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Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, AustraliaSchool of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, AustraliaCardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, AustraliaSchool of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia
Department of Cardiology, St. Vincent’s Hospital, Sydney, NSW, AustraliaSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW, AustraliaSchool of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia
With the rapid rollout of COVID-19 vaccinations, numerous associated and suspected adverse events have been reported nationally and worldwide. Literature reporting confirmed cases of pericarditis and myocarditis following SARS-CoV-2 mRNA vaccinations has evolved, with a predominance in adolescent males following the second dose.
Methods
This was a retrospective analysis of all patients presenting to St Vincent’s Hospital, Sydney, Australia with suspected COVID-19 vaccine-related myocarditis and pericarditis. The Brighton Collaboration Case Definitions of Myocarditis and Pericarditis were used to categorise patients into groups based on diagnostic certainty. Cardiac magnetic resonance imaging findings were reviewed against updated Lake Louise Criteria for diagnosing patients with suspected myocarditis.
Results
We report 10 cases of confirmed, possible or probable myocarditis and pericarditis. The mean age of presentation in the vaccine group was 33±9.0 years. The most common presenting symptom was pleuritic chest pain (n=8, 80%). Eight patients (80%) had electrocardiogram (ECG) abnormalities (n=6 pericarditis, n=2 myocarditis). Five patients (50%) had a minimum 24 hours of cardiac monitoring. One patient had multisystem inflammatory syndrome following vaccination (MIS-V) with severely impaired left ventricular ejection fraction and required admission to the intensive care unit.
Discussion and Conclusion
Cardiac complications post mRNA vaccines are rare. Our case series reflects the worldwide data that vaccine-related myocarditis and pericarditis most frequently occur in young males, following the second dose of the vaccine. These cardiac side effects are mild and self-limiting, with adequate responses to oral anti-inflammatories. One patient developed a severe reaction, with no fatal cases.
COVID-19 Excess Mortality Collaborators Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21.
COVID-19 Excess Mortality Collaborators Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21.
]. Vaccinations have served as the key driver to curb excess mortality from COVID-19 infection worldwide. Mathematical models have revealed that vaccinations have more than halved the potential global death toll, with an estimated 19.8 million deaths from COVID-19 averted as a result of vaccination [
]. In recent months, literature reporting confirmed cases of pericarditis and myocarditis following SARS-CoV-2 mRNA vaccinations has evolved, with a predominance in adolescent males, especially adolescents following the second dose [
At the time of writing, four COVID-19 vaccinations have been approved by the Therapeutic Goods Administration (TGA) for use in Australia: Comirnaty (Pfizer-BioNTech) vaccine, approved on 25 January 2021; Vaxzevria (AstraZeneca) vaccine approved on 15 February 2021; Spikevax (Moderna) vaccine approved on 9 August 2021; and Nuvaxovid (Novavax) vaccine approved on 20 January 2022. From the 27.3 million Pfizer-BioNTech doses administered in Australia to 2 January 2022, there have been 415 reports of likely myocarditis and 735 reports of likely pericarditis [
]. From the 1.8 million Moderna doses administered in Australia to 2 January 2022, there have been 40 reports of likely myocarditis and 52 reports of likely pericarditis [
]. It is unclear how many of these cases are a direct consequence of the vaccine versus coincidental. Thus, it is imperative to analyse episodes of vaccine-related myocarditis and pericarditis assessed by a cardiology team at a quaternary centre according to standardised definitions. Expediting the availability of this information to Australian clinicians is essential in informing local practice.
This study aims to identify and analyse all cases of confirmed, possible or probable vaccine-related myocarditis and pericarditis presenting to a major cardiac quaternary institution since the beginning of the Pfizer vaccine launch.
Methods
This was a retrospective analysis of all patients presenting to St Vincent’s Hospital, Sydney with suspected COVID-19 vaccine-related myocarditis and pericarditis. Patients were identified in the hospital’s Emergency Department Information System (EDIS) database using codes “myocarditis” or “pericarditis” between 1 February 2021 and 31 December 2021. Each patient’s medical record was reviewed for administration of COVID-19 Pfizer-BioNTech, Astra-Zeneca, and Moderna vaccines prior to presentation.
The Brighton Collaboration Case Definitions of Myocarditis and Pericarditis were used to categorise patients into groups based on diagnostic certainty (Tables 1 and 2) [
]. These were chosen as they reflect the case definitions utilised by the Australian Technical Advisory Group on Immunisation (ATAGI) in their published guidelines to practitioners on the adverse effects following mRNA COVID-19 vaccination [
]. Cardiac magnetic resonance imaging (CMR) findings were reviewed against updated Lake Louise Criteria (LLC) for diagnosing patients with suspected myocarditis [
]. Any diagnostic uncertainty was addressed by a senior cardiologist, defined as a Society for Cardiovascular Magnetic Resonance (SCMR)/European Association of Cardiovascular Imaging (EACVI) Level 3 Expert Reader.
Table 1Case definitions for myocarditis based on level of diagnostic certainty.
Myocarditis Case Definition and Levels of Diagnostic Certainty
Level of Certainty 1 (Definitive Case)
Level of Certainty 2 (Probable Case)
Level of Certainty 3 (Possible Case)
Histopathologic examination of myocardial tissue showing myocardial inflammation (autopsy or endomyocardial biopsy)
Clinical Symptoms, at least one of:
•
Acute chest pain or pressure
•
Palpitations
•
Dyspnoea on exertion, at rest, lying supine
•
Diaphoresis
•
Sudden death
Clinical Symptoms, at least one of:
•
Acute chest pain or pressure
•
Palpitations
•
Dyspnoea on exertion, at rest, lying supine
•
Diaphoresis
•
Sudden death
OR
AND
AND
Elevated myocardial biomarkers, at least one of:
•
Troponin T
•
Troponin I
ANDAbnormal imaging study, at least ONE of the following Abnormal CMR, with at least one of:
• Patchy oedema on T2 weighted study
• LGE on T1 weighted study involving at least one non-ischemic regional distributional with recovery OR
Testing supporting diagnosis, at least ONE of the following:
Abnormal CMR (see Level 1 definition)
OR
Abnormal TTE (see Level 1 definition)
OR
ECG abnormalities that are new and/or normalise on recovery, at least one of:
•
Paroxysmal or sustained atrial or ventricular arrhythmias (PACs, PVCs, SVT, VT, abnormal Q waves, low voltages)
Table 2Case definitions for pericarditis based on level of diagnostic certainty.
Pericarditis Case Definition and Levels of Diagnostic Certainty
Level of Certainty 1 (Definitive Case)
Level of Certainty 2 (Probable Case)
Level of Certainty 3 (Possible Case)
Histopathologic examination of myocardial tissue showing pericardial inflammation (autopsy or pericardial biopsy)
Clinical Symptoms, at least one of:
•
Acute chest pain or pressure
•
Palpitations
•
Dyspnoea on exertion, at rest, lying supine
•
Diaphoresis
•
Sudden death
Clinical Symptoms, at least one of:
•
Acute chest pain or pressure
•
Palpitations
•
Dyspnoea on exertion, at rest, lying supine
•
Diaphoresis
•
Sudden death
OR
AND
AND
Abnormal testing, at least TWO of the following:
Evidence of abnormal fluid collection or pericardial inflammation by imaging (TTE, CMR, CT)
OR
ECG abnormalities that are new or normalise on recovery (must have all findings below)
•
Diffuse concave upward ST segment elevation
•
ST segment depression in augmented vector right
•
PR depression throughout the leads without reciprocal ST segment changes
OR
Physical examination finding (at least one finding below):
•
Pericardial friction rub
•
Distant heart sounds
•
Pulsus paradoxus
Abnormal testing, at least ONE of the following:
Evidence of abnormal fluid collection or pericardial inflammation by imaging (TTE, CMR, CT)
OR
ECG abnormalities that are new or normalise on recovery (at least one of the following)
•
Diffuse concave upward ST segment elevation
•
ST segment depression in augmented vector right
•
PR depression throughout the leads without reciprocal ST segment changes
OR
Physical examination finding (at least one finding below):
•
Pericardial friction rub
•
Distant heart sounds
•
Pulsus paradoxus
Abnormal testing, at least ONE of the following: Abnormal chest radiograph showing enlarged heart OR Non-specific ECG abnormalities that are new or normalise on recovery other than lose listed in Level of Certainty 1 or 2
AND
AND
No alternative diagnosis for symptoms
No alternative diagnosis for symptoms
Adapted from the Brighton Collaboration Case Definitions for acute myocarditis and acute pericarditis (2021) [
Patients were analysed for demographics, hospital length of stay (LOS), number of vaccine doses prior to presentation, time since last vaccine, history of cardiovascular disease (CVD); and clinical features. An elevated troponin level was defined as a troponin I value above 20 ng/L. Cardiac evaluation included electrocardiogram (ECG), transthoracic echocardiogram (TTE), and cardiac magnetic resonance (CMR). Systolic dysfunction was defined by a left ventricular ejection fraction (LVEF) less than 55% on TTE [
Normal reference intervals for cardiac dimensions and function for use in echocardiographic practice: a guideline from the British Society of Echocardiography.
]. CMR assessment included presence and location of late gadolinium enhancement (LGE), with significance determined in conjunction with other parameters forming the LLC, that being >1 focal non-ischaemic region of LGE and T2 regional or global increase in T2 signal intensity.
Ethics
The study was approved by the St Vincent’s Hospital, Sydney, Australia HREC 2021/ETH11961.
Statistical Analysis
Descriptive statistics were calculated for all study variables. Quantitative variables were summarised with means and standard deviations, and medians with interquartile ranges.
Data Presentation
To aid clinician education and identification of future cases, we describe the summary of the case series, and then each confirmed case in further detail. This includes clinical finding, imaging findings and treatment.
Results
A total of 97 cases of pericarditis and nine cases of myocarditis were identified during the study period. In total, 10 cases of confirmed, probable or possible myocarditis and pericarditis following Pfizer-BioNTech COVID-19 vaccine were identified (Table 3). Of the 97 cases of “pericarditis”, after Cardiology review, five patients were treated as probable cases and one as a suspected case of pericarditis. There were three confirmed cases and one possible case of myocarditis.
Table 3Demographics, clinical characteristics and treatment of 10 patients with myocarditis and pericarditis following Pfizer-BioNTech COVID-19 vaccination, 1 February 2021–31 December 2021.
Abbreviations: ECG, electrocardiogram; ICU, intensive care unit; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
The mean age of presentation in the vaccine group was 33±9.0 years. There were eight males (80%) and two females (20%). In the myocarditis group, three cases were male, and one case was female, with a combined mean age of 30.5±8.1 years. In the pericarditis group, six cases were male with a mean age of 34.7±9.2 years.
The mean time from vaccination dose to symptom onset was lower in the myocarditis group (4.3±2.6 days) versus the pericarditis group (9.8±5.4 days); however, given the small sample size, we were unable to obtain a meaningful p-value (Table 4). In total, there were six presentations that followed the first dose and five presentations that followed the second dose. One patient (Case 7) had a history of underlying CVD.
Table 4Average age, length of stay and time from vaccine dose to symptom onset of 10 patients with myocarditis and pericarditis following Pfizer-BioNTech COVID-19 vaccination, 1 February 2021–31 December 2021.
Average Age (years)
Average Length of Stay (days)
Average Time From Vaccine Dose to Symptom Onset (days)
The most common presenting symptom was pleuritic chest pain (n=8, 80%). One patient (Case 2) presented with non-pleuritic chest pain, accompanied by myalgia, lethargy and cough. One patient (Case 3), presented with syncope (Table 3).
Eight patients (80%) had ECG abnormalities (n=6 pericarditis, n=2 myocarditis), including ST elevation and PR depression (n=6), atrial fibrillation (n=1), biphasic T waves in V3-V4 (n=1). Eight patients had normal systolic function, and one patient had severely impaired LVEF (Case 2).
Five patients (50%) had a CMR. The Full Width Half Maximum technique (FWHM) was used, showing evidence of late gadolinium enhancement on myocardial T1 images for two cases (Case 1 and Case 3). T1 mapping values (RR 1100–1300 ms) have been included in Table 5. Myocardial extracellular volume fraction (ECV) could not be accurately measured. Seven patients (70%) had a minimum 24 hours of cardiac monitoring. Three patients (30%) were discharged from the Emergency Department (ED) with Cardiology follow-up. One admitted patient developed atrial fibrillation with a rapid ventricular rate. The total mean LOS was 4.0±6.1 days, with a mean LOS of 7.3±8.7 days in the myocarditis group and 1.8±1.1 days in the pericarditis group. One patient required admission to the intensive care unit (ICU) for monitoring and inotropic support.
Table 5Advanced Imaging findings of 10 patients with myocarditis and pericarditis following COVID-19 vaccination, 1 February 2021–31 December 2021.
Myocarditis
Pericarditis
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
TTE LV size and function
Normal LV size and function
Severe LV impairment and dilation
Normal LV size and function
Normal LV size and function
Normal LV size and function
Normal LV size and function
Normal LV size and function
Normal LV size and function
Normal LV size and function
Normal LV size and function
TTE LVEF (%)
65%
15%
60%
65%
60%
65%
55%
65%
60%
65%
TTE RV function
Normal RV size and function
Severe RV impairment
Normal RV size and function
Normal RV size and function
Normal RV size and function
Normal RV size and function
Normal RV size and function
Normal RV size and function
Normal RV size and function
Normal RV size and function
TTE evidence of pericardial effusion
Trivial
Small
No
No
No
No
No
Trivial
Trivial
No
Cardiac MRI performed
Yes
Yes
Yes
No
No
Yes
No
No
Yes
No
Cardiac MRI evidence of LGE on T1 images
Subepicardial and mid-mural LGE of the basal inferior and inferolateral walls
Gadolinium not given
Subepicardial LGE of basal inferior wall
N/A
N/A
No LGE
N/A
N/A
No LGE
N/A
T1 value (msec)
1,418
1,153
1,175
N/A
N/A
1,167
N/A
N/A
1,060
N/A
Cardiac MRI evidence of oedema on T2 images
Yes
Yes
Yes
N/A
N/A
No
N/A
N/A
No
N/A
Cardiac MRI evidence of pericardial effusion
No
Yes
No
N/A
N/A
No
N/A
N/A
Trivial
N/A
Abbreviations: LGE, late gadolinium enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; N/A, not applicable; RV, right ventricular; T2, transverse relaxation time; TTE, transthoracic echocardiogram.
A 17-year-old male, non-smoker, presented to ED with pleuritic chest pain commencing three days following his first dose of Pfizer-BioNTech vaccine. He was on isotretinoin for acne vulgaris.
On examination, his heart rate (HR) was 92 beats per minute (bpm), blood pressure (BP) 116/71 mmHg, respiratory rate (RR) 18 breaths per minute, and oxygen saturation (SpO2) of 99% on room air. He was afebrile and cardiovascular examination was normal. ECG was normal. Laboratory findings showed an elevated troponin I, with a peak of 6,990 ng/L (reference range [RR] 0–10 ng/L), raised C-reactive protein (CRP) of 10.8 mg/L (RR<5.0 mg/L) and normal white blood cell count (WCC) of 8.6x109/L (RR 4.0–11.0x109/L). Respiratory virus PCR was negative for SARS-CoV-2.
TTE showed normal biventricular size and systolic function and a trivial pericardial effusion CMR showed large volume subepicardial and mid-mural LGE of the basal inferior and inferolateral walls with elevated T2 values, consistent with an active inflammatory process (Figure 1). Telemetry was unremarkable.
Figure 1Cardiac magnetic resonance imaging (MRI) for Case 3. LGE views showing late gadolinium enhancement in the basal inferior wall (A) short axis view (B) long axis view (C) elevated T2 values suggestive of active inflammation.
He was treated with paracetamol and ibuprofen and discharged on day five from admission.
Case 2
A 35-year-old male tested positive for COVID-19 on 12 August 2021. He did not require hospitalisation and met the criteria for COVID-19 infection clearance on 5 September 2021. Three weeks later, he received his first dose of the Pfizer-BioNTech COVID-19 vaccine on 24 September 2021. Six days later he presented to a local ED with chest pain, myalgia, lethargy and cough. His medical history was significant for unmedicated asthma. He had no known history of cardiovascular disease. A COVID-19 PCR was negative, and ECG was normal. Laboratory findings demonstrated WCC of 17.3x109/L, CRP of 157 mg/L and a D-dimer of 0.33 mg/L (RR<0.25 mg/L). Troponin I was normal <3 ng/L. He had an acute kidney injury with a creatinine of 112 μmol/L (RR 60–110 μmol/L). TTE was normal. He was discharged within 24 hours, diagnosed with vaccine-associated symptoms.
Two days later, he re-presented to ED with vomiting, diarrhoea and a maculopapular blanching rash. Serology showed a rising CRP of 269 mg/L, however the troponin I remained normal (<3 ng/L). Chest radiograph showed right-sided consolidation. He was admitted and commenced on broad-spectrum antibiotics.
Two days into his admission, he developed cardiogenic shock requiring inotropic support. Laboratory tests showed a rising troponin I, peaking at 1,474 ng/L and brain natriuretic peptide (NT-pro-BNP) of 5,600 ng/L (RR<100 ng/L). TTE showed an LVEF<40% with increased left ventricular dimensions, small posterior pericardial effusion (5–7mm) and mild bi-atrial enlargement.
On day four of admission, he developed worsening respiratory distress and haemodynamically unstable atrial fibrillation (AF) and required urgent intubation and synchronised direct-current cardioversion. A TTE at this time showed severe global systolic impairment and dilation with an LVEF of 15% and stable small pericardial effusion, necessitating veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and commencement of anakinra and parenteral corticosteroids. He was decannulated from VA-ECMO and extubated on day 11.
A day 12 CMR revealed elevated T1 and T2 values consistent with myocardial oedema and computed tomography coronary angiogram (CTCA) on day 22 excluded coronary artery disease (CAD).
The clinical impression was that of a multisystem inflammatory syndrome in adults (MIS-A) following both COVID-19 and vaccination, justifying immunosuppressive therapy with anakinra, corticosteroids and intravenous immunoglobulin (IVIG). Expert panel evaluation of the case reached consensus on the diagnosis of Pfizer-BioNTech induced myocarditis leading to a subsequent multisystem inflammatory syndrome following vaccination (MIS-V) [
Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data.
], given the patient’s full recovery from COVID-19 and timing of vaccine administration in addition to other relevant clinical criteria being met. The patient was transferred to the inpatient rehabilitation unit on day 21.
Case 3
A 38-year-old male presented to the ED following a syncopal episode eight days after his second dose of the Pfizer-BioNTech vaccine. He had no significant medical history, reporting daily use of e-cigarettes.
On examination, his vital signs showed a HR of 89 bpm, a BP of 94/58 mmHg, and SpO2 of 99% on room air. His cardiovascular examination was unrevealing.
ECG showed sinus rhythm with biphasic T waves in leads V3 and V4 (Supplementary Figure 1). Laboratory findings showed normal serial troponin I measurements (8 ng/L and 7 ng/L). There was an elevated WCC of 12.9x109/L and normal CRP of 3.8 mg/L.
TTE was normal. CMR revealed subtle subepicardial LGE of the basal inferior wall with elevated T2 values consistent with active inflammation, likely representing myocarditis (Figure 2).
Figure 2Cardiac magnetic resonance imaging (MRI) for Case 3. LGE views showing subtle late gadolinium enhancement in the basal inferior wall (A) short axis view (B) long axis view (C) elevated T2 values suggestive of active inflammation.
The patient was admitted under Cardiology and treated with paracetamol and ibuprofen. Within 24 hours of his admission, he discharged against medical advice and was lost to follow up.
Case 4
A 32-year-old female, presented to the ED with a one-day history of chest pain exacerbated by supine positioning, occurring one day after her second Pfizer-BioNTech vaccine, with associated fatigue and myalgia. There was no significant past medical history.
On examination, her vitals showed a HR of 68 bpm, a BP of 123/87 mmHg, and SpO2 of 98% on room air. Her examination and ECG were normal. Laboratory findings showed an elevated troponin I of 29 ng/L and normal WCC of 9.2x109/L and CRP 54 mg/L. A bedside TTE and chest radiograph were normal.
Ibuprofen and colchicine were commenced based on possible pericarditis, and she was discharged on the same day, without readmission.
Case 5
A 30-year-old male, presented to the ED with acute onset central chest pain commencing seven days following his first dose of the Pfizer-BioNTech vaccine, which was exacerbated with supine positioning. His medical history was significant for a 1.5 pack-year smoking history and 12 months of chloromethamphetamine misuse, ceased 2 months prior.
On examination, his HR was 80 bpm, BP 120/80 mmHg, RR of 20 breaths per minute, and SpO2 of 100% on room air. Examination revealed a pericardial rub without murmurs.
ECG showed sinus rhythm with widespread 2 mm ST elevation and PR depression (Figure 3). Laboratory findings showed a normal troponin I, elevated WCC of 12.1x109/L with a predominant neutrophilia of 8.0x109/L (RR 2.0–7.5x109/L) and normal CRP 1.4 mg/L.
Figure 3Electrocardiogram (ECG) for Case 5 showing diffuse ST segment elevation and PR segment depression.
The patient was treated with ibuprofen and discharged from ED with Cardiology follow-up in one week. At follow-up, he was asymptomatic with resolution of the abnormal ECG findings (Figure 4).
Figure 4Follow-up electrocardiogram (ECG) for Case 5, 1 week post discharge showing resolution of abnormal ECG findings.
A 32-year-old male presented to the ED with intermittent, dull, left-sided chest pain commencing four days following his second Pfizer-BioNTech vaccine. His medical history was significant for asthma managed with budesonide/formoterol.
On examination, his HR was 93 bpm, BP 131/80 mmHg, RR 16 breaths per minute and SpO2 of 96% on room air. His cardiovascular examination revealed muffled heart sounds and a pericardial rub.
ECG showed sinus rhythm with widespread PR depression (Supplementary Figure 2). Laboratory findings showed a normal troponin I of 2 ng/L, WCC of 4.9x109/L and CRP 3.4 mg/L.
TTE and CMR were normal.
The patient was treated with ibuprofen and a short course of colchicine. He was discharged after 48 hours, with no recurrent symptoms or readmission at follow-up.
Case 7
A 55-year-old male presented to ED with sharp, substernal chest pain commencing 15 days following his first Pfizer-BioNTech vaccine. Chest pain was exacerbated in the supine position with associated dyspnoea. His background was significant for CAD requiring stenting of the right posterior descending and left anterior descending coronary arteries, thyroidectomy and 40-pack year smoking history. Medications included aspirin and levothyroxine. On examination, his HR was 88 bpm, BP 145/106 mmHg, RR 18 breaths per minute and SpO2 of 96% on room air.
ECG showed sinus rhythm with widespread 2 mm ST elevation and PR depression (Supplementary Figure 3. Laboratory findings showed a normal troponin I of 6 ng/L, elevated WCC of 18.5x109/L and CRP of 8.2 mg/L and 89.2 mg/L on day one and day two of admission, respectively.
TTE was normal and CMR was not performed.
The patient was treated with paracetamol, ibuprofen and a short course of colchicine. He was discharged home after 48 hours and referred for Cardiology follow-up.
Case 8
A 32-year-old male presented to ED with acute onset pleuritic chest pain commencing nine days following his first dose of the Pfizer-BioNTech vaccine, exacerbated with inspiration and lying supine and relieved when sitting forward. He had a 13-pack year smoking history, including weekly inhaled cannabis for insomnia.
This episode followed a recent uncomplicated hospital admission for possible idiopathic pericarditis seven weeks prior, managed with ibuprofen as required. During this episode ibuprofen was weaned based on a reasonable response, however the patient subsequently developed pronounced symptoms after vaccination.
On examination, his HR was 103 bpm, BP 144/90 mmHg, RR 14 breaths per minute and SpO2 of 97% on room air. His examination was normal.
ECG showed sinus rhythm with diffuse ST segment elevation and PR segment depression (Figure 5), in addition to Spodick’s sign (down-sloping TP segment) that were more marked than from his previous admission (Supplementary Figure 4). Laboratory findings showed a normal troponin of 3 ng/L, elevated WCC of 14.2x109/L and CRP of 47.5 mg/L.
Figure 5Electrocardiogram (ECG) for Case 8 on presentation post Pfizer COVID-19 vaccination showing diffuse ST segment elevation and PR segment depression in leads II, III, aVF; in addition to Spodick’s sign (downsloping TP segment) in leads II, III and V3-V6.
TTE showed a trivial pericardial effusion, consistent with imaging from his preceding admission. CMR was not performed.
The patient was diagnosed with confirmed pericarditis, precipitated by the Pfizer-BioNTech vaccine. He was managed with ibuprofen and colchicine, and discharged home after 24 hours with a plan for Cardiology follow-up.
Case 9
A 28-year-old male presented to ED with a one-week history of left-sided pleuritic chest pain commencing three weeks following his second dose of the Pfizer-BioNTech vaccine. His medical history was significant for daily use of e-cigarettes and limited alcohol consumption.
On examination, his HR was 77 bpm, BP 142/75 mmHg, and SpO2 of 98% on room air. His examination was normal.
ECG showed sinus rhythm with 1 mm ST segment elevation in leads V3-V6, incomplete right bundle branch block, left anterior fascicular block; and high J-point in lead II (Supplementary Figure 5).
Laboratory findings showed a normal serial troponin I (7 ng/L and 3 ng/L), WCC of 8.0x10⁹/L and CRP of 0.3 mg/L.
TTE showed a trivial pericardial effusion, confirmed on CMR.
The patient was treated with paracetamol and ibuprofen and was discharged home on day four without readmission. There was a complete resolution of symptoms at one-month Cardiology follow-up.
Case 10
A 31-year-old female, non-smoker, presented to ED with a five-day history of constant left-sided chest pain commencing five days after her first Pfizer-BioNTech vaccine, with an associated bitemporal headache.
On examination, her HR was 72 bpm, BP 134/85 mmHg and SpO2 of 100% on room air. Cardiovascular examination was normal.
ECG showed sinus rhythm with widespread PR segment depression and ST segment elevation in leads II, III and V4-6 (Supplementary Figure 6). Laboratory findings showed a normal troponin I of 2 ng/L (reference range 0–10 ng/L), WCC of 5.2x10⁹/L and CRP 0.6 mg/L.
TTE was performed, which was normal.
The patient was discharged on day of admission with ibuprofen and a 3-month course of colchicine, without readmission.
Discussion
COVID-19 has been the first disease event since the 1918 H1N1 Spanish influenza (flu) pandemic resulting in an urgent global healthcare response [
COVID-19 Excess Mortality Collaborators Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21.
]. Australia is one of the few countries worldwide with a negative excess mortality rate; that is, 18,100 less deaths between 1 January 2020 to 31 December 2021 versus what would be expected based on past trends had the pandemic never occurred [
COVID-19 Excess Mortality Collaborators Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21.
]. Much of this success can be attributed to Australia’s border closures, lockdowns, social distancing measures and mask wearing. This allowed for necessary time for mass vaccination programs, the key driver in Australia’s response to curb the excess mortality of COVID-19.
Vaccination remains the mainstay in the global COVID-19 response. COVID-19 vaccination has overwhelmingly been shown to prevent hospitalisation, ICU admissions and deaths from COVID-19 infection. A meta-analysis comparing 58 studies showed that two doses of any COVID-19 vaccine were 97% effective at preventing symptomatic COVID, 93% effective at preventing hospitalisation and 95% effective at preventing COVID-19 related deaths [
]. Thus, despite the potential for adverse effects, it is overwhelmingly clear that the benefit of vaccination far outweighs the risks in the management of COVID-19.
In this case series, we report 10 cases of confirmed, probable, or possible vaccine-related myocarditis and pericarditis presenting through a single Australian quaternary centre. Whilst no cases of myocarditis or pericarditis were reported in the Pfizer or Moderna COVID-19 vaccine phase III clinical trials, this Australian series adds to a growing body of evidence of vaccine-associated myocarditis and pericarditis [
]. To our knowledge, this is the largest Australian case series currently available.
The findings of our case series reflect the worldwide data that vaccine-related myocarditis and pericarditis is more frequent in young males, and after the second dose of the vaccine. The findings largely show cardiac side effects are mild and self-limiting, with adequate responses to oral anti-inflammatories. One patient developed a severe reaction, MIS-V, requiring admission to ICU for circulatory support. There were no fatal cases (Table 3). There were none of the reported fatal cardiac complications of COVID-19, including coronary thrombosis, pulmonary embolus, acute coronary syndrome, heart failure and ventricular arrhythmias [
]. This is supported by an Australian observational study, which also found that clinical cardiac complications were low in patients hospitalised with COVID-19 [
Our study supports the body of evidence that the incidence of COVID-19 vaccine-related myopericarditis is low. It has been shown that the incidence of myopericarditis following COVID-19 vaccination is no different to that following vaccination against non-COVID-19 pathogens, and is less than the incidence seen in smallpox vaccines [
]. Nonetheless, the incidence remains clinically significant given the mass global vaccination rates and increased surveillance in the COVID-19 era.
Our centre is an advanced heart failure centre with the facilities for endomyocardial biopsy. However, given Pfizer-BioNTech COVID-19 vaccine-related myocarditis and pericarditis is largely self-limiting, there has been no clinical imperative to warrant endomyocardial biopsy in any of our cases to date. Another reason is the increasing access to advanced imaging services, allowing for same-day CMR. This imaging allows deeper assessment of the degree of inflammation using oedema mapping, as well as presence of myocardial scarring with LGE. In addition, given that the sample taken in endomyocardial biopsy is from the septum of the right ventricle, it is possible to miss areas of inflammation.
The potential mechanisms for mRNA-based vaccination cardiac side effects are still poorly understood. Multiple hypotheses have been proposed, including a non-specific innate inflammatory response or a molecular mimicry mechanism between viral spike protein and an unknown cardiac marker [
]. However, it is still unclear why the male gender has been observed to be affected more commonly. There was an increasing number of Pfizer-BioNTech COVID-19 vaccinations being administered in Australia between the period of July 2021–December 2021 and our cases were also observed within the same time-period. In our cohort, nine patients were treated with simple analgesia on a case-by-case basis, with one individual requiring advanced supportive treatment with admission to ICU for VA-ECMO, anakinra, corticosteroids and IVIG, having developed MIS-V on a background of previous COVID-19 infection.
A retrospective observational study performed by Diaz et al. [
] investigated monthly rates of first-time hospital diagnoses of myocarditis and pericarditis across 40 centres, comparing the pre-vaccine and vaccine period. It was evident that there was an increase in cases within the vaccine period. Incidence was found to be highest among young men, with the median time to discharge being two days, with no documented readmission or mortality [
]. Two patients proceeded to receive the second mRNA-vaccination after the onset of myocarditis, and neither patient developed worsening symptoms or systolic dysfunction.
As per the ATAGI guidelines, it is recommended, if a patient develops anaphylaxis or serious vaccine-attributable adverse events after the first dose, and there are no contraindications to the Astra-Zeneca vaccine, to proceed with Astra-Zeneca as a second dose at 4–12 weeks after the initial mRNA-Pfizer dose [
]. This was implemented in two of our patients with no adverse outcomes.
Immunity induced by both SARS-CoV-2 vaccination and COVID-19 infection primes the immune system and ultimately provides protection from future re-infection [
]. In our case of fulminant myocarditis (Case 2), the aetiology was initially unclear, considering both the recent COVID-19 infection and mRNA vaccination. MIS is a post-inflammatory syndrome affecting multiple organs and has been described to typically develop 2–12 weeks after recovery from COVID-19 infection, with first cases reported amongst children (MIS-C) in Europe during 2020 [
]. MIS-V is a phenomenon that has also been described in the literature, with the first case report occurring in an individual who presented with arm pain post Pfizer-BioNTech vaccine, followed by fevers, diarrhoea, abdominal pain and a diffuse erythematous rash with subcutaneous emphysema, elevated troponin and inflammatory markers, and a small pericardial effusion on TTE, having tested negative to COVID-19 [
]. Although this index case was independent of a preceding COVID-19 infection, a clinical picture of MIS needs to be evaluated in the context of vaccination timing, as well as naivety, versus preceding COVID-19 when considering a diagnosis of MIS-V. As outlined earlier, expert consensus was utilised for Case 2 after treatment for MIS had already been instituted, which deemed MIS-V to be the overarching diagnosis in keeping with the Brighton Collaboration Network definition [
Whilst serious adverse effects are rare following COVID-19 infection and mRNA vaccination, the ideal timing of vaccination for this population who have been previously infected remains unclear. A recent publication studied antibody and T-cell responses in a cohort of 14 subjects with prior mild–moderate COVID-19 infection who received the Pfizer BNT162b2 vaccine compared to 27 uninfected subjects [
T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study.
]. It was found that prior COVID-19 infection resulted in improved vaccine response in both the B and T cell compartment. In vaccine recipients with prior COVID-19, the first vaccine dose induced high antibody concentrations comparable to seronegative vaccine recipients after two injections, and thus a single dose post infection with COVID-19 is sufficient [
T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study.
At time of writing, the US Centers for Disease Control and Prevention (CDC) guidelines suggest that an individual who has had COVID-19 can be vaccinated with a COVID-19 vaccine and there is no requirement to delay vaccination [
]. The guidelines also suggest that vaccination can be deferred for up to six months as past infection reduces the chance of re-infection during this time period [
]. There do not appear to be any current imaging criteria or specific guidelines for administration of the vaccine post infection, and this is an area for ongoing interest.
Cardiac transplantation recipients are another population of interest at our institution, for whom the International Society for Heart and Lung Transplantation and the American Society of Transplantation have released guidelines and recommended vaccination of both patients with heart failure and heart transplant recipients [
The ideal timing of vaccination post-transplantation remains uncertain; however, it has been recommended to delay vaccination for at least one month following surgery and three months from the commencement of immunosuppressive therapy [
At time of writing, the TGA has recommended administration of a third Pfizer and Moderna vaccination for all individuals ages 16 years and over, at least 3 months after the completion of their primary dose course.
Conclusion
The overall risk of myopericarditis after receiving COVID-19 vaccine is low. This series adds to a growing body of evidence that there is an association between COVID-19 vaccination and subsequent myocarditis and pericarditis, with predominance in young males. However, the resulting disease process has been largely self-limiting, with no deaths reported at our centre. Ultimately, the evidence still points towards the benefits of vaccination against COVID-19 outweighing its potential harms. As we move forward into the next long-term phase of the pandemic with booster vaccinations, it would be beneficial to see the formal development of an algorithm to guide and standardise management of suspected cases of COVID-19 vaccine-induced myocarditis and pericarditis.
Disclosures
Nicole Bart has received educational grants from Pfizer on transthyretin amyloidosis (ATTR).
Normal reference intervals for cardiac dimensions and function for use in echocardiographic practice: a guideline from the British Society of Echocardiography.
Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data.
T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study.
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