The true prevalence of myocarditis in patients with COVID-19 is unknown. The saturation of the health care system in the first few months of the pandemic and the clinical treatment driven by the respiratory symptoms undermined the identification of the more severe cardiac features. In addition, the numerous published reports did not differentiate between myocardial damage and myocarditis and used varying diagnostic approaches.

In patients hospitalized with COVID-19, the average prevalence of definitive/probable myocarditis was estimated to be 2.4 cases/1000 hospitalized patients21 and, in this context, there may have been elevated mortality (20.4%).22 Beyond the confines of the hospital setting, the risk of myocarditis increased by about 10 times in the month after a positive SARS-CoV-2 test, and its development was more frequent in men (60%).23

Echocardiographic changes have been reported to occur in up to 40% of hospitalized patients, although not all of these changes might be secondary to myocarditis.24 Some CMR studies have described findings compatible with myocarditis in hospitalized patients, such as nonischemic late enhancement and native T1 and T2 prolongation in 20%, 73%, and 60%, respectively.25,26 However, in young asymptomatic or paucisymptomatic patients, cardiac involvement is seen in just 0.5% to 3% of cases.27

The autopsy findings of persons with COVID-19 revealed a highly variable cardiac involvement. The largest work identified classic myocarditis in 7.2% of autopsies, with a predominace of other types of changes, such as cellular ischemia, inflammatory infiltration without myocarditis, and microvascular and macrovascular thrombi.28

With the initiation of the vaccination campaign for young people, cases were notified of myocarditis and/or pericarditis after administration of the mRNA vaccines (Comirnaty, BioNTech, Germany/Pfizer, United States; and Spikevax, Moderna, United States).29–33 In contrast to the myocarditis associated with COVID-19, postvaccination myocarditis generally shows a benign course.34

The available data were reviewed by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency,35 which concluded that myocarditis and pericarditis are adverse reactions that can occur after mRNA vaccine administration, with a very low frequency overall and with highest risk for young men several days after the second dose. Their generally benign clinical course means that the risk-benefit balance is still favorable after vaccination, considering the efficacy of the vaccines in preventing COVID-19-related hospitalizations and deaths. Similar conclusions were reached by the American Centers for Disease Control and Prevention.36

Two epidemiological studies conducted in France37 and Nordic countries38 confirmed an increased risk of myocarditis and pericarditis after mRNA vaccine vaccination, particularly in young males (12-29 years) in the first week after administration of the second dose and with a frequency depending on the vaccine administered (13 cases with Spikevax and 3 cases with Comirnaty per 100 000 young people vaccinated).

The data on the risk after a third dose are scarce39; the incidence of myocarditis in a cohort of young people aged between 18 and 24 years was estimated to be 11/100 000 vaccinated in the 2 weeks after the third dose,40 and there are no clear differences between the second and third doses.

Although numerous cases of clinically suspected myocarditis have been reported in patients with SARS-CoV-2 infection, few cases have been histologically confirmed.9 Initially, due to a selection bias for severe hospitalized patients, fulminant presentations were reported, with elevated need for inotropic or mechanical support. In the context of severe patients with associated pneumonia, mortality can be 6.6% at 3 months.21 Among the patients with fulminant myocarditis, those without associated multisystem inflammatory syndrome (MIS) show a more aggressive cardiological course, with greater need for mechanical support and higher mortality.52 In addition, there is a prognostic implication in the detection of myocardial damage, not only due to the myocarditis, and it has been correlated with an increase in readmissions53 and 30-day mortality in patients admitted for COVID-19.54 The presence of cardiovascular risk factors and/or previous heart disease has been associated with more severe clinical symptoms and worse prognosis, especially in patients with a history of heart disease, whose mortality can be as high as 40%.55–57

The prognosis of the initially more benign clinical symptoms, particularly in the out-of-hospital setting, is less well defined and is limited to series of patients with different inclusion and diagnostic criteria. For example, in a case-control study with young symptomatic outpatients after COVID-19, the prevalence of myocarditis on CMR was 8%, with subsequent progressive improvement in enhancement and without clinical events during follow-up.58

The incidence of myocarditis in the case of reinfection with SARS-CoV-2 is unknown, as well as its characteristics with respect to cases found during the initial infection.

Finally, most cases of myocarditis related to vaccination against SARS-CoV-2 are mild and resolve within 1 to 3 weeks.20 More than 90% of patients have a complete clinical recovery in the first 3 to 6 months.17 Severe cases are infrequent, without differences by sex, and no relationship has been found with previous heart disease.59

Outpatient follow-up is recommended after hospital discharge. Clinical evaluation with ECG and TTE is mandatory in all patients, although there are no definitive guidelines on the required intervals. In patients with early improvement without ventricular dysfunction and mild extension in the CMR study, follow-up should be performed at 3 to 6 months. In patients with higher risk (ventricular dysfunction, extensive myocarditis, high arrhythmic risk), early follow-up seems appropriate. In patients with high arrhythmic risk, Holter-ECG is advisable. If clinical status worsens during follow-up, hospitalization, CMR, and/or endomyocardial biopsy should be considered, depending on the severity of the disease.41

Regarding the imaging follow-up of myocarditis of other etiologies, a CMR study at 6 to 12 months of follow-up allows stratification of prognosis according to edema persistence, the absence of a reduction in late enhancement vs the acute-phase study,60 and the localization pattern of residual enhancement.61 In the context of myocarditis due to SARS-CoV-2 infection or vaccination, there are no long-term evidence or established guidelines on the optimal follow-up time for imaging tests. From the available evidence, changes in the native T1 value and late enhancement seem to persist at 3 months vs controls and to disappear at 4 to 6 months after COVID-19-associated myocarditis.62,63 For their part, small series show a normalization of ventricular function and myocardial edema, with persistence of late enhancement 3 months after postvaccination myocarditis,64 which seems to fall until reaching a minimal residual level and without adverse clinical events at 6 months.65 In patients with mild COVID-19 and without initial cardiovascular involvement, CMR does not show changes at 6 months of follow-up.66 Accordingly, taking into account the available data, it seems prudent to propose a follow-up that includes CMR67,68 at about 6 months after diagnosis, which can be brought forward in patients with persistent symptoms who have experienced complications (ventricular arrhythmias or dysfunction), high-level athletes, or at-risk professionals.69

There are no solid data on the possible measures that could minimize the risk of myocarditis/pericarditis development. Some results suggest that a gap between the first and second doses exceeding 56 days could decrease the probability of myocarditis/pericarditis onset70 without impacting vaccine efficacy.71 However, these last results are based on pre-Omicron data, which is why their extrapolation to subsequent epidemiological scenarios might be limited.

There are currently no vaccines available in Spain that represent an alternative for patients diagnosed with myocarditis/pericarditis associated with administration of an mRNA vaccine. Adenovirus-based vaccines are not recommended in young people due to the possible development of an infrequent syndrome called severe thrombotic thrombocytopenia. Recently, myocarditis/pericarditis has been identified as a possible adverse reaction to the available protein-based vaccine (Nuvaxovid, Novavax, United States).

Equally, there is no scientific evidence enabling determination of the optimal approach to patients who have developed myocarditis or pericarditis after administration of a vaccine dose. From the clinical perspective and according to the principles of prudence and biological plausibility, the general recommendation is to not administer additional doses to this group of patients, although it seems reasonable to individualize the intervention based on each patient's characteristics. The proposed algorithm is illustrated in figure 4.

Figure 4.

Algorithm for determining the administration of new doses of an mRNA vaccine against SARS-CoV-2 to patients with previous postvaccination myocarditis. CMRI, cardiac magnetic resonance imaging; mRNA, messenger RNA; PET, positron emission tomography; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

(0.27MB).

The incidence of symptomatic infection with SARS-CoV-2 in pediatric patients is low (1%-2%) and the symptoms are typically mild or nonexistent.72 In addition to respiratory involvement, MIS has been reported in children (MIS-C); it is an infrequent postinflammatory complication (in 8% of hospitalized children; in 0.5%-3% of the general pediatric population with COVID-19) but with a potentially severe clinical course. MIS-C is related to poor immunoregulation in individuals with genetic susceptibility, more than with a direct effect of the virus. Its immunological profile and clinical manifestations differ from those of acute COVID-19 infection67 and share overlapping features with those of other inflammatory diseases.73 MIS-C appears 2 to 6 weeks after the first infection with SARS-CoV-2 and progresses with cardiovascular involvement in most patients; ventricular dysfunction, myocarditis, arrhythmias, and coronary inflammation have been reported72,74–76 and up to 64% of patients may require intensive pediatric care.77 The diagnosis of MIS-C requires evidence of active or previous infection with SARS-CoV-2 and must include ECG, blood tests, and imaging tests, with echocardiography recommended in all patients. In patients with suspected myocardial damage, CMR should be performed in the acute phase and at 1 to 6 months of follow-up in patients with an initial pathological CMR or with coronary aneurysms.67 The management of MIS-C includes respiratory and hemodynamic support in the most severe cases78 and involves drugs in most patients. The first-line immunomodulatory treatment includes IVIG and systemic corticotherapy, although it may require anakinra and tocilizumab.75 In addition, antiplatelet and antithrombotic therapy is used in selected patients. Antiviral agents are not currently recommended. Prognosis is favorable in most patients, although a mortality rate of 1% has been reported in patients with more severe symptoms.78

Vaccination against COVID-19 is approved for individuals aged 5 years or older, and the main scientific societies recommend systematic vaccination of the pediatric population.78,79

Myocarditis is one of the causes of sudden cardiac death in athletes.80 Accordingly, the initial reports of an elevated incidence of COVID-19-associated myocarditis in athletes raised strong concerns.27 However, more recent registries indicate that cases of myocarditis are rare in athletes who have had COVID-19 (0.4%).81,82

To decrease the risk of severe cardiac events after COVID-19, numerous protocols have been proposed to screen athletes before they resume training or competitive sports. In addition to achieving the safe resumption of sports activity, these protocols must avoid unnecessary limitations, so that athletes can restart their regular physical activity as soon as possible, given the major associated cardiovascular, metabolic, psychological, and emotional benefits.

The screening protocols after COVID-19 infection or vaccination against COVID-19 should be based on the severity of the clinical symptoms and the presence of cardiac symptoms. According to some of the current protocols,41,83 asymptomatic athletes or those with a less than 1-week history of mild noncardiac symptoms (fever, cough, odynophagia, general malaise, myalgia) do not require any tests to return gradually to sports activity as long as they are asymptomatic (excluding anosmia and ageusia) and have completed the required self-isolation. In these cases, and as for other common viruses, medical assessment is not necessary.84 However, athletes who have experienced cardiopulmonary symptoms (chest pain or tightness, palpitations, dyspnea, syncope, and presyncope) or have persistent (> 7 days) symptoms or who have required hospitalization with suspected cardiac involvement must always undergo medical assessment before resuming sports activity.41,83 In these cases, the evaluation should include ECG, echocardiography, and measurement of the hs-cTn and, in if there are pathological findings, confirmation with CMR.

If myocarditis is confirmed after COVID-19 infection or vaccination, moderate- or high-intensity physical exercise is not recommended for 3 to 6 months.85 Resumption of sports activity must be gradual, once the athlete is asymptomatic, with normal functional capacity and without arrhythmias on maximal cardiac stress testing and Holter-ECG (long-duration with a physical exercise session included) and without data on the residual involvement in CMR (preserved left ventricular ejection fraction and absence of edema and/or fibrosis).85 However, we recommend individual assessment of all patients and propose a specific follow-up.

The recommendations collected in the present document are summarized in table 1.