Myocarditis is defined as inflammation of the myocardium characterized by cardiomyocyte necrosis and diagnosed by using established clinical and immunohistologic criteria. Infectious agents have been identified as the most frequent etiologic factors, but myocarditis may also accompany autoimmune diseases, hypersensitivity reactions, or toxins. Previously, enteroviruses were the primary viral agent, but nowadays, adenoviruses and parvovirus B-19 are the most frequent causes of infective myocarditis.1 The cardiotropism of coronaviruses (CoV) and acute myocarditis (AM) induced by CoV have been described in previous literature. During the novel CoV disease-19 (COVID-19) pandemic, data from the literature revealed myocardial injuries caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2–6 Cardiac involvement in COVID-19 leads to elevation of at least one cardiac biomarker and is associated with a worse prognosis.7,8 Myocardial injury can occur due to the effects of direct viral-mediated cytopathy and cardiomyocyte necrosis on the angiotensin convertase enzyme 2.9 Indirect myocardial damage in COVID-19 caused by hyperinflammation and cytokine storms triggered by SARS-CoV-2, hypoperfusion, β-adrenergic overstimulation, thrombosis and thromboembolism has previously been identified, along with lung injury and subsequent hypoxia increasing cardiac stress and leading to heart damage.9
In rare cases, children might develop pediatric inflammatory multisystem syndrome associated with SARS-CoV-2 (PIMS-TS) or multisystem inflammatory syndrome in children (MIS-C) temporally associated with COVID-19, 3–4 weeks after experiencing symptomatic or asymptomatic COVID-19. In 1 report, the incidence of MIS-C was 2 per 100,000. While many children with MIS-C met the criteria for complete or incomplete Kawasaki disease (KD), most of the cases of MIS-C occurred in older children and adolescents. In comparison to KD, myocardial injury is frequent during MIS-C.6–8,10 Heart damage was described in 30%–40% of patients with MIS-C.11
Our study aims to compare the clinical presentation, laboratory and echocardiographic parameters, treatment, clinical course, and outcomes of AM related and unrelated to SARS-CoV-2.
MATERIAL AND METHODS
A retrospective study included children under the age of 18 with AM treated at the Mother and Child Health Care Institute from January 2018 to November 2020. The diagnosis of AM was made based on the criteria of the European Society of Cardiology (ESC); the diagnosis of MIS-C temporally associated with COVID-19 was based on the criteria of the US Centers for Disease Control and Prevention.8,12,13 We divided the patients into 2 groups depending on whether their AM was related or unrelated to SARS-CoV-2: AM unrelated to SARS-CoV-2 and AM related to SARS-CoV-2. Children with positive antibodies or a polymerase chain reaction (PCR) to SARS-CoV-2 or COVID-19 exposure within the previous 4 weeks before symptom onset were classified into the group with AM related to SARS-CoV-2. The other patients were classified into the group with AM unrelated to SARS-CoV-2. The groups were compared according to clinical presentation, laboratory and echocardiography parameters, ECG, clinical course and disease outcome.
Patients were treated according to the protocol for AM and MIS-C.8,12,13 The impact of the therapy applied was analyzed by a control laboratory analysis and echocardiography examination on the third day in hospital and at discharge. In all patients, a PCR test was performed to detect cardiotropic viruses in the blood sample and a nasopharyngeal swab. During the SARS-CoV-2 pandemic, a serologic examination for SARS-CoV-2 was performed using the enzyme-linked immunosorbent assay technique and the immunochromatography technique.
Statistical Analysis
The data was processed using the statistical software SPSS 25.0 for Windows 10. All statistical methods were considered significant if the P-value was ≤0.05. The descriptive statistics included the mean values, median, SDs, and the interquartile range (IQR) of the parameters monitored. The difference in the distribution of specific parameters among the groups tested was determined using the χ2 or Fisher’s test. The normality of the distribution of the numerical variables was tested using the Shapiro-Wilk and Kolmogorov-Smirnov tests. The comparison between the groups was made using the Student’s t test and the Mann-Whitney U test. Paired T-tests and Wilcoxon tests were used to compare 2 related samples. Binominal logistic regression analysis was used to explain the relationship between the dependent binary variable and the independent variables.
RESULTS
The retrospective study included 24 patients, 18 boys and 6 girls, with an average age of 11.8 ± 6.5 years. Seven patients had AM related to SARS-CoV-2. In 5 of 7 patients, neutralizing SARS-CoV-2 antibodies were detected, and in 2 of 7 patients, the virus was isolated by the RT-PCR technique in a nasopharyngeal swab. In 8 of 17 patients with AM unrelated to SARS-CoV-2, cardiotropic viruses were isolated in a blood sample (2 EBV, 2 enterovirus, 2 Parvo B-19, 1 HHV6, 1 CMV). All patients with AM related to SARS-CoV-2 were older than 7, while 6 of 17 patients with AM unrelated to SARS-CoV-2 were older than 7 (P = 0.006).
Children with AM related to SARS-CoV-2 had higher body temperatures than pre-pandemic patients (39.17 ± 1.27 °C vs. 37.6 ± 1.27 °C; P = 0.014). Patients with AM related to SARS-CoV-2 were more likely to have polymorphous cutaneous rash, conjunctival effusion, headache and abdominal pain (Fig. 1). The myocardial injury manifested on the fifth day of the acute illness (IQR 5–7) in patients with AM related to SARS-CoV-2, whereas the myocardial injury manifested on the fifth (IQR 2–5) day of the acute illness in patients with AM unrelated to SARS-CoV-2 (P = 0.02). Acute fulminant myocarditis occurred more frequently in patients with AM unrelated to SARS-CoV-2 than in AM related to SARS-CoV-2. MIS-C was diagnosed in 6 adolescents, while 2 of 6 had MIS-C shock. ECG abnormalities were observed in 17 of 24 patients (6 of 7 during the SARS-CoV-2 pandemic). Prolonged the corrected QT interval was registered in 6 of 24 children, all of whom had MIS-C (P < 0.001). On admission, the values of cTnI, creatine kinase MB (CK-MB), lactate dehydrogenase, SGOT and platelet count were higher in children with AM unrelated to SARS-CoV-2, while the C-reactive protein (CRP) value was higher in patients with AM related to SARS-CoV-2 (Table 1). No difference was observed between groups in the echocardiography parameters (Table 2). Segmental wall motions were more common in patients with AM unrelated to SARS-CoV-2 than in patients with AM related to SARS-CoV-2 (P = 0.05). Two patients with AM related to SARS-CoV-2 had increased diameters (z score > 2) of their coronary arteries (CA), whereas no CA dilatation was registered in patients before the COVID-19 pandemic (2 of 7; P = 0.07). Cardiac magnetic resonance imaging in 66.6% of patients with AM unrelated to SARS-CoV-2 showed late gadolinium enchantment in the acute phase; none of the patients with AM related to SARS-CoV-2 had positive late gadolinium enchantment in the acute phase.
TABLE 1. -
The Differences Between Laboratory Parameters in Patients With AM Related and Unrelated to SARS-CoV-2
|
SARS-CoV-2 |
Other |
P
|
| cTnI (ng/mL) |
0.14 (IQR 0.05–3.5) |
2.33 (IQR 0.77–11.1) |
0.012
|
| CK-MB (IJ/L) |
3 (IQR 2–8) |
27.0 (IQR 11.5–84.5) |
0.003
|
| CK (IJ/L) |
72.0 (IQR 45.0–135.0) |
195.5 (IQR 93.5–643.5) |
0.071 |
| SGOT (IJ/L) |
46.0 (IQR 16.0–68.0) |
56.0 (IQR 31.5–100.5) |
0.011
|
| SGPT (IJ/L) |
35.0 (IQR 15.0–64.0) |
23.0 (IQR 15.25–34.75) |
NS |
| LDH (IJ/L) |
434.0 (IQR 339.0–527.0) |
719.0 (IQR 595.25–1535.0) |
0.011
|
| NT-proBNP (pg/mL) |
3911.0 (IQR 596.0–>5000) |
944.0 (IQR 47.5–>5000) |
NS |
| CRP (mg/L) |
133.0 (IQR 46.5–208.0) |
18.0 (IQR 2.2–92.6) |
0.028
|
| WBC (109/L) |
9.2 (IQR 5.8–13.8) |
11.2 (IQR 9.7–14.6) |
NS |
| Plt (1012/L) |
126 (IQR 111.0–176.9) |
292.0 (IQR 250.5–371.5) |
<0.001
|
| Albumine (g/L) |
40 (IQR 32.0–44.0) |
41.0 (IQR 34.75–45.75) |
NS |
| Creatinine (μmol/L) |
73 (IQR 63.0–105.0) |
50.0 (IQR 35.5–76.5) |
0.001
|
| Na (mmol/L) |
133 (IQR 133.0–140.0) |
137.0 (IQR 134.0–140.0) |
0.08 |
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; Hgb, hemoglobin; LDH, lactate dehydrogenase; Na, sodium; NS, non significant; NT-proBNP, N-terminal-pro hormone BNP; Plt, platelet; WBC, white blood cells.
TABLE 2. -
The Differences Between Echoacrdiogarphic Parameters in Patients With AM Related and Unrelated to SARS-CoV-2
|
SARS-CoV-2 |
Admission |
Third day |
Discharge |
| Mean |
SD |
P
|
Mean |
SD |
P
|
Mean |
SD |
P
|
| EDD Z score |
Unrelated |
1.6 |
2.0 |
NS |
2.2 |
2.4 |
NS |
1.6 |
1.9 |
0.02 |
| Related |
0.6 |
0.9 |
0.7 |
1.1 |
−0.5 |
0.9 |
| ESD Z score |
Unrelated |
2.5 |
2.5 |
NS |
2.0 |
3.8 |
NS |
1.7 |
2.6 |
NS |
| Related |
2.2 |
1.1 |
0.9 |
1.2 |
−0.2 |
0.7 |
| IVSd Z score |
Unrelated |
1.4 |
0.8 |
NS |
2.0 |
1.3 |
NS |
1.0 |
0.5 |
NS |
| Related |
1.2 |
0.4 |
1.1 |
0.5 |
1.3 |
0.5 |
| PWd Z score |
Unrelated |
1.6 |
1.1 |
NS |
2.1 |
0.6 |
NS |
1.9 |
1.1 |
NS |
| Related |
1.3 |
0.7 |
1.4 |
0.7 |
1.5 |
0.7 |
| EF (%) |
Unrelated |
52.7 |
14.7 |
NS |
50.3 |
15.4 |
NS |
55.9 |
16.4 |
NS |
| Related |
48.9 |
9.8 |
60.8 |
6.5 |
67.4 |
4.6 |
| FS (%) |
Unrelated |
27.3 |
9.6 |
NS |
31.2 |
11.1 |
NS |
31.6 |
11.4 |
NS |
| Related |
24.7 |
6.1 |
32.8 |
5.5 |
36.8 |
3.1 |
EDD indicates end-diastolic diameter; EF, ejection fraction; ESD, end-systolic diameter; FS, fraction of shortening; IVSd, intraventricular septal diastolic diameter; NS, non significant; PWd, posterior wall diastolic diameter.
;)
FIGURE 1.: The clinical manifestations of pediatric AM related and unrelated to SARS-CoV-2.
The medications used to treat the AM in both groups are presented in Table 3. Inotropic drug support was used for shorter durations in patients with AM related to SARS-CoV-2 (4, IQR 2–5.5) than in children with AM unrelated to SARS-CoV-2 (8, IQR 6.25–12; P = 0.02). Mechanical respiratory support was only required by patients with AM unrelated to SARS-CoV-2 (41.2%) (P = 0.04).
TABLE 3. -
The Medications Used to Treat the
Pediatric AM Related and Unrelated to SARS-CoV-2
|
Unrelated to SARS-CoV-2, n (%) |
Related to SARS-CoV-2, n (%) |
P
|
| Furosemide/spironolactone |
10 (58.8) |
6 (85.7) |
0.35 |
| ACE inhibitors |
12 (70.6) |
6 (85.7) |
0.36 |
| Aspirin |
6 (35.3) |
6 (85.7) |
0.07 |
| Immunomodulatory drugs |
|
|
|
| IVIG |
9 (52.9) |
5 (71.4) |
0.65 |
| CS |
8 (47.1) |
3 (42.8) |
1.0 |
| Inotrope drugs |
|
|
|
| Dopamine |
6 (35.3) |
3 (42.8) |
1.0 |
| Milrinone |
8 (47.1) |
4 (57.1) |
1.0 |
| Low-molecular weight heparin |
3 (17.6 |
5 (71.4) |
0.02 |
ACE indicates angiotensin convertase; CS, corticosteroids.
The analysis showed that children with AM unrelated to SARS-CoV-2 had a significant reduction in their cardiomyocytolisis markers [cTnI, and creatine kinase MB (CK-MB)]. A significant reduction of CRP, cTnI, N-terminal-pro hormone BNP and creatinine value was observed in children with AM related to SARS-CoV-2, while the platelet counts and albumin level gradually increased (Fig. 2).
FIGURE 2.: The changes of the laboratory parameters in children with AM related and unrelated to SARS-CoV-2. NT-proBNP indicates N-terminal-pro hormone BNP.
We identified that patients with AM related to SARS-CoV-2 had a significant reduction in their end-diastolic diameter and end-systolic diameter Z scores during their inpatient treatment. Additionally, children with AM related to SARS-CoV-2 had significant improvement of left ventricle (LV) systolic function on the third day in hospital (Fig. 3). In patients with AM unrelated to SARS-CoV-2, no statistically significant improvement of the echocardiographic parameters being tracked was observed. On discharge, CAs were of appropriate diameter.
FIGURE 3.: The changes of the echocardiographic parameters in children with AM related to SARS-CoV-2. EDD indicates end-diastolic diameter; EF, ejection fraction; ESD, end-systolic diameter; FS, fraction of shortening; NS, non significant.
The intensive care unit stay lasted 9.5 days (IQR 9.5–13.7) in the group with AM unrelated to SARS-CoV-2 group, and 8 days (IQR 4.5–11.5) in the group with AM related to SARS-CoV-2 (P = non significant). Inpatient treatment lasted 10 days (IQR 8–19.5) in the group with AM unrelated to SARS-CoV-2 and 13 days (IQR 8–17) in SARS-CoV-2 patients (P = non significant). During the inpatient treatment, 24-hour ECG Holter monitoring in 3 patients showed a ventricular rhythm disturbance: 1 patient with AM related to SARS-CoV-2 had premature ventricular contractions (bigeminy) and 2 patients with AM unrelated to SARS-CoV-2 had ventricular tachycardia (1 non-sustained and 1 sustained). In 7 patients with AM unrelated to SARS-CoV-2, adverse events were observed (3 patients died, and 4 of 17 developed dilated cardiomyopathy [DCM]), while none of the patients had adverse events during the pandemic (P = 0.04). Patients with acute fulminant myocarditis (AFM) had increased risk of developing DCM (odds ratio 48, 95% confidence interval 2.3–977.2; P = 0.01).
DISCUSSION
In pediatric patients with myocarditis, a broad spectrum of clinical presentations was observed, ranging from asymptomatic to severe acute heart failure, and sudden death.1,12 Chest pain is a typical symptom of myocardial necrosis, frequently present in patients with AM unrelated to SARS-CoV-2, while abdominal pain occurred often in patients with AM related to SARS-CoV-2. Notwithstanding the fact that heterogeneous clinical presentation is common in pediatric myocarditis, patients with AM related to SARS-CoV-2 were more likely to have atypical signs similar to KD, such as polymorphous cutaneous rash, and bilateral conjunctival effusion. These symptoms suggest the presence of a systemic inflammatory response induced by SARS-CoV-2. The incidence of atypical or classic KD increased during the SARS-CoV-2 pandemic, but children with KD-like during the pandemic were older and displayed digestive and neurologic symptoms, shock and myocardial involvement more frequently.10 Consequently, this condition was identified as KD-like, MIS-C or PIMS and presented 3–4 weeks after COVID-19 in a genetically susceptible child.7,8 In our study, 6 of 7 of those with AM related to SARS-CoV-2 had MIS-C. Five of 6 children had positive neutralizing antibodies, so the MIS-C is interpreted as a delayed, postinfectious and immune-mediated complication of the primary disease. Additionally, one of the triggers of KD is the development of immune complexes in the circulation.2 Because of this and the fact that most of the children had positive antibodies, it could be concluded that the formation of immune complexes might play a role in the development of myocardial inflammation during MIS-C. Circulating immune complexes induce endothelial injury, vasculitis, and activation of complement and coagulation cascades, producing immune-mediated inflammation, hypoxia and thrombosis.2,7,14,15
Some patients with SARS-CoV-2 who had AFM had a different outcome.15,16 AFM was observed in 7 of 24 patients in our study, but only in patients with AM unrelated to SARS-CoV-2 (41.2%). The risk of DCM rose 48-fold in patients with AFM. The prevalence of shock in MIS-C is 32%–76%, while in our study, 33.3% of patients had shock syndrome.10,11
Arrhythmic myocarditis may present with a spectrum of life-threatening brady- and tachyarrhythmias. Myocardial electrical instability most frequently presents as ventricular arrhythmias in male adolescents.17 Children with COVID-19 had less harmful arrhythmias, along with supraventricular tachycardia, premature atrial and ventricular complexes, and first-degree atrioventricular blocks.6 In our study, 2 patients with AM unrelated to SARS-CoV-2 had ventricular tachycardia, while 1 patient with AM related to SARS-CoV-2 had bigeminy. All of our patients with MIS-C had a prolonged the corrected QT interval, which could be a consequence of the inflammation and change in the activity of the ion channels.4
We showed that patients with AM related to SARS-CoV-2 had a higher CRP value, and lower serum markers of cardiomyocytolisis (cTnI, CK-MB, lactate dehydrogenase, SGOT) than the patients with AM unrelated to SARS-CoV-2. This could be a consequence of a mild cardiomyocyte necrosis in patients with MIS-C and COVID-19, with the cardiac injury resulting from the immune-mediated myocardial injury. During the inpatient treatment, cardiomyocytolisis markers gradually diminished in patients with AM unrelated to SARS-CoV-2. Additionally, we observed a significant reduction of CRP and the N-terminal-pro hormone BNP value in the group of patients with AM related to SARS-CoV-2 and an elevation of the platelet count. Patients with MIS-C had low albumin and sodium levels and elevated transaminases, similar to patients with KD. An increased capillary permeability in patients with KD might cause decreased albumin and sodium levels, which is used as a marker of severity in some prediction scores.14,18 Thrombocytopenia could result from a consumptive coagulopathy with raised D-dimers, as in the patients with KD.7,14
The most common echocardiographic finding associated with myocarditis is a DCM phenotype of LV, even though echocardiography is normal in some patients.1 Echocardiographic examination identified mild to moderate systolic LV dysfunction and dilated LV in both groups. Segmental wall motion abnormalities were frequently identified in patients with AM unrelated to SARS-CoV-2, while dilated CAs were common in patients with AM related to SARS-CoV-2. The incidence of CA abnormalities was 9%–24% in patients with MIS-C, but the pathologic mechanism has not been elucidated.7
Intravenous immunoglobulin (IVIG) therapy has antiviral and immunomodulating effects and is used in AM and KD,1,14,19,20 but the ESC did not recommend using IVIG to treat AM in patients with COVID-19 due to a lack of evidence.5 In 58.6% of patients, we prescribed IVIG therapy. In 1 patient with AM related to SARS-CoV-2, IVIG-resistance was observed, so we administered IVMP. According to the scoring system defined by Kobayashi et al, our patient was at high-risk of developing refractory KD.14
The clinical course of patients with myocarditis varies from partial or full clinical recovery in a few days to end-stage heart failure requiring mechanical and drug-circulating support or heart transplantation.1 Short use of inotropes and prompt recovery of LV systolic function was observed in patients with AM related to SARS-CoV-2; their ejection fraction and fraction of shortening had improved on the third day, immediately after the therapy was applied. This rapid recovery might be linked to immune-mediated myocardial inflammation with a mild cardiomyocytes necrosis, myocardial stunning or edema, caused by the cytokine storm and hyperinflammatory response to SARS-CoV-2 in genetically susceptible children. Data from the literature showed similar results to ours (median of 2 days from diagnosis to LV recovery).7 On discharge, all patients with AM related to SARS-CoV-2 had normal echocardiography results. No significant improvement was observed in the patients with AM unrelated to SARS-CoV-2. In fact, patients with AM unrelated to SARS-CoV-2 AM had more frequent adverse outcomes; 3 patients died during inpatient treatment, and 4 developed DCM. That can be explained by the more extensive cardiomyocyte necrosis in patients with AM in the pre-pandemic group.
CONCLUSIONS
We found the essential differences in clinical presentation, laboratory parameters, echocardiography finding, clinical course, and disease outcome in patients with AM related and unrelated to SARS-CoV-2. The short duration of acute illness, segmental wall motion abnormalities, markedly elevated cTnI and CK-MB, typical clinical manifestations, slow response to the therapy used, and the increased incidence of AFM and adverse outcomes suggest extensive cardiomyocyte degeneration in patients with AM unrelated to SARS-CoV-2.
The prolonged fever, along with strong indications of systemic inflammation in laboratory parameters, lower cardiomyocytolisis markers, myocardial injury, similar clinical presentation to atypical KD, positive neutralizing antibodies, short-term use of inotropes and prompt recovery of LV on the third day in hospital identified in patients with AM related to SARS-CoV-2 may underlie a possible new spectrum inflammatory disease that causes an immune-mediated myocardial injury with mild cardiomyocyte necrosis and a favorable prognosis.
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