key: cord-0025974-hh643w7m
authors: Chua, Gilbert T; Kwan, Mike Yat Wah; Chui, Celine S L; Smith, Robert David; Cheung, Edmund Chi-Lok; Tian, Tian; Leung, Miriam T Y; Tsao, Sabrina Siu Ling; Kan, Elaine; Ng, Wing Kei Carol; Man Chan, Victor Chi; Tai, Shuk Mui; Yu, Tak Ching; Lee, Kwok Piu; Wong, Joshua Sung Chih; Lin, Ying Kit; Shek, Chi Chiu; Leung, Agnes Sze Yin; Chow, Chit Kwong; Li, Ka Wah; Ma, Johnny; Fung, Wai Yuk; Lee, Daniel; Ng, Ming Yen; Wong, Wilfred Hing Sang; Tsang, Hing Wai; Kwok, Janette; Leung, Daniel; Chung, Kin Lai; Chow, Chun Bong; Chan, Godfrey Chi Fung; Leung, Wing Hang; To, Kelvin Kai Wang; Yuen, Kwok Yung; Lau, Yu Lung; Wong, Ian Chi Kei; Ip, Patrick
title: Epidemiology of Acute Myocarditis/Pericarditis in Hong Kong Adolescents Following Comirnaty Vaccination
date: 2021-11-28
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab989
sha: b19611ce8b4186d1f8844b8ea4d47d879c34ba73
doc_id: 25974
cord_uid: hh643w7m

BACKGROUND: Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination. METHODS: This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for COVID-19 vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine Adverse Event Response and Evaluation Programme. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analysed. RESULTS: Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. 29 (87.88%) were males and 4 (12.12%) were females, with a median age of 15.25 years. 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management.The overall incidence of acute myocarditis/pericarditis was 18.52 (95% Confidence Interval [CI], 11.67-29.01) per 100,000 persons vaccinated. The incidence after the first and second doses were 3.37 (95%CI 1.12-9.51) and 21.22 (95%CI 13.78-32.28 per 100,000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI 2.38-12.53) and 37.32 (95% CI 26.98-51.25) per 100,000 persons vaccinated. CONCLUSIONS: There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose.

The COVID-19 infection in children is generally mild, but serious complications, such as Paediatric Multisystem Inflammatory Syndrome -Temporally Associated with SARS-CoV-2 (PIMS-TS), can occur. 1 Prolonged social distancing policies have also led to significant psychosocial impacts on children and their families in the community. 2 Enormous efforts have been made to control the spread of the virus through universal vaccination to achieve herd immunity to return us to a semblance of normality. Fosun-BioNTech to adolescents by lowering of the age limit from 16 to 12 years after reviewing the available evidence by the Advisory Panel on COVID-19 Vaccines of the Food and Health Bureau, HKSAR Government. 3 The Drug Office of the Department of Health (DH), the drug regulatory authority in Hong Kong, has implemented a pharmacovigilance system for COVID-19 vaccines that monitors reports of adverse events following immunization (AEFI). The COVID-19 vaccine Adverse event Response and Evaluation (CARE) Programme was set up, an active surveillance system, to evaluate AEFI data from the general population using electronic medical records from Hospital Authority and vaccination records from the DH. The CARE programme actively identifies AEFI and conduct epidemiological study to evaluate the association between vaccinations and subsequent adverse event. 4, 5 A c c e p t e d M a n u s c r i p t 8 The Comirnaty is a messenger RNA (mRNA) vaccine that is highly effective in preventing hospitalizations and deaths due to COVID-19. 6 Although Comirnaty has a favourable safety profile, various regulatory agencies have advocated continuous monitoring of its safety, as rare and longterm adverse reactions might not have been detected in the clinical trials and early post-marketing reports. 7 Recently, there have been emerging case reports of acute myocarditis following mRNA COVID-19 vaccination in healthy young adolescent and adult males. [8] [9] [10] The United Kingdom has only approved offering one dose of the Pfizer-BioNTech vaccine to healthy adolescents aged 12 to 15 years old so far, instead of giving the recommended two doses. 11 Yet an in-depth population-based investigation of the age-specific incidence of acute myocarditis/pericarditis following mRNA COVID-19 vaccination in Asian adolescents is lacking. This study aims to report the clinical characteristics and estimate the incidence of acute myocarditis following vaccination with Comirnaty in adolescents in Hong Kong.

This was a population cohort study aimed at identifying all suspected cases of acute myocarditis in adolescents aged between 12 and 17 years who received the Comirnaty vaccine between 14 June 2021 and 4 September 2021. All individuals receiving the Comirnaty vaccine have also consented to their vaccination records being linked to their corresponding comprehensive electronic health records held by the Hospital Authority (HA), the major publicly funded healthcare provider, through the CARE Programme. 4 All suspected cases of acute myocarditis/pericarditis that occur within 14 days after receiving either the first or the second dose of the Comirnaty vaccine and admitted to one of the HA hospitals are reported to the Advanced Incident Reporting System (AIRS) on admission, a system for HA to report adverse drug events and AEFI to DH.

A c c e p t e d M a n u s c r i p t Separated cases related to the first dose or to the second dose were also calculated. Acute myocarditis/pericarditis related to the first dose was defined as the first cases within 14 days of the first dose. Acute myocarditis/pericarditis related to the second dose was defined as the first cases within 14 days of the second dose. The 14 days was the upper end of the reporting of myocarditis/pericarditis cases following vaccination according to the DH and HA reporting policies.

The incidence of clinically confirmed myocarditis/pericarditis per 100,000 doses administered as well as number of cases per 100,000 doses for first dose and second dose were estimated. We calculated 95% confidence intervals (95% CI) for all incidences calculated using Poisson distribution. The incidence rate of acute myocarditis/pericarditis associated with the Comirnaty vaccine was A c c e p t e d M a n u s c r i p t 11 compared with the background incidence rate of acute myocarditis/pericarditis in 2020 using per 100,000 per 14-days. Sensitivity analyses were conducted using (1) the background incidence rate in 2018 and 2019 and the average background incidence rate from 2011 to 2020 using per 100,000 per 14-days and (2) changed the incidence using per 28-days. Subgroup analysis was conducted by sex.

Some comparisons to background years were not possible as there were zero cases of myocarditis/pericarditis recorded in background years. Median and interquartile ranges (IQR) were used to describe skewed data. All statistical tests were two-sided and p-values at a level of 5% were considered statistically significant. Statistical analyses were conducted using R version 4.0.3 (www.Rproject.org). For quality assurance, two investigators (ECC and RDS) independently conducted the statistical analyses. 

Between 14 June and 4 September 2021, a total of 33 cases of myocarditis/pericarditis within 14 days following vaccination with Comirnaty were identified. Twenty-five (75.76%) were definite, 7 (21.21%) were probable and 1 (3.03%) were possible cases ( Table 1 ). The patients were all Chinese adolescents with no history of cardiac diseases. 29 (87.88%) were males and 4 (12.12%) were females, with a median age of 15.25 years. 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. These patients developed myocarditis/pericarditis at a median of 2 days after receiving the last dose of the vaccine. 13 The overall incidence for acute myocarditis/pericarditis was 18.52 (95% CI 11.67-29.09) per 100,000 persons vaccinated. The incidence after the first and second doses were 3.37 (95%CI 1.12-9.51) and 21.22 (95%CI 13.78-32.28) per 100,000 persons vaccinated, respectively (Table 2 ). Incidence was higher among male adolescents compared to females ( Table 2) . Incidence rates compared with previous years' background rates are shown in Table 2 and Supplementary Tables 1 -3 . Compared to the background incidence rate of acute myocarditis/pericarditis in 2020 there were significantly higher incidence rate differences in those vaccinated ( Table 2 ). Sensitivity analyses using the background incidence rate in 2018, 2019 and 2020 and the average background incidence rate from 2011 to 2020 using per 100,000 per 28-days also demonstrated significantly higher incidence rate differences in those vaccinated which was consistent with the main results (Supplementary tables 4 -8) .

A c c e p t e d M a n u s c r i p t 13 Among males after their first dose, there was a significantly higher incidence rate difference compared the background rate in 2020. After the second dose there was significantly higher incidence rate difference between the background rate in 2020 and all participant and males (Tables   3) .

To our best knowledge, this is the first study in adolescents using data from the territory-wide post-COVID-19 vaccination monitoring system to analyse the incidence of acute myocarditis/pericarditis associated with the Comirnaty vaccine for adolescents in Asia.

Our analysis revealed that the overall incidence of acute myocarditis/pericarditis in adolescent following the Comirnaty vaccination was 18.52 per 100,000 persons vaccinated. Majority cases involved healthy adolescent males after receiving the second dose. No other infective causes including SARS-CoV-2 infection were identified. Conservative management with NSAIDs was sufficient. This higher incidence of myocarditis/pericarditis following Comirnaty vaccination than other jurisdictions is likely related to the heightened vigilance of healthcare professionals and the public, 14 as well as the highly efficient CARE Programme for the monitoring and reporting of AEFI across Hong Kong. 10 Our pharmacovigilance system was able to capture mild cases of acute myocarditis/pericarditis and reveal the real-world incidence of acute myocarditis/pericarditis following the Comirnaty vaccination. Since the Pfizer-BioNTech vaccine was approved for large-scale immunization in many countries, there has been a higher observed risk of acute myocarditis/pericarditis among younger males receiving this vaccine. 15 The first reports in Israel were of five young males who developed mild myocarditis following vaccination with the BioNTech mRNA COVID-19 vaccine. 16 vaccines to military personnel. 9 In children, so far, only one case series reported myocarditis following vaccinations with mRNA COVID-19 vaccines. These seven cases were males aged 14 to 19 years who presented with transient mild symptoms, elevated troponin, and MRI changes suggestive of acute myocarditis or perimyocarditis. They were treated with NSAIDs, steroids, or intravenous immunoglobulin. 8 So far, all adults and adolescents with myocarditis/pericarditis following COVID-19

vaccinations, including those reported in the current study, have been mild cases. 17 While the pathophysiology of acute myocarditis/pericarditis following the mRNA COVID-19 vaccine is still unclear and the observation that only mRNA-based COVID-19 vaccines are associated with acute myocarditis remains unexplained. The causal association between mRNA vaccine and myopericarditis has recently been suggested in a mouse model. Higher systemic levels of mRNA lipid nanoparticles due to inadvertent intravenous injection or rapid return from the lymphatic circulation was proposed to increase this risk. 18 Further studies to delineate the pathophysiology of acute myocarditis/pericarditis associated with mRNA-based COVID-19 vaccines is urgently needed.

The US Center for Disease Control and Prevention (CDC) reported that the expected rates of myocarditis/pericarditis following the Comirnaty vaccination would be the highest among males aged between 12 and 29 years old, estimating 40.6 per million second doses administered. 10 The incidence rate of myocarditis/pericarditis following the Comirnaty vaccination in Hong Kong was much higher than those reported from the United States. 10, 19 However, it is important to note that the risk of myocardial injury in healthy young individuals including athletes following COVID-19 infection is also considerably high, 20 ranging from asymptomatic cases with abnormal cMRI only to fulminant myocarditis due to COVID-19. 21, 22 Preliminary data in Israel demonstrated a 51% effectiveness after receiving one dose Pfizer-BioNTech vaccine among older adults. 23 This study has several strengths and limitations. All subjects presented to the accident and emergency department or in the outpatient clinics in the public system received comprehensive reviews and investigations to rule out the possibility of myocarditis/pericarditis because of viral infection, and cMRI to confirm subtle inflammation of the myocardium. However, asymptomatic subjects and subjects with transient and subtle symptoms of acute myocarditis/pericarditis, such as tachycardia and mild chest discomfort, might not seek medical consultation or have sought medical consultation in the private sector which were not reported. Some patients had negative MRI results because not all MRI suites in Hong Kong's public hospitals have the capability for T1 and T2 mapping to calculate the extracellular volume, leading to lower sensitivities and unable to meet the 2018 Lake Louise Criteria for the diagnosis of myocarditis. Furthermore, the incidence of acute myocarditis/pericarditis following the COVID-19 vaccination remained to be high, possibly attributed to increased awareness of possible acute myocarditis/pericarditis following vaccination with COVID-19 vaccines compared with other jurisdictions, as well as to the CARE Programme to capture AEFI.

The high incidence of acute myocarditis/pericarditis following Comirnaty vaccination among adolescents presented in this study is representable as the HA receives majority of emergency A c c e p t e d M a n u s c r i p t 16 admissions in Hong Kong. 4 Finally, different criteria were likely used by clinicians in generating a diagnostic code among the non-vaccinated individuals for the calculation of the background myocarditis/pericarditis incidence as it was in a non-research setting. Nevertheless, we have included myocarditis and pericarditis of all causes, including idiopathic cases, for the calculation of the background incidence.

Chinese adolescent males have a higher risk of acute myocarditis/pericarditis following vaccination with Comirnaty, especially after the second dose. Medical professionals and recipients of the Comirnaty vaccine should be vigilant regarding the symptoms of acute myocarditis/pericarditis.

Observations on the incidence of myocarditis/pericarditis following the Comirnaty vaccination after changing to one-dose vaccination as well as the rate of COVID-19 infections among adolescents shall be conducted.

A c c e p t e d M a n u s c r i p t 17 M a n u s c r i p t 23 M a n u s c r i p t 29 A c c e p t e d M a n u s c r i p t 30 

Clinical Characteristics and Transmission of COVID-19 in Children and Youths During 3 Waves of Outbreaks in Hong Kong

Vulnerability and resilience in children during the COVID-19 pandemic. Eur Child Adolesc Psychiatry

Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study. The Lancet Infectious Diseases

Two-dose COVID-19 vaccination and possible arthritis flare among patients with rheumatoid arthritis in Hong Kong

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

First Month of COVID-19 Vaccine Safety Monitoring -United States

Symptomatic Acute Myocarditis in Seven Adolescents Following Pfizer-BioNTech COVID-19 Vaccination

Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military

Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices -United States

The Government of the HKSAR

mRNA COVID vaccine and myocarditis in adolescents

Myocarditis Occurring After Immunization With mRNA-Based COVID-19 Vaccines

Myocarditis following COVID-19 mRNA vaccination. Vaccine

Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older

Intravenous injection of COVID-19 mRNA vaccine can induce acute myopericarditis in mouse model

Myocarditis and Pericarditis After Vaccination for COVID-19

Evaluation for Myocarditis in Competitive Student Athletes Recovering From Coronavirus Disease 2019 With Cardiac Magnetic Resonance Imaging

Fulminant Myocarditis With ST Elevation and Cardiogenic Shock in a SARS-CoV-2 Patient. Cureus

Cardiac involvement in consecutive elite athletes recovered from Covid-19: A magnetic resonance study

Scientific Committees under CHP issue consensus interim recommendations on COVID-19 vaccination. The Government of the Hong Kong Special Administrative Region

A c c e p t e d M a n u s c r i p t ^ Cases 34 and 35 presented >14 days after receiving the second doses, therefore they were only included in the sensitivity analyses (supplementary table 4  -8) CRP -C reactive protein; ECG -electrocardiogram; ECHO -echocardiogram; ECV -extracellular volume; EGE -early gadolinium enhancement; Gd -Gadolinium; hsTnI -high-sensitivity troponin I; hsTnT -high-sensitivity troponin T; LGE -late gadolinium enhancement; LV -left ventricle; LVFS -left ventricle fractional shortening; SOB -shortness of breath; STD -ST depression; STE -ST elevation; STIR -short tau inversion recovery; T2W -T2-weighted; TWI -T wave inversion; TnT -troponin T