http://dx.doi.org/10.7775/rac.v91.i1.20597
ORIGINAL
ARTICLE
Multisystem Inflammatory Syndrome in Children: The Importance
of Early Evaluation of Laboratory Parameters
Síndrome inflamatorio multisistémico en pediatría:
importancia de la evaluación inicial de los parámetros de laboratorio
Julián Rodríguez Kibrik1, Mariana E. Cazalas1, María Lucila Petrillo1, Gonzalo G. Guiñazú1, Claudio Moros1, Hyon J. Choe1, Alejandro Goldsman1, María GrippoMTSAC,1, Ángela SardellaMTSAC,1, Silvia Baleani1
1 Department of
Pediatric Cardiology, Hospital de Niños Dr. Ricardo Gutiérrez (HNRG).
Address
for reprints: Julián Rodríguez
Kibrik. División Cardiología del Hospital General de Niños Dr. Ricardo
Gutiérrez. Sánchez de Bustamante 1451, PB (CP 1425). C.A.B.A. E-mail: jota.rodriguez1@gmail.com
This
paper received Dr. Rodolfo Kreutzer Award during the 48th Argentine Congress of
Cardiology
ABSTRACT
Background: Multisystem inflammatory syndrome in
children (MIS-C) is an uncommon condition associated with COVID-19 with a wide
spectrum of presentations, ranging from Kawasaki-like disease to multisystem
involvement with shock. The association between the laboratory characteristics
and unfavorable outcome has been described, but the cut-off points associated
with higher risk have not yet been defined.
Objective: The aim of this study was to describe and
analyze the characteristics of patients with MIS-C and their associations with
the laboratory findings.
Methods: We conducted an analytical and
retrospective study of pediatric patients hospitalized between May 2020 and June
2021 with diagnosis of MIS-C in Hospital General de Niños Dr. Ricardo Gutiérrez
(HNRG). The cohort was made up of 23 patients, 17 female (53.13%) and 15 male
(46.87%); mean age was 7.67 years (range 0.5-14.91). Ten patients (31.25%)
presented shock.
Clinical and echocardiographic data and
values of high-sensitive troponin I, N-terminal pro–B-type natriuretic peptide
(NT-proBNP), platelets and lymphocytes at the time of diagnosis were obtained
and compared between those with shock during evolution (group 1) and those
without shock (group 2).
Results: There was a significant difference in
baseline elevated NT-proBNP values between both groups (p = 0.008), but not in
troponin levels and lymphocyte and platelet counts. Of the 13 patients who
required inotropic agents, 58% had baseline lymphopenia (p = 0.006 vs those who
did not require inotropic drugs).
Conclusions: Although mortality due to MIS-C is low,
cardiac involvement and hemodynamic impairment may be common. The availability
of a commonly used laboratory tool for patient categorization could help to
mitigate risks and obtain early referral to specialized centers.
Key words: Systemic Inflammatory Response Syndrome -
COVID-19/Complications - Natriuretic Peptide, Brain - Lymphopenia -
Thrombocytopenia - Child- Child, Preschool
RESUMEN
Introducción: El síndrome inflamatorio multisistémico en
pediatría (SIM-C) es una infrecuente entidad asociada a COVID-19 con un amplio
espectro de presentación: desde un cuadro similar a la enfermedad de Kawasaki a
una afectación multisistémica con shock. Se han descripto asociaciones entre
valores de laboratorio y mala evolución, pero no existen puntos de corte que
predigan la misma.
Objetivo: El objetivo de este estudio fue describir
y analizar las características de los pacientes con SIM-C y las relaciones de
estas con los hallazgos de laboratorio.
Material y métodos: Se realizó un estudio analítico y
retrospectivo de niños internados con diagnóstico de SIM-C entre mayo 2020 y
junio 2021 en el HNRG. Se estudiaron 32 pacientes, 17 femeninas (53,13%) y 15
masculinos (46,87%), edad promedio de 7,67 años (rango 0,5-14,91). Diez de los
pacientes (31,25%) presentaron shock. Se obtuvieron datos clínicos,
ecocardiográficos y valores de troponina I ultrasensible, NT-proBNP, plaquetas
y linfocitos al momento del diagnóstico; y se analizaron comparativamente entre
quienes presentaron shock durante la evolución (Grupo 1) y quienes no (Grupo
2).
Resultados: La diferencia en un valor inicial de
NT-proBNP elevado fue estadísticamente significativa entre ambos grupos
(p=0,008), en tanto que la troponina y el recuento de linfocitos y plaquetas,
no. De los 13 pacientes que requirieron inotrópicos, el 58% presentó linfopenia
inicialmente (p=0,006 vs aquellos que no los necesitaron)
Conclusiones: Si bien la mortalidad debido al SIM-C es baja,
la afectación cardiovascular y el compromiso hemodinámico en los pacientes que
presentaron este síndrome puede ser frecuente. Poder contar con una herramienta
de laboratorio ampliamente difundida para la categorización de pacientes podría
ayudar a mitigar riesgos y obtener una derivación temprana a centros
especializados.
Palabras claves: Síndrome de Respuesta Inflamatoria
Sistémica - COVID-19/Complicaciones - Péptido Natriurético Encefálico - Linfopenia
- Trombocitopenia - Niño - Preescolar
Received: 09/27/2022
Accepted: 02/07/2022
INTRODUCTION
Since the SARS-CoV-2 infection emerged in December 2019,
multiple presentations and associated syndromes have been described.
Multisystem inflammatory syndrome in children (MIS-C or PIMS) is one of the
most aggressive presentations. This rare complication usually occurs between 2
to 6 weeks after the onset of SARS-CoV-2 infection.
Initially, severe pediatric cases were rare, and SARS-CoV-2
did not severely affect the pediatric population. Then, isolated cases of
incomplete or atypical Kawasaki-like disease and toxic shock syndrome temporally
associated with SARS-CoV-2 infection began to be reported. (1,2)
Nowadays, MIS-C has a wide spectrum of presentations, ranging
from a Kawasaki-like syndrome to multisystem involvement with shock. The
incidence of Kawasaki-like disease is 3.7 to 30 times higher than the usual
incidence of typical cases. (2,3) Cardiac involvement in MIS-C is greater
than that of typical Kawasaki's disease, (4) ranging from 30% to 80%, (2,5-7) and accounts for the highest
morbidity and mortality rates.
The association between the laboratory characteristics and
unfavorable outcome (8,9) has been described, but the cut-off
points associated with higher risk have not yet been defined.
The primary objective of the study was to describe the
clinical presentation and compare baseline laboratory parameters between
patients with diagnosis of MIS-C with shock and without shock in a pediatric
referral center in the Autonomous City of Buenos Aires. The secondary objective
was to analyze the difference in positive troponin and N-terminal pro–B-type
natriuretic peptide (NT-proBNP) levels, and to establish cut-off points for
these parameters.
METHODS
We conducted an analytical and retrospective study of patients
hospitalized between May 2020 and June 2021 with diagnosis of MIS-C in Hospital
General de Niños Dr. Ricardo Gutiérrez (HNRG). A total of 32 patients were
admitted during that period.
Multisystem inflammatory syndrome in children was considered
following the definition of the National Ministry of Health (https://www.argentina.gob.ar/salud/coronavirus-COVID-19/casos-pediatria):
- Patients between 0–19 years of age with fever ≥ 3
days and documented SARS-CoV-2 infection; with ≥2 of the following:
1. Cutaneous rash or non-purulent conjunctivitis or signs of
mucocutaneous involvement (mouth, hands or feet).
2. Hypotension or shock.
3. Signs of myocardial dysfunction, pericarditis, valvulitis
or coronary artery anomalies (including echocardiographic findings or elevated
troponins and NT-proBNP).
4. Evidence of coagulopathy: elevated prothrombin time (PT),
elevated partial thromboplastin time (PTT), elevated d-dimer.
5. Acute gastrointestinal symptoms (diarrhea, vomiting, or
abdominal pain)
- AND elevated markers of inflammation: C-reactive protein
(CRP), erythrocyte sedimentation rate (ESR), or procalcitonin and no other
obvious cause of inflammation.
The clinical, cardiological and laboratory data of each
patient were retrieved from the medical records (MR). The patients were
classified in two groups: group 1 (with shock) and group 2 (without shock).
Shock was defined as hypotension (blood pressure < 2 SD below the 50th
percentile for sex, height and age, Argentine Society of Pediatrics) refractory
to fluid resuscitation, and requirement of pressor drugs documented in the MR.
The laboratory parameters analyzed were high-sensitive
troponin I (VIDAS® High-sensitive troponin I assay- BioMerieux),
NT-proBNP (VIDAS® NT-proBNP2- BioMerieux), platelets and lymphocytes
at the time of diagnosis. The cut-off points reported by the reference
laboratory were used to determine whether these values were abnormal: troponin
I >19 ng/L; lymphopenia: < 1000 lymphocytes/mm3;
thrombocytopenia: platelet count < 150 000/mm3 and NT proBNP >
300 pg/mL.
These parameters were considered because, according to the
literature, troponin is a marker of cardiac injury, thrombocytopenia has a high
positive predictive value for cardiac involvement, NT proBNP showed correlation
with cardiac dysfunction and severe lymphopenia has a high association with
shock. (8-10)
At the same time, complementary cardiological tests, as
electrocardiogram (ECG) and echocardiography, were performed to evaluate parameters
of cardiac involvement during the disease. To define cardiac involvement, we
used a synthesis of the definitions provided by Pignatelli (5) and Valverde (7): presence of any arrhythmia,
premature atrial or ventricular contractions, sustained or nonsustained atrial
or ventricular tachycardias, atrioventricular (AV) block of any degree,
ventricular repolarization changes; reduced left ventricular systolic function
(measured by any method); left ventricular (LV) dilation > +2 z score
values; valvular regurgitation; any type of pericardial effusion; dilation of
coronary arteries; or elevated cardiac enzymes (CK-MB, troponin). Sinus
tachycardia was not included as sign of organ injury because this symptom is
nonspecific in patients with fever.
Fractional shortening (FS) was used
to determine left ventricular systolic function and measured in M-mode echocardiography
in a circumferential section of the left ventricle at the level of the
papillary muscles using left ventricular diastolic dimension (LVDD) and left
ventricular systolic dimension (LVSD) as reference: (LVDD-LVSD)/LVDD x 100. A reduction in FS below 30% was
considered systolic dysfunction.
Statistical analysis
Firstly, we made a descriptive analysis of the population
included and studied the differences between group 1 and group 2. Qualitative
variables are presented as absolute value and percentage and were compared with
the chi-square test or Fisher's exact test. Quantitative variables are presented
as mean and standard deviation and are compared with the t-test. Then, we
compared the clinical and mean laboratory parameters between both groups and
reported the differences. Finally, ROC curves were constructed to analyze the
discrimination ability of troponin and NT-proBNP between both groups, and
cut-off values were established. All the statistical calculations were
performed using SPSS Statistic 25.0 software package (IBM, Chicago, IL).
Ethical considerations
As this was an observational and retrospective study, we did
not perform any intervention on the patients that did not comply with clinical
practice standards and consensus statements corresponding to the disease. The
study was conducted following the Law 3301 of the city of Buenos Aires, the
recommendations of the Declaration of Helsinki and the Guidelines for Good
Clinical Practice. The data are encrypted to protect patients' confidentiality
(Law 25 326).
RESULTS
A total of 32 patients with diagnosis of MIS-C were analyzed;
15 were male (46.9%) and 17 were female (53.1%). Mean age on presentation was
7.67 years (range 0.5-14.91 years). Cardiac diseases and anomalies of the
kidney and urinary tract were the most common comorbidities (Table 1). Most patients had positive serological test for SARS-CoV-2
(28 patients of 32); of the remaining 4, 2 had a previously documented
infection and the other 2 had positive epidemiological linkage for COVID-19.
Table 1. Demographic characteristics and
comorbidities
|
Baseline
characteristics |
Group 1
(patients with shock) |
Group 2
(patients without shock) |
p value |
|
Age |
6.2 ± 0.77 years |
8.33 ± 0.99 years |
0.20 |
|
Female sex |
50% |
54% |
0.80 |
|
Place of
residence (PBA) |
70% |
68% |
0.92 |
|
Comorbidities |
2/10 patients: 1 with one kidney. myelomeningocele with
ventriculoperitoneal shunt and 1 levo transposition of great arteries |
6/22 patients: 1 VSD repaired; 1
malnourished with ASD; 1 chronic kidney disease; 1 rapidly progressive
glomerulonephritis; 1 mitral valve dysplasia;
1 grade 4 vesicoureteral reflux. |
0.66 |
ASD:
atrial septal defect. PBA: Province of Buenos Aires. VSD: ventricular septal
defect.
Group 1 was made up of 10 patients (31.2%) and group 2 of 22
(68.8%) Baseline NT proBNP value was not obtained in 3 patients (all in group 2)
and baseline lymphocyte and platelet counts were not recorded in 1 patient in
group 1. Mean age in group 1 was 6.2 years, ranging from 2.41 to 10.16 years,
and 8.33 years in group 2, with a wider range of 0.5 to 14.91 years. Almost
70% of patients in both groups came from the Province of Buenos Aires. There
were no significant differences in the baseline characteristics of each group
in terms of age, sex, place of residence and comorbidities. (Table 1)
Congenital heart defects were the most common comorbidities
(levo transposition of the great arteries, atrial septal defect, repaired
ventricular septal defect without residual shunt, and mitral valve dysplasia
without dysfunction), and history of anomalies of the kidney and urinary tract
(rapidly progressive glomerulonephritis, grade 3 vesicoureteral reflux, chronic
kidney disease and a patient with one kidney and myelomeningocele).
After obtaining the clinical, echocardiographic and
laboratory data, the mean results in each group were compared (Table 2, Figure
1). Mean
length of hospital stay was 11.6 days, significantly longer in patients with
shock requiring admission to the pediatric intensive care unit (PICU): 17 days
vs. 9.2 days (p < 0.001). Twp patients in group 2 had prolonged
hospitalization due to social issues. A total of 13 children required inotropic
agents (due to shock or myocardial dysfunction without shock).
Table 2. Clinical, echocardiographic, and
laboratory data in patients with and without shock
|
|
Group 1
(patients with shock) |
Group 2 (patients without
shock) |
p value |
|
Number of patients |
10 |
22 |
– |
|
Length of
hospital stay |
17 ± 2.2 days |
9.2 ± 1.5 days |
< 0.001 |
|
Cardiac
involvement |
9/10 (90%) |
18/22 (81%) |
0.551 |
|
Left-sided
valve regurgitation |
8/10 (80%) |
11/22 (50%) |
0.108 |
|
2.<t0/>First
or second-degree AV block. |
1/10 (10%) |
3/22 (13.6%) |
0.772 |
|
Repolarization
abnormalities †. |
4/10 (40%) |
9/22 (40%) |
0.964 |
|
Pericardial
effusion |
8/10 (80%) |
5/22 (22.7%) |
0.001 |
|
Coronary artery dilation |
3/10 (30%) |
1/22 (4.5%) |
0.009 |
|
FS (%) |
31.7 ± 1.97 |
39.2 ± 2.15 |
0.027 |
|
Troponin I
(ng/L) |
643.7 ± 478.7 |
171.3 ± 70.8 |
0.188 |
|
NT-proBNP
(pg/mL) |
19 770 ± 9024 |
7332. ± 5109.3 |
0.008 |
|
Platelets (n/mm3) |
166 333 ± 27 079 |
219 590 ± 19 129 |
0.154 |
|
Lymphocytes (n/mm3) |
2853 ± 1220 |
1893 ± 259 |
0.766 |
†
repolarization abnormalities: T wave flattening, T wave inversion, ST-segment
elevation. FS: fractional shortening.
Fig. 1. The left of each
row shows the distribution of a determined value (platelets, proBNP,
high-sensitive troponin I and lymphocytes) expressed as mean and standard error
according to the presence (1 or YES) or absence (0 or NO) of shock. The right
side shows the distribution chart for each value expressed as median and the
dispersion of values also according to the presence (1 or YES) or absence (0 or
NO) of shock.
The incidence of cardiac involvement was 84.4% (27 patients),
all with at least one abnormal parameter. The most common abnormalities were
elevation of high-sensitive troponin I above the laboratory reference values
(21 patients, 77%), mitral or aortic valvular regurgitation of any kind in 19
patients (70%), repolarization abnormalities in the electrocardiogram (13
patients, 48%) and systolic dysfunction (8 patients, 29.6%). Coronary artery
dilations occurred in 4 patients (12.5%), 3 in group 1 and 1 in group 2
(p=0.009). Other disorders included first- or second-degree AV block and
incomplete right bundle branch block; all these findings recovered after
appropriate treatment was initiated. Ventricular function measured by FS was
reduced in group 1: 31.7 ± 1.97 vs. 39.2 ± 2.15% (p = 0.027). Pericardial
effusion documented by echocardiography was significantly more common in
patients with shock (80% vs. 22.7%; p = 0.001)
Thrombocytopenia (platelet count < 150 000/ mm3)
on admission was present in 30% (3/10) of patients with shock, while in group 2
the incidence was 13% (3/22), p = 0.138. Lymphopenia (lymphocyte count <
1000/mm3) was present in 4 patients in group 1 (40%) and in 4 in the
control group (18%), with no statistically significant differences (p = 0.14).
Among those requiring any inotropic agent, lymphopenia was present in 7 (58.3%)
of the 12 patients with baseline lymphocyte count available, while among the 19
patients who did not require inotropic drugs, only 1 (5.2%) had lymphopenia
upon diagnosis (p = 0.006). The specificity of lymphopenia for the use of
inotropic drugs was 95%, with a positive predictive value of 88%. There were no
differences in the absolute value of platelets and lymphocytes between both
groups.
High-sensitive troponin I was elevated (> 19 ng/L) in
21/32 patients (65.6%), 80% (8/10) in group 1 and 59% (13/22) in group 2. Mean
troponin value was higher in group 1, but this difference was not statistically
significant (p = 0.188). The best cut-off value of troponin I defined by the
ROC curve was 50 ng/L, and when we used this value as a dichotomous variable
(positive-negative), the positivity rate was 80% in group 1 vs. 31.8% in group
2 (p = 0.01).
With the cut-off point of NT-proBNP established by the
reference laboratory (high if > 300 pg/mL), a baseline positivity rate of
90% (9/10) was observed in patients with shock, and of 89% (17/19 tested) in
the control group. Mean NT-proBNP levels were significantly higher in patients
with shock (19 770 vs. 7332 pg/mL, p = 0.008).
The analysis of the ROC curve demonstrated that the best
cut-off value of NT-proBNP to predict shock was 3900 pg./mL. This cut-off value
and the adjusted cut-off value of high-sensitive troponin I (50 ng/L) were used
in combination. These variables were dichotomized (both values positive vs. any
other combination) and analyzed. The combination had a negative predictive
value (NPV) of 86% for shock.
DISCUSSION
We described 32 patients meeting criteria for MIS-C. The
characteristics of the population in terms of age on presentation and
distribution by sex are similar to those described in other series, (6-8,11-13) with a slight predominance of female
patients. Patients in group 1 were younger. While 31% presented shock during
disease progression, 40% required use of any inotropic agent.
Cardiac involvement did not differ from other publications
and was about 84%. While the incidence of coronary artery dilation reported by
international publications was 8-24%, the incidence in our series was 12.5%. (4,5,8,11,14,15) Pericardial effusion was present in
40% of patients, with significant differences between group 1 and group 2.
The main difference between the studies by Valverde and
Pignatelli in the definition of cardiac involvement lies in the classification
of valvular regurgitation; Pignatelli's criteria are more restrictive, as they
only include moderate or severe regurgitation. We believe that trivial, mild or
moderate left-sided valve regurgitations should be considered as markers of
organ injury despite having healed after treatment, even though this criterion
increases the total number of patients with cardiac involvement.
Although mortality associated with this disease has been
reported, there were no deaths in our series. (5)
Pignatelli found that elevated troponin values and thrombocytopenia
had high sensitivity and negative predictive value for requirement of PICU
stay. In our series, patients with the highest mean troponin and NT-proBNP
values and the lowest platelet count had an unfavorable course with shock,
although the only statistically significant value was that of NT-proBNP. After
adjusting for ROC curves, elevated troponin levels were also associated with
shock.
When analyzing laboratory data in relation with the use of
inotropic agents, the results are similar to those of the international
literature (described in patients requiring PICU): high-sensitive troponin I (p
= 0.029), NT-proBNP (p = 0.002), and lymphopenia (p < 0.001), showed a
statistically significant difference between patients who required inotropic
agents and those who did not.
According to our experience, we consider that the role of
pediatric cardiologists is still essential when considering the best therapy
for each patient. The possible cardiac involvement implies routine collection
of samples for laboratory tests and performing an ECG and echocardiogram on
hospital admission.
The strength of this study lies in the collection of most of
the data searched, since there were few missing values in the context of the
health emergency due to the pandemic. The general characteristics of the
population were not significantly different from those of the populations
reported in other studies. The statistically significant data obtained can be
associated with an adverse clinical course in patients with MIS-C.
The number of patients and the retrospective design
constitute the main weakness of this study. While not all centers have
availability of measuring troponin or NT-proBNP, blood differential and
platelet count are widely available.
CONCLUSION
Multisystem inflammatory syndrome in children may affect any
organ. In our study we observed a high incidence of cardiac involvement and
significant differences in coronary artery dilation and pericardial effusion
between those with and without shock; therefore, we consider that the initial
evaluation by pediatric cardiologists is essential for the management of patients.
The presence of lymphopenia or elevated NT-proBNP and troponin values should be
considered for the initial therapeutic approach in both peripheral centers and
referral hospitals.
Conflict of Interests
No conflicts of Interest or financing concerning the study
have been declared.
(See authors’ conflict of interests forms on the
web/Additional material.)
Sources of funding
None
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