Features and follow-up of patients affected by noninflammatory myocarditis after coronavirus disease 2019 vaccination.

To the Editor Although acute myocarditis has not been described as an adverse event in landmark trials of coronavirus disease 2019 (COVID-19) vaccines, it has been frequently reported as a rare complication in the real world.1–6 The prognosis of this self-limiting condition is generally good, but little is known about the long-term outcomes.2 This work aims to report a single-center experience giving new insights into this topic. Methods We describe four cases diagnosed with myocarditis7 at Sant’Andrea Hospital in Rome, Italy, within 24–96 h after receiving a dose of COVID-19 vaccination between 1 August and 15 October 2021. All patients underwent blood tests, ECG and echocardiography at the time of presentation. All patients underwent cardiovascular magnetic resonance (CMR) within a few weeks from the onset of symptoms. All patients received an outpatient evaluation including ECG and echocardiography after a median of 6 months. Follow-up CMR at 6 months was performed and compared with the previous one in all four patients. Results Key characteristics of each case are included in Table 1. All patients had chest pain and elevated troponin levels on presentation to the emergency department. Serum C-reactive protein levels were very low and procalcitonin levels were in the normal range in all but one patient. None developed an increase in white blood cell count or changes in erythrocyte sedimentation rate. Abnormal ECG findings were recorded only in one patient presenting nonspecific ST changes. Echocardiography demonstrated preserved left ventricular (LV) ejection fraction (EF) and no regional wall motion abnormalities in all patients; pericardial effusion was present in three patients. The two patients who underwent CMR within 4 weeks of symptom onset had findings of myocardial edema with one having also late gadolinium enhancement (LGE). Conversely, the two CMRs performed after 4 weeks of onset showed LGE without myocardial edema. Hospitalization ranged 3–4 days. All patients were treated with NSAIDs, beta blockers and ACEi. None of the patients had in-hospital sustained arrhythmias or suffered from clinical acute heart failure, and all had normal cardiac function at discharge. All were asymptomatic and had not complications or rehospitalizations during follow-up. After 6 months from the onset, none had persistent ECG changes or echocardiographic alterations and inflammatory biomarkers were in the normal range. On 6 months, follow-up, CMR findings of myocardial edema disappeared in all cases, but areas of LGE present in the acute phase persisted almost unchanged in terms of extent and distribution. Table 1 - Key characteristics of patients with acute myocarditis following coronavirus disease 2019 vaccination Case 1 Case 2 Case 3 Case 4 Age (years) 39 20 54 21 Gender Male Male Female Female Coronary artery disease risk factors No No Hypertension, dyslipidemia No Cardiovascular history Previous myocarditis No No No Known prior COVID-19 infection No No No No Symptoms Chest pain, generalized malaise Chest pain Chest pain, dyspnea Chest pain, dyspnea, fever COVID19 vaccine doses prior to symptom onset 1 1 1 2 COVID19 vaccine manufacturer Johnson & Johnson Moderna Pfizer Pfizer Days from vaccination to symptom onset 3 3 2 2 SARS-COV-2 PCR testing Negative Negative Negative Negative Serum hsTnI (pg/ml) 5734 9313 158 390 Serum BNP (pg/ml) 43 Not obtained 64 Not obtained Serum CRP (mg/dl) 1.1 0.03 0.12 5.78 Serum PCT (ng/ml) 0.02 0.02 0.02 0.06 Serum ESR (mm/h) 17 2 12 8 ECG No abnormal findings No abnormal findings Nonspecific ST changes No abnormal findings TTE LVEF (%) 57 63 61 58 Pericardial effusion No Yes Yes Yes Anatomic coronary artery assessment Not obtained Nonobstructive (ICA) Nonobstructive (ICA) Not obtained Time from clinical onset to first CMR 5 weeks 8 weeks 4 weeks 2 weeks First CMR findings LGE with sub-epicardial distribution in the mid-basal inferolateral wall (not present in the previous CMR)Pericardial enhancementNo edema LGE with mesocardial distribution in the mid-apical inferolateral wallNo edema Focal edema with sub-epicardial distribution in the basal lateral wallNo LGE LGE with sub-epicardial distribution in the basal inferolateral wallFocal and linear sub-epicardial edema in the same segments Oxygen support No No No No Length of stay (days) 4 3 4 3 Discharge medications (in addition to chronic therapy) Ibuprofen Aspirin Ibuprofen Aspirin Follow-up 6 months 6 months 6 months 6 months Time from clinical onset to second CMR 6 months 6 months 6 months 6 months Second CMR findings LGE with sub-epicardial distribution in the mid-basal inferolateral wall unchangedPericardial enhancementNo edema LGE with mesocardial distribution in the mid-apical inferolateral wall unchangedNo edema No LGENo edema LGE with sub-epicardial distribution in the basal inferolateral wall unchangedNo edema BNP, brain natriuretic peptide (normal range 0–65 pg/ml); CMR, cardiovascular magnetic resonance; CRP, C-reactive protein (normal range 0–0.5 mg/dl); COVID-19, the coronavirus disease of 2019; ESR, erythrocyte sedimentation rate (normal range 2–25 mm/h); hsTnI, high-sensitivity troponin I (normal range 0–34 pg/ml); ICA, invasive coronary angiography; LGE, late gadolinium enhancement; PCT, procalcitonin (normal range <0.05 ng/ml); TTE LVEF, transthoracic left ventricular ejection fraction. Comment Acute myocarditis following COVID-19 vaccination is a well defined clinical entity characterized in most cases by a presentation with chest pain and troponin I elevation without impairment of left ventricular ejection fraction (LVEF) and a benign in-hospital course.8,9 An atypical finding compared with other forms of myocarditis3 and in previously reported vaccine-associated10–12 is the prevalent absence of inflammatory serological changes, suggesting a noninflammatory pathophysiology. With respect to the CMR findings, all patients in acute phase met at least one of the two updated 2018 Lake Louise CMR main criteria for acute myocarditis.13 Of note, sub-epicardial LGE was a frequent finding and persisted mostly unchanged after a follow-up of 6 months. In nonvaccine-associated myocarditis, the presence of LGE is generally associated with increased risk of adverse cardiovascular events during follow-up. However, data are lacking with regard to the prognostic significance of persistent LGE in the absence of severe LV dysfunction and remodeling. In this setting, prolonged clinical and instrumental follow-up is recommended as these findings may reflect the extensive myocardial derangement potentially leading to future evolution to LV remodeling or late arrhythmias.14 Interestingly, the localization of LGE to the inferolateral LV segments on CMR was similarly seen in other case series11 and seems to carry a better prognosis compared with LGE localized to the septal segments.15 Nevertheless, further investigations are needed to determine the prognostic impact of these findings in the context of myocarditis following COVID-19 vaccination (Fig. 1).Fig. 1: Cardiovascular magnetic resonance findings. (a) Case 1 CMR on acute phase: PSIR sequences. Short-axis view, basal segments. The image shows a linear area of LGE with sub-epicardial distribution in the inferolateral wall (arrow). (b) Case 1 CMR after 6 months of follow-up: PSIR sequences. Short-axis view, basal segments. The image shows the persistence of pericardial enhancement (∗) and linear sub-epicardial LGE in the inferolateral wall of left ventricle (arrow). (c) Case 2 CMR on acute phase: PSIR sequences. Long-axis view. The image shows an area of LGE with mesocardial distribution in the mid-apical inferolateral wall (arrows). (d) Case 2 CMR after 6 months of follow-up: PSIR sequences. Long-axis view. The image shows the persistence of the area of LGE with mesocardial distribution in the mid-apical inferolateral wall (arrows). (e) Case 3 CMR on acute phase: STIR sequences. Short-axis view. The image shows focal edema with sub-epicardial distribution in the basal lateral wall (arrow). (f) Case 3 CMR after 6 months of follow-up: STIR sequences. Short-axis view, basal segments. The image shows the dissolution/disappearance of the myocardial edema previously detected in the lateral wall. (g) Case 4 CMR on acute phase: PSIR sequences. Short-axis view. The image shows a liner area of LGE with sub-epicardial distribution in the basal inferolateral wall (arrow). (h) Case 4 CMR after 6 months of follow-up: PSIR sequences. Short-axis view, basal segments. The image shows the persistence of liner area of LGE. CMR, cardiovascular magnetic resonance; LGE, late gadolinium enhancement.Conflicts of interest There are no conflicts of interest.