses, resulting from overactivation of T cells
J. Clin. Med. 2022, 11, 2219 8 of 10
5. Conclusions
Our data suggest that there is no increase in the incidence of myocarditis and peri-
carditis in COVID-19 recovered patients compared to uninfected matched controls. Further
J. Clin. Med. 2022, 11, 2219 9 of 10
longer-term studies will be needed to estimate the incidence of pericarditis and myocarditis
in patients diagnosed with COVID-19.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jcm11082219/s1, Figure S1. Number of patients with positive
PCR in the COVID-19 cohort by month during the study period. Table S1. ICD-10 codes for cardiac
risk factors. Table S2. Crude and adjusted HRs for myocarditis. Table S3. Crude and adjusted HRs
for pericarditis.
Author Contributions: Conceptualization, J.G.; Data curation, E.D.; Formal analysis, E.D. and
R.R.H.; Investigation, S.T., O.T. and D.H.; Methodology—E.D. and G.S.; Project administration, J.G.;
Supervision, A.A.; Validation, S.T. and J.G.; Writing–original draft, O.T.; Writing–review & editing,
S.T. and J.G. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, and approved by the Institutional Review Board of Kaplan Medical Center (KMC-123-
2021), Date of approval 24 June 2021.
Informed Consent Statement: Patient consent was waived due to de-identified retrospective
cohort study.
Data Availability Statement: The data presented in this study is available on request from the
corresponding author.
Acknowledgments: The authors would like to thank Galit Shefer for her assistance in research design,
The Clalit Research Institute for their assistance in data analysis and the Kaplan Medical Center Heart
team for their support.
Conflicts of Interest: The authors declare no conflict of interest.
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