Age-adjusted NT-proBNP could help in the early identification and follow-up of children at risk for severe multisystem inflammatory syndrome associated with COVID-19 (MIS-C)

Table 1 World Health Organization case definition for Multisystem inflammatory syndrome in children

All criteria must be met
Age 0 to 19 yr
Fever ≥ 3 d
Clinical signs of multisystem involvement (at least 2 of the following):
Rash, bilateral non purulent conjunctivitis, or mucocutaneous inflammation (oral, hands, or feet)
Hypotension or shock
Cardiac dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin/BNP)
Evidence of coagulopathy (prolonged PT or PTT; elevated D-dimer)
Acute gastrointestinal symptoms (diarrhea, vomiting, or abdominal pain)
Elevated markers of inflammation (e.g., ESR, CRP, or procalcitonin)
No other obvious microbial cause of inflammation, including bacterial sepsis and staphylococcal/streptococcal toxic shock syndromes
Evidence of SARS-CoV-2 infection with any of the following:
Positive SARS-CoV-2 RT-PCR
Positive serology
Positive antigen test
Contact with an individual with COVID-19 either laboratory confirmation of SARS-CoV-2 infection by RT-PCR, serology, or antigen test, or known COVID-19 exposure within 4 weeks before symptom onset

MIS-C: Multisystem inflammatory syndrome in children; PT: Prothrombin time; PTT: Partial thromboplastin time; ESR: Erythrocyte sedimentation rate; CRP: C reactive protein; RT-PCR: Real time polymerase chain reaction; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 2 Demographic data and clinical presentation of the study population

N = 17	Results
Age (yr)2	3 (2-9)
Weight (kg)2	17 (12-34)
Gender (male)1	9 (53)
Ethnicity (white)1	14 (82)
Comorbidity1	1 (6)
Known previous COVID-19 disease (4-8 wk before)1	4 (24)
Contact with known COVID-19 case1	7 (41)
IgG antibodies to SARS-CoV-21	15 (88)
SARS-CoV-2 RT-PCR positive test1	7 (41)
Fever1	17 (100)
Days of fever2	4 (3-4)
Cutaneous rash1	7 (41)
Conjunctivitis1	7 (41)
Lymphadenopathy1	5 (29)
Palmar or plantar erythema1	3 (17)
Changes in oral mucosa1	6 (35)
Respiratory symptoms1	3 (17)
Hypoxemia1	2 (12)
SpO2 (%)2	98 (97-99)
Gastrointestinal symptoms1	10 (58)
Neurological symptoms1	3 (17)
Heart failure (age-based Ross score > 5)1	11 (65)
Cardiogenic/Vasoplegic shock1	3 (17)
Tachycardia1	13 (76)
Heart rate (bpm)2	150 (120-160)
Hypotension1	4 (23)
Systolic arterial pressure (mmHg)2	97 (75-106)
Diastolic arterial pressure (mmHg)2	60 (40-68)

¹Data presented in frequency and percentage.

²Data presented in median and interquartile range.

IgG: Immunoglobulin G; RT-PCR: Real-time polymerase chain reaction; SpO2: Oxygen saturation; bpm: Beats per minute; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 3 Baseline laboratory and echocardiographic data of the study population

N = 17	Results
Leukocytes (/µL)2	9930 (83490-12250)
Leukocytosis1	4 (23)
Lymphocytes (/µL)2	1480 (680-3100)
Lymphopenia1	9 (53)
Hemoglobin (g/dL)2	10.7 (8-12.2)
Anemia1	8 (47)
Thrombocytes (/µL)2	161000 (120000-238000)
Thrombocytopenia1	5 (29)
Dimer D (ng/mL)2	3504 (3284-5290)
Coagulopathy1	7 (41)
CRP (mg/L)2	171 (121-201)
Procalcitonin (ng/mL)2	3.2 (1.4-10.2)
Ferritin (ng/mL)2	789 (552-978)
Creatinine (mg/dL)2	0.5 (0.4-0.57)
Urea (mg/dL)2	23 (19-31)
AKI1	2 (11)
Sodium (mEq/L)2	134 (131-137)
Hyponatremia1	8 (47)
GPT (U/L)2	40 (25-66)
Hypertransaminemia1	6 (35)
pH2	7.37 (7.34-7.4)
pCO2 (mmHg)2	37 (33-39)
HCO3 (mmol/L)2	23 (21-24)
Acidosis1	4 (23)
NT-proBNP (pg/mL)2	5221 (2638-10020)
NT-proBNP (Z-log value adjusted for age)2	4.62 (4.46-5.23)
High NT-proBNP (Z-log for age > 2)1	17 (100)
Very high NT-proBNP (Z-log for age > 4)1	12 (71)
hs-TnI (ng/L)2	35 (10-116)
High hs-TnI (> 50 ng/L)1	5 (29)
LVEF (%)2
LV dysfunction, n (%)1
Maximal CA diameter (Z-score)2
CA dilation1

¹Data presented in frequency and percentage.

²Data presented in median and interquartile range.

CRP: C reactive protein; AKI: Acute kidney injury; NT-proBNP: N-Terminal Pro-Brain Natriuretic Peptide; Hs-TnI: High Sensitivity-Troponin I; LVEF: Left ventricle ejection fraction; LF: Left Ventricle; CA: Coronary artery.

Table 4 Treatment and clinical outcomes of the study population

N = 17	Results
IVIG1	14 (82)
Steroids1	16 (94)
Aspirin1	15 (88)
LWH1	3 (17)
Anakinra1	3 (17)
Tocilizumab1	1 (6)
Antibiotics1	15 (88)
Diuretics1	10 (53)
Beta blockers1	6 (35)
ACEIs1	6 (35)
Antiarrhythmics1	0 (0)
Oxygen (nasal cannula)1	2 (11)
CPAP1	1 (6)
Mechanical ventilation1	1 (6)
Inotropics1	7 (41)
ECMO1	0 (0)
Resistance to immunomodulatory therapy1	4 (23)
PICU admission1	7 (41)
PICU stay (days)2	3.5 (3-4.5)
LOS hospitalization (days)2	7 (5-10)
Heart failure at discharge1	1 (6)
Myocardial dysfunction at discharge1	1 (6)
Coronary artery dilation at discharge1	2 (11)
Raised hs-TnI or NT-proBNP at discharge1	9 (53)
Cardiac medications at discharge1	8 (47)
Any cardiac sequelae or medications at 1 month follow-up1	0 (0)
Death1	0 (0)

¹Data presented in frequency and percentage.

²Data presented in median and interquartile range.

IVIG: Intravenous immunoglobulin; LWH: Low molecular weight heparin; ACEis: Angiotensin-converting enzyme inhibitors; CPAP: Continuous positive airway pressure; ECMO: Extracorporeal membrane oxygenation; PICU: Pediatric intensive care unit; LOS: Length of stay; Hs-TnI: High sensitivity-troponin I; NT-proBNP: N-Terminal pro brain natriuretic peptide.

Table 5 Dynamics of cardiac parameters during the follow-up in this study. Comparison between groups regarding duration of respiratory support

Cardiac parameter	Admission	24 h after AIT	Discharge	After 1-mo fu.
NT-proBNP (Z-log value adjusted for age)2	4.62 (4.46-5.23)	3.78 (3.26-4.87)1	1.79 (0.66-2.5)1	0.72 (0.21-1.29)1
Log (10)-Hs-TnI (ng/L)2	35 (10-116)	13 (5-35)1	10 (10-13)1	10 (10-10)
LVEF (%)2	58 (48-65)	68 (65-70)1	70 (66-72)	70 (68-71)
Coronary arteries maximal dimension (Z-score for BSA)2	1.39 (0.56-2.66)	1.2 (0.77-1.5)	1 (0.5-1.2)1	0.8 (0.51-1.2)
Age-based Ross classification for heart failure in children2	8 (4-12)	3 (2-7)1	0 (0-0)1	0 (0-0)

¹P value < 0.05 for Wilcoxon sign rank test comparing the indicated value with the value in the previous time (its left column).

²Data presented in median and interquartile range.

NT-proBNP: N-Terminal pro-brain natriuretic peptide; Hs-TnI: High sensitivity-troponin I; LVEF: Left ventricle ejection fraction; BSA: Body surface area.

Table 6 Comparison of clinical, laboratory and echocardiographic characteristics according to the need of pediatric intensive care unit admission and inotropic support during hospitalization

Variable	PICU admission (n = 7; 41%)	No PICU admission (n = 10; 59%)	P value
Age (mo)2	6 (1-12)	2.5 (2-8)	NS.
Male sex1	8 (53)	14 (56)	NS.
Weight (kg)3	5 (71)	4 (40)	NS.
Days of fever2	4 (2-5)	4 (3-4)	NS.
Age-based Ross score2	16 (11-19)	4 (2-8)	0.003
Lymphocytes (/µL)2	1240 (720-5940)	1552 (1260-3100)	NS.
CRP (mg/L)2	171 (120-237)	167 (131-201)	NS.
Procalcitonin (ng/mL)2	3.6 (1.3-21.6)	2.5 (1.4-8.8)	NS.
Ferritin (ng/mL)2	814 (552-2789)	750 (517-878)	NS.
Dimer D (ng/mL)2	3436 (2461-9434)	4728 (3284-5290)	NS.
NT-proBNP (Z-log for age)2	5.41 (4.62-6.51)	4.48 (4-5)	0.016
Troponin I (ng/L)2	40 (10-909)	27 (10-43)	NS.
LVEF (%)2	48 (45-65)	62.5 (57-67)	0.034
Maximal CA diameter (Z-score)2	1.2 (0.55-1.4)	1.5 (0.5-3)	NS.

¹Data presented in frequency and percentage.

²Data presented in median and interquartile range.

³Data presented in mean and standard deviation.

CRP: C reactive protein; NT-proBNP: N-Terminal Pro-Brain Natriuretic Peptide; LVEF: Left ventricle ejection fraction; CA: Coronary artery; PICU: Pediatric intensive care unit; NS. (P > 0.05).

Table 7 Correlation analysis of the relationship between N-terminal pro-brain natriuretic peptide and all the cardiac continuous variables explored in this study

NT-proBNP (Z-log value adjusted for age)	Correlation coefficient	P value
hs-TnI (ng/L)	0.47	0.045
Age-based Ross score for heart failure	0.76	0.003
LVEF (%)	-0.55	0.021
Maximal CA diameter	-0.21	NS.

NT-proBNP: N-Terminal Pro-Brain Natriuretic Peptide; Hs-TnI: High sensitivity-troponin I; LVEF: Left ventricle ejection fraction; CA: Coronary artery; NS. (P > 0.05).