Study design and participants
This was a single-center prospective study conducted at the “Aghia Sofia” Children’s Hospital, Athens, Greece, which is the largest tertiary pediatric hospital in Greece and a reference center for pediatric heart disease. Children aged 0–16 years old with a diagnosis of MIS-C, who were admitted to the hospital from January 01, 2021, to September 30, 2022, were included in the study. All study participants fulfilled the Centers for Disease Control and Prevention (CDC) and/or the World Health Organization Criteria (WHO) MIS-C criteria [24, 25].
Patient information such as demographic (age, gender) and clinical (comorbidities, heart rate, clinical presentation, Intensive Care Unit admission, treatments, outcome) data were obtained. In addition, the following laboratory data were recorded: complete blood count, inflammation markers including C-reactive protein (CRP), procalcitonin, ferritin and cardiac biomarkers, including high sensitivity (hs)-Troponin T (cut-off level = 14 pg/mL) and N-terminal prohormone of B-type Natriuretic Peptide (NT-proBNP). The cut-off level of NT-proBNP was determined according to published normal reference values per age [26]. Upon admission, children underwent a comprehensive echocardiographic assessment with conventional as well as strain measurements. The echocardiographic assessment was repeated at the follow-up period.
Echocardiographic Examination
A. Conventional Echocardiography
Transthoracic 2D Echocardiographic examination was performed by two experienced pediatric cardiologists, using the Vivid E90 and Vivid E7 Ultrasound System (GE HealthCare, Chicago, IL, USA), according to the guidelines and standards for performing a pediatric echocardiogram of the American Society of Echocardiography [27]. The following echocardiographic parameters were recorded: aortic dimension, left atrial diameter, pulmonary artery diameter, left ventricular diastolic diameter and left ventricular systolic diameter. The LVEF and the Fractional Shortening (FS) were calculated by M Mode measurements. LVEF over 55% (LVEF ≥ 55) and FS from 28–46% were considered normal [28]. Parameters of the coronary arteries like left coronary diameter, right coronary diameter, left circumflex and left anterior descending branch were also measured. In accordance with the American Heart Association guidelines for KD, classification of CAA was performed based on the Z-score system as following: no coronary involvement (Z-score: always < 2), dilation only (Z-score: 2 to < 2.5 or if initially < 2, an ≥ 1 decrease in Z-score during follow-up), small aneurysm (Z-score: ≥2.5 to < 5), medium aneurysm (Z-score: ≥5 to < 10 and absolute dimension < 8 mm) and large or giant aneurysm (Z-score: ≥10 or absolute dimension ≥ 8 mm) [29].
Diastolic function was assessed with the use of Pulsed Wave (PW) Doppler and Tissue Doppler Imaging (TDI). The parameters early (E) and late (A) peak mitral inflow velocity and E/A ratio, were calculated by PW Doppler [30]. TDI was used to calculate e prime (e’) in the septal and lateral aspect of the left heart and subsequently the E/e' ratio was calculated [31].
B. Speckle-tracking Echocardiography (STE)
In parallel, longitudinal strain (LS) analysis of the left ventricle, by STE, was performed real time, using the GE Automated Function Imaging (AFI) Software (GE Healthcare, Chicago, IL, USA). Specifically, echocardiography loops were selected from the most appropriate apical 4-, 3- and 2- Chamber (C) views [32]. Subsequently, a line was loosely traced along the endocardium of the left ventricle [32]. The software selected acoustic markers which followed the myocardial movement [32]. The contractility in the area selected was measured by automatic frame-by-frame tracking of these markers [32]. Global Longitudinal Strain (GLS) and GLS rate were calculated for the entire trail of the myocardium of the left ventricle (basal, mid, and apical segments of 2 opposite walls in each view) [32]. As per published literature, GLS values >-18% indicated reduced systolic function [11, 33].
Ethical issues
The study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from the participants parents. The study protocol was approved by the scientific and bioethics committee of “Aghia Sophia” Children's Hospital (No 5893).
Statistical analysis
Absolute and relative frequencies (%) were used to describe the qualitative variables such as demographics and categorized variables (normal vs. abnormal). Mean, Standard Deviation (SD), median, and interquartile range (IQR) were used for quantitative data. Differences between paired samples were assessed using paired t-test or Wilcoxon Singed Ranks Test, respectively for normal and non-normal data. McNemar test was used for associations between baseline and follow-up measurements for categorized data. The assumption of normality was checked through kurtosis and skewness. The statistical significance level was set at p-value ≤ 0.05. Statistical analysis was performed using SPSS version 26.0 (IBM Corp., Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp). Results
Patients’ baseline characteristics
In the present study, a total of 25 children diagnosed with MIS-C were included. The mean (± SD) age of the children was 8.53 (± 3.66) years. Among the study participants, 16/25 (64%) were females and 9/25 (36%) were males. The baseline demographic, clinical and laboratory characteristics of the study population are presented in Table 1.
Table 1
Descriptive statistics of demographic and clinical characteristics, and laboratory measurements in children diagnosed with MIS-C
Age (years) | 8.53 ± 3.66 |
Gender female* | 16 (64) |
Underlying Comorbidities* | 3 (12) |
Symptoms* |
Fever | 25 (100) |
Gastrointestinal Symptoms | 21 (84) |
Cardiovascular Involvement | 20 (80) |
Mucocutaneous Involvement | 16 (64) |
Respiratory Symptoms | 8 (32) |
Neurocognitive Symptoms | 4 (16) |
Treatment* |
IVIG | 25 (100) |
Corticosteroids | 24 (96) |
Aspirin | 11 (44) |
Biologic Agents (Anakinra) | 6 (24) |
Antibiotics | 22 (88) |
PICU admission* | 14 (56) |
Mortality* | 0 (0) |
Complete Blood Count in the acute phase |
Haemoglobin (g/dL) | 10.78 ± 1.13 |
White blood cells (103 cells/µL) ‡ | 11.64 (7.40) |
Neutrophils (103 cells/µL) | 10.15 ± 5.50 |
Lymphocytes (103 cells/µL)‡ | 1.28 (1.09) |
Platelets (103 cells/µL) | 266.68 ± 131.26 |
Inflammatory markers in the acute phase |
CRP (mg/L) | 74.93 ± 61.68 |
Procalcitonin (µg/L)‡ | 1.04 (1.28) |
Ferritin (µg/L)‡ | 347.00 (748.00) |
Cardiac enzymes in the acute phase |
hs-Troponin (pg/mL)‡ | 8.07 (14.52) |
NT-proBNP (pg/mL)‡ | 2875.00 (7713.00) |
Notes: Values are referred to as: mean ± standard deviation (SD), ‡median (interquartile range) or *absolute frequencies (relative frequencies, %). |
Abbreviations: MIS-C; Multisystem Inflammatory Syndrome in children after COVID-19, IVIG; Intravenous Immune Globulin, PICU; Pediatric Intensive Care Unit, CRP; C-reactive protein, hs-Troponin; high sensitivity Troponin, NT-proBNP; N-terminal prohormone of brain natriuretic peptide.
Most of the children that participated in the study (22/25, 88%) were previously healthy (Table 1). Three children had underlying comorbidities. Specifically, one child had ventricular septal defect and a bicuspid aortic valve, another child had a history of transfusion-dependent homozygous beta-thalassemia, and a third child was diagnosed with Noonan’s syndrome without cardiac manifestations.
The most common symptom in our cohort of MIS-C patients was fever (25/25, 100%), followed by gastrointestinal symptoms (21/25, 84%). Cardiovascular involvement was also frequent, as it was observed in 20 out of 25 participants (80%). In the acute phase, the most common treatments were Intravenous Immunoglobulin (IVIG) (25/25, 100%) and corticosteroids (24/25, 96%). Most children also received antibiotics (22/25, 88%), while 11 out of 25 (44%) received aspirin and 6 out of 25 (24%) were treated with the biological agent Anakinra. Admission to the pediatric ICU was required in 14 out of 25 children (56%). No death was reordered in our cohort and all MIS-C patients recovered (Table 1).
On admission, serum concentrations of inflammatory markers were elevated in the majority of the participants. Specifically, mean CRP (± SD) was 74.93 ± 61.68 mg/L and most participants (19/25, 76%) had raised levels of CRP. The median (IQR) serum concentration of ferritin was 347.00 (748.00) μg/L and the median (IQR) Procalcitonin was 1.04 (1.28) μg/L (Table 1).
Regarding the cardiac biomarkers, on admission, median (IQR) hs-Troponin was 8.07 (14.52) pg/mL and hs-Troponin was elevated in 7 out of 25 participants (28%). Median (IQR) NT-proBNP was 2875.00 (7713.00) pg/mL and most of the participants (20/25, 80%) had NT-proBNP concentrations above the cut-off level (Table 1).
Cardiological Assessment
MIS-C patients underwent cardiological evaluation upon admission and at a follow-up of a mean (±SD) of 285.16 (±137.93) days (range:1.20-18.56 months). In a subset of patients (14/25), in parallel with conventional 2D-Echocardiography measurement, LV-GLS measurement was also obtained at admission and at a follow-up of a median of 208 (110) days (range:5.3-18 months). The findings of Heart rate measurement, conventional 2D Echocardiography and STE with LV-GLS analysis are presented in Table 2.
Table 2: Heart Rate and Echocardiographic findings of Standard Two- Dimensional Echocardiography and Speckle-Tracking Echocardiography with Left Ventricle Global Longitudinal Strain analysis on admission and on the follow-up period of children diagnosed with MIS-C
Parameters
|
Admission
|
Follow-up
|
p-value
|
Heart Rate (bpm)
|
102.87 ± 22.96
(n=15)
|
90.00 ± 14.56
(n=15)
|
0.017 a
|
Standard Echocardiography
|
LVEF (%)‡
|
66.00 (8.00)
(n=25)
|
66.00 (6.70)
(n=25)
|
0.345 b
|
Number of children (%)* with normal LVEF
|
23/25 (92.0%)
(n=25)
|
25/25 (100%)
(n=25)
|
-
|
SV (mL) ‡
|
51.40± 22.58
(n=5)
|
49.20 ± 13.22
(n=5)
|
0.776 a
|
FS (%)‡
|
35.50 (7.00)
(n=21)
|
36.00 (6.00)
(n=21)
|
0.601 b
|
Speckle-Tracking Echocardiography
|
GLS (%)
|
-18.02 ± 4.40
(n=14)
|
-20.31 ± 1.91
(n=14)
|
0.070 a
|
Portion of children (%)*
with normal GLS
|
8/14 (57.1%)
|
13/14 (92.9%)
|
0.063 c
|
|
|
|
|
|
Notes: Values are referred to mean ± standard deviation (SD), ‡median (interquartile range) or *absolute frequencies (relative frequencies, %). P-value obtained after: a paired samples t-test, b Wilcoxon Singed Ranks Test, c McNemar test.
Abbreviations: MIS-C; Multisystem Inflammatory Syndrome in children after COVID-19, bpm; beats per minute, LVEF; Left Ventricle Ejection Fraction, SV; Stroke Volume, FS; Fractional Shortening, GLS; Global Longitudinal Strain.
Findings on admission
Upon admission, the mean (±SD) heart rate was 102.87 (± 22.96) beats per minute (bpm) (n=15). Regarding the assessment of systolic heart function with conventional 2D Echocardiography, upon admission, median (IQR) LVEF was 66.00 (8)% and only in two participants out of 25 (9.5%) the LVEF was less than 55%. The mean SV (n=5) was 51.40 (± 22.58) mL and median (IQR) FS (n=21) was 35.50 (7.00)% (Table 2). FS was normal in 20 out of 21 participants (95.2%) (FS normal range: 28-46%). In addition, diastolic function was also assessed with the use of conventional echocardiography and in all the participants that measurements were obtained, E/e’ was normal (8/8, 100%). In one case (1/9, 11.1%), the E/A ratio was less than 1, indicating mild diastolic dysfunction.
Most of the patients that where assessed had to some extent valvular insufficiency. Specifically, 15 out of 16 patients (93.75%) had mild mitral regurgitation and one participant had moderate mitral regurgitation. Additionally, 15 out of 16 patients had mild tricuspid regurgitation (93.75%). Finally, on the acute setting, only one child (1/18, 5.5%) had developed coronary artery dilation which eventually resolved on follow-up.
In parallel, in a subset of the participants (n=14), systolic heart function was also assessed with STE with LV-GLS analysis. On admission, mean (±SD) LV-GLS was -18.02 (± 4.40)%. LV-GLS was abnormal (>-18) in 6/14 (42.9%) cases (Table 2). Among the six patients that had impaired LV-GLS, five patients had preserved LVEF.
Findings on follow-up
During the long-term follow-up, mean heart rate was statistically significantly lower at 90.00 (± 14.56) bpm, than on admission (p-value=0.017). Median (IQR) LVEF was 66.00 (6.70)% Mean (±SD) SV was 49.20 (±13.22) mL and median (IQR) FS was 36.00 (6.00)%. The differences in the FS and SV measurements were not statistically significant at follow-up compared to admission (Table 2). On follow-up, LVEF and FS were normal in all the participants that were measured (25/25, 100% and 21/21, 100%, respectively). Regarding the diastolic heart function, all participants that were evaluated for diastolic dysfunction, had normal E/A ratio and E/e’ (>1 and <14 respectively) (20/20, 100% and 18/18, 100% respectively).
As for valvular dysfunction, 7 out of 23 (30.4%) patients were diagnosed with mild mitral regurgitation. Regarding the tricuspid valve, 17 out of 23 (73.91%) patients were diagnosed with tricuspid regurgitation.
In the subset of participants (n=14), in which LV-GLS analysis was performed, on follow up, mean (±SD) LV-GLS was -20.31 (±1.91)% (p-value=0.07). LV-GLS returned to normal in most of the participants, that had abnormal GLS in the acute setting (Figure 1), (p-value=0.063). Only in one patient (1/14, 7.1%) LV-GLS was abnormal on follow-up, despite the presence of normal LVEF (Table 2). The evolvement of LV-GLS impairment of a patient with MIS-C, from the acute phase until a seven-month follow-up, is presented in Figure 1.