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\begin{document}

\title{Clinical Spectrum and Outcome of Neonatal Multi-System Inflammatory
Syndrome (MIS-N) - A Prospective Cohort Study.}



\author[1]{Siddu Charki}%
\author[1]{Patil S V}%
\author[1]{Lavanya P}%
\author[1]{Nandakishore K.}%
\affil[1]{Shri BM Patil Medical College}%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
\let\center\flushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{AIMS:} To analyze the clinical spectrum in Neonates with MIS-N
based on the time of presentation and also to assess the use of
immunomodulator therapy in MIS-N. \textbf{SUBJECTS AND METHODS:} We
studied 100 neonates, delivered at BLDE (DU) Shri B M Patil Medical
College Hospital admitted to Level III-A NICU from JULY 2020 to MAY
2021. 98 neonates had high titers of Ig G antibodies and negative for
COVID Antigen. We categorized the cohorts into EARLY MIS-N
(\textless{}72 hrs) and LATE MIS-N (\textgreater{}72 hrs).
\textbf{RESULTS:} 58 presented as EARLY MIS-N with Respiratory Distress
in 40 (70\%), cardiac dysfunction 34 (60\%), PPHN 12(20\%), Fever
12(20\%), seizures 12(20\%), encephalopathy in 6(10\%), sepsis-like
features 6(10\%), had elevated inflammatory markers like CRP (30\%),
D-Dimer (70\%), Ferritin (30\%), cardiac biomarkers like BNP (60\%), LDH
(30\%) and ECHO showing LV dysfunction in 50\%. LATE MIS-N presented
mostly with fever 28(70\%), sepsis-like features 24(60\%), Respiratory
Distress in 16(40\%), cardiac dysfunction 12 (30\%), hypoglycemia
4(10\%) parotitis 4(10\%), had significantly elevated inflammatory
markers like CRP (70\%), D-Dimer (50\%), Ferritin (70\%), cardiac
biomarkers like BNP (40\%), LDH (20\%) and ECHO showing LV dysfunction
in 20\%, dilated coronaries in 20 \%, PPHN in 10\%. Oxygen and
respiratory support requirement was more in EARLY presenters and IVIG
and steroid requirement was more in LATE presenters.
\textbf{CONCLUSION:} We observed that maternal SARS COV2 antibodies
transferred transplacentally and neonatal antibodies acquired after
COVID 19 infection can cause MIS-N in neonates. The immunomodulator
therapy is required in severe cases of MIS-N only.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION:}

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS- CoV2) associated
with multisystem inflammatory syndrome in children (MIS-C) has been
reported widely across the world {[}1, 2{]}. The exact pathogenesis for
MIS-C remains indefinable. Post-infectious Virus-induced immune
dysregulation appears to play a predominant role {[}3{]}. The immature
Immune system in neonates may not produce adequate SARS-CoV-2
antibodies. However, a large study cohort has demonstrated recently
regarding efficient transplacental transfer of immunoglobulin (IG-G)
antibodies from mother to fetus {[}4{]}. These immunoglobulins are
generally protective against SARS-CoV-2 infection, but the
transplacental transfer of immunoglobulin along with in-utero transfer
of other inflammatory cytokines might imitate a process to MIS-C,
causing immune activation and featuring as a multisystem inflammatory
syndrome in neonates (MIS-N) {[}5{]}. Sero conversion response to
SARS-CoV-2 infection has been seen within 2--3weeks of symptomatic
infection, with both immunoglobulins (IG-M and IG-G) levels depicted in
plasma {[}6, 7{]}.

Neonates who had perinatal SARS-CoV-2 infection can also cause an
antibody response, and there is suspicion that there may be a late-onset
manifestation with a presentation same as MIS-C seen in children
{[}8{]}. This condition has been reported in the neonates, presenting
with fever and multisystem involvement especially myocarditis clinically
or with raised biomarkers such as LDH and ProB-type natriuretic peptide
(proBNP) {[}9{]}.The possible manifestations in neonates presenting with
MIS-N has only been reported in a small number of cases {[}5, 10--16{]}.
In this study we present a clinical spectrum of 98 neonate's cohort
presenting with MIS-N with multi system involvement.

\textbf{METHODS:}

This study was conducted in Level IIIA NICU of BLDE (DU), Shri B M Patil
Medical College, Hospital and Research Centre, Vijayapura from North
Karnataka, Southern INDIA, between July 2020 and May 2021. A cohort of
newborns presenting with multi-system involvement, along with the
presence of SARS-CoV2 antibodies, was identified and enrolled in the
study. Treating intensivists followed clinical protocols and management
guidelines published by joint recommendation from the Federation of
Obstetric and Gynecological Societies of India (FOGSI), National
Neonatology Forum of India (NNF), and Indian Academy of Pediatrics (IAP)
{[}18, 19{]}. These guidelines were adapted from the Indian Council of
Medical Research (ICMR) protocol June 2020 which was based on the World
Health Organization (WHO)/Centre for Disease Control (CDC) guidelines.

SARS-CoV2 antigens testing was done using the real-time polymerase chain
reaction (RTPCR) method for nasopharyngeal swabs and SARS-CoV2
immunoglobulins were tested on Roche Cubase411 by ECLIA method in both
maternal and neonatal blood samples. This method detects total number of
antibodies against SARS-CoV-2, levels \textgreater{} 1.00 S/CO index
were considered positive. The baseline investigations include complete
blood count (CBC), C-reactive protein (CRP), D-dimer and coagulation
profile in all cases, Serum Ferritin was monitored when a suspicion of
cytokine storm arises. In cardiac involvement cases, lactate
dehydrogenase (LDH), Pro B-type natriuretic peptide (proBNP) were done
to assess myocardial dysfunction, and also echocardiography (ECHO) was
done. Immunomodulator therapy was based on above mentioned guidelines
and recommendations.

\textbf{INCLUSION CRITERIA:}

The definition of MIS-N from CDC criteria was used along with published
definitions to define neonatal COVID infection, {[}21, 22{]} and agreed
upon certain inclusion criteria. Once common neonatal conditions
mimicking multi- system presentations (E.g., sepsis, birth asphyxia,
pneumonia, other common condition) were ruled out by the neonatologist,
MIS-N was considered in neonates meeting the following criteria

1. Symptoms presenting from birth to the first four weeks of life.

2. Fever along with two or more systems involvement (fever, if present,
is suggestive but not mandatory for diagnosis in the newborn).

3. Evidence of raised inflammatory markers such as CRP, D Dimer, and
Ferritin.

4. Evidence of SARS-CoV-2 antibodies in the neonate (considered
mandatory for a diagnosis of MIS) and SARS-CoV-2 antigen to be negative
during the presentation to rule out active SARS-CoV-2 infection to
support the immunological process.

\textbf{EXCLUSION CRITERIA}

Neonates in which SARS-CoV-2 antibodies were present but the clinical
presentation was not suggestive of multisystem nature were excluded.

\textbf{Methodology:} Cohort of MISN cases was subdivided based on the
timing of presentation , to differentiate the possible source of SARS-
CoV-2antibodies:

\textbf{1. Early MISN (within 1st 72 h of life)} --- hypothesized as
presenting due to transplacental transfer of maternal
SARS-CoV-2antibodies.

\textbf{2. Late MISN (more than 72 h of life)} --- hypothesized as
occurring either due to antibodies produced secondary to
SARS-CoV-2infection in the new born or transplacental transfer of
maternal SARS-CoV-2 antibodies.

The following data was collected in reported cases in pre-defined
structured proforma:

\begin{enumerate}
\tightlist
\item
  Birth gestation, weight, etc.
\item
  Serology: maternal and neonatal Serology for SARS- CoV-2 --- both
  antigen and antibodies to ascertain the mode of transmission
\item
  Clinical features and laboratory results
\item
  Management and outcomes
\end{enumerate}

Age-specific normal ranges were used for analysis of laboratory
investigations. Deranged values were defined as serum Ferritin values
of\textgreater{}260ng/ml in term newborn and \textgreater{}200ng/ml in
preterm {[}23{]}, D-dimer\textgreater{}2000ng/ml, ProB-type natriuretic
peptide (pro-BNP)\textgreater{}700pg/ml, and serum lactate dehydrogenase
\textgreater{}450U/l {[}24{]}. Echocardiogram (ECHO) was performed to
look for abnormal coronary dilatation and cardiac
dysfunction/contractility. Cardiac dysfunction or myocarditis on ECHO
was considered when left ventricular (LV) ejection fraction (EF) is
decreased \textless{}55\% and fractional shortening (FS) \textless{}26\%
on functional echocardiography {[}25{]}. Parental consent was obtained
from each case. Institutional Ethics committee, approval was taken.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Results:}

A total of 100 neonates reported to be diagnosed and treated for MIS-N
were analyzed. Two were excluded as they had RTPCR positive.
Ninety-Eight cases were therefore analyzed as shown in case selection
flows diagram (Fig-1).

\textbf{EARLY MIS-N:} Out of total 98 cases, 58(60\%) cases were Early
MIS-N, out of which 46 (80\%) presented on Day-1 and 12 (20\%) on Day-2
of life. In these 35cases (60\%) were preterm and 23(40\%) were term
gestation. The clinical and laboratory parameters were assessed in this
group. The most common clinical findings noted in the neonates were two
system involvements, RDS in 40(70\%) neonates, 34(60\%) cardiac
dysfunction, 12 (20\%) PPHN, 12(20\%) fever, 12(20\%) seizures, 6 (10\%)
Encephalopathy, sepsis-like features in 6(10\%), no hypoglycemia or
parotitis noted as in Late MIS-N. (Table-1)

\textbf{Table 1- Clinical parameters and presentations based on time of
presentation in both groups}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Clinical parameters and presentations}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Early MIS-N(\textless{}72hrs)} \textbf{(n = 58)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Late MIS-N(\textgreater{}72hrs)} \textbf{(n= 40)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Number of cases\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
58 (60\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
40(40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gestation: preterm Preterm \textless{}37weeks Term [?]37 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
35 (60\%) 23(40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14 (35\%) 26(65\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.064\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Age of presentation\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Day 1: 46(80\%) Day 2: 12(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Week 1: 12 Week2: 04 Week 3 : 08 Week 4: 16\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NA\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Clinical presentation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Distress\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
40 (70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cardiac dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (59\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12 (30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.005}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PPHN\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(21\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
04 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.159\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Fever\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28(70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Seizures\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
03(7.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.075\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Encephalopathy\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
01(2.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.138\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sepsis like\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24(60\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypoglycemia\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
04(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.025}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Parotitis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
04(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.025}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{LATE MIS-N} : Out of total 98 cases, 40(40\%) cases were Late
MIS-N, out of which 12 presented on 1\textsuperscript{st} week, 4 on
2\textsuperscript{nd} week, 8 on 3\textsuperscript{rd} week, 16 on
4\textsuperscript{th} week. In these 14 cases (35\%) were preterm and
26(65\%) were term gestation. The clinical and laboratory parameters
were assessed in this group. Fever 28(70\%) and sepsis-like features 24
(60\%) along with other system involvement like RD in 16(40\%), 4(10\%)
PPHN, 3(7.5\%) Seizures, 1(2.5\%) Encephalopathy 12(30\%) cardiac
dysfunction, 4(10\%) hypoglycemia, 4(10\%) parotitis was observed in
Late MIS-N.

\textbf{Table 2- Lab parameters and ECHO findings in both groups.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{LAB PARAMETERS}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Early MIS-N (\textless{}72hrs)} \textbf{(n = 58)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Late MIS-N (\textgreater{}72hrs)} \textbf{(n= 40)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{1. Inflammatory markers}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CRP\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28(70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
D-Dimer\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
40(70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
20(50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.058}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ferritin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28(70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{2. cardiac biomarkers}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BNP\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34(60\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16(40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.070}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LDH\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17 (30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.299\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{3. Hematological}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Leucocytosis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Leukocytopenia\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.956\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Thrombocytopenia\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.014}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Thrombocytosis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Coagulation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.014}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{4.ECHO parameters}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LV dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34(59\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.005}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Dilated coronaries\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PPHN\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(21\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.159\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pericardial effusion\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.014}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{DIAGNOSTIC ASSESSMENT:}

All 98 neonates presented were positive titers for SARS CoV 2 IgG
antibodies and negative SARS CoV 2 antigen during the presentation. SARS
CoV 2 antigens were tested on RTPCR in mothers 34 tested positive, SARS
CoV 2 IgG antibodies were positive in 56.

\textbf{EARLY MIS-N:} Inflammatory markers were elevated in these
neonates with raised CRP in 17(30\%), D-Dimer 40(70\%), Ferritin
17(30\%), Elevated cardiac biomarkers like Pro-BNP in 34 (60\%), LDH 17
(30\%). Hematological parameters showed leukocytopenia 6(10\%),
thrombocytopenia 6(10\%), Deranged coagulation 6(10\%), ECHO parameters
showed LV dysfunction in 34(59\%) of cases, PPHN in 12(20\%).

\textbf{LATE MIS-N:} Inflammatory markers were elevated in these
neonates with raised CRP in 28(70\%), D-Dimer 20(50\%), Ferritin
28(70\%), Elevated cardiac biomarkers like Pro-BNP in 16(40\%), LDH 8
(20\%). Hematological parameters showed leucocytosis 8(20\%),
leukocytopenia 4 (10\%), thrombocytopenia 12(30\%), Deranged coagulation
12(30\%), ECHO parameters showed LV dysfunction in 12(30\%) of cases,
Dilated coronaries 8(20\%), PPHN 4(10\%) and pericardial effusion
4(10\%).

\textbf{RESPIRATORY SUPPORT} :

In early presentation, most neonates required non-invasive ventilation
23(40\%), 12(20\%) were on ventilator as primary support, 6(10\%) on
Nasal Oxygen.

In late MIS-N, respiratory support requirement was low, Noninvasive
4(10\%) compared to Early MIS-N neonates, 4 (10\%) on ventilator, nasal
oxygen support 8(20\%).

\textbf{CARDIAC SUPPORT:}

Inotropes usage was more in EARLY MIS-N with 29(50\%) neonates; IV
Sildenafil was used only in 8(20\%) neonates. Neonates with LATE MIS-N
required inotropic support in 8(20\%) neonates and IV Sildenafil in 4
(10\%) neonates with PPHN.

\textbf{THERAPEUTIC INTERVENTIONS:}

Steroids and IVIG use was more in late MIS-N group with 28(70\%) and
18(45\%) respectively. where as in EARLY MIS-N 08(14\%) neonates
required steroids, 8(14\%) neonates required IVIG. Antibiotic therapy
was given to neonates with sepsis-like features, 17(30\%) in EARLY group
and 28(70\%) in LATE group. (Table-3)

\textbf{OUTCOME:}

In the Early MIS-N group, 56 neonates were discharged home, and two
neonates succumbed to the illness. 39 neonates in Late MIS-N were
discharged home, one neonate succumbed. Out of 95 survivors,
neonatologists had no concerns with respect to the development or
long-term morbidities for any of the cohorts except for two who were
lost to follow up.

\textbf{TABLE 3- Management and Outcome of Neonates in both groups.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{LAB PARAMETERS}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Early MIS-N (\textless{}72hrs)} \textbf{(n = 58)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Late MIS-N (\textgreater{}72hrs)} \textbf{(n= 40)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{1.Respiratory support}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Oxygen\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.179\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-invasive\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23(40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ventilation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.159\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{2. cardiac support}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Inotropes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29(50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.159\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sildenafil\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4(10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.573\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{3.Immunomodulator therapy}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Steroids\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28(70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IVIG\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18(45\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{4.Antibacterial therapy}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17(30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28(70\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2(3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1(2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.789\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Discharge\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
56(97\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
39(98\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{COMPARATIVE ANALYSIS:}

We analyzed clinical presentation and outcomes of all 98 babies based on
the timing of presentation correlating with the possible mechanism. 58
presented early within 72hours of life, 40 presented beyond 72 hours of
life. RDS 40(70\%) and PPHN 12(20\%) tend to be more common during early
presentation, variable presentations like fever; sepsis-like features,
seizures and encephalopathy were also observed. Fever 28(70\%) and
24(60\%) sepsis like features (poor feeding, lethargy) tends to be more
common presentation in Late MIS-N. Inflammatory markers were elevated
more in late presentation group. Immunomodulatory therapy with steroids
and IVIG use was high in Late MIS-N group.

\textbf{DISCUSSION:}

MIS-C is the new emerging challenge in the pediatric population in the
COVID-19 pandemic, with few cases reported world-wide {[}27{]}. As MIS-C
generally occurs after an interval period following SARS-CoV-2
infection, correlating with the timing of developing anti-spike
antibodies (IgG), its etiology being aberrant cellular or humoral
adaptive immune responses triggering inflammation or mediating organ
damage {[}3,27,28{]}. In newborns, SARS-CoV-2infection can present
either as an early-onset infection, likely due to vertical or
intrapartum transmission {[}29{]} of SARS-CoV-2 or late-onset SARS-CoV-2
infection, more than 72 h after birth, which might have acquired via
close contacts {[}21{]}.

Transplacental transmission of SARS-CoV-2 is observed to be less common
in term neonates due to lack of expression of angiotensin- converting
enzyme (ACE)2 and transmembrane protease serine 2 (TMPRSS2) by
trophoblasts , these are two main host membrane receptors for SARS-CoV-2
entry; however, this increase the concerns in preterm {[}30{]}. Maternal
SARS-CoV2 infection leads to formation of protective anti-spike IgG
antibodies which cross the placenta and offer protection to newborns
along with secretory IgA which can be secreted in breast milk {[}31{]}.
However, it is phrased that in certain genetically susceptible newborns,
the antibodies can bind to receptors on macrophages and neutrophils
causing activation of cytokines leading to various manifestations of
MIS-N. It is also reported that some newborns may develop MIS-N due to a
mechanism similar to MIS-C, due to autoantibody-mediated immune
dysregulation in response to perinatally acquired SARS-CoV2 infection
{[}30{]}

It was postulated that neonates may have less inflammation, milder
COVID-19 illness, and faster recovery when compared to pediatric
population and adults due to passive transfer of protective maternal IgG
antibodies, immature immune system, presence of fetal hemoglobin, and
lower angiotensin- converting enzyme-2 (ACE-2) expression {[}32, 33{]}.
MIS-N is emerging as a new challenge with a few cases being reported
globally {[}34{]}. This study reports variety of clinical manifestations
of MIS-N, which is hypothesized to be caused by transplacental transfer
of SARS-CoV2 antibodies and antibodies d in the neonate post-infection
with SARS-CoV-2.

The diagnosis of SARS-CoV-2 infection in neonates due to vertical
transmission not only requires positive SARS- CoV2 antigen in
respiratory secretions for both the mother and neonate but also
demonstration of the virus in amniotic fluid and cord blood along with
the neonatal disease attributable to COVID-19 {[}35{]}. Diagnosing MIS-N
in neonates is challenging. MIS-N is identified to be a disease
manifesting by antibody-mediated immune activation affecting various
organs rather than the infection itself {[}3{]}. Hence, to differentiate
neonatal SARS- CoV2 infection from MIS-N, the neonate should be negative
for SARS-CoV2 antigen but positive for SARS-CoV2 antibodies,
transplacentally transmitted from the mother. The clinical
manifestations of MIS-N are same as that of sepsis-like illnesses,
making it difficult to differentiate between them on clinical grounds
alone.

In our cohort, we scrutinized the cases that were treated as MIS-N by
neonatologists and categorized them into EARLY MIS-N and LATE MIS-N. The
preterm neonates tend to present early compared to term neonates with
the more severe disease commonly presenting as respiratory distress and
cardiac dysfunction, as observed by Lima et al. {[}10{]}. Fever was a
striking symptom in late presenting neonates and in term neonates
leading to postnatally acquired MIS-N, but skin manifestations and
gastrointestinal symptoms were uncommon, in contrast to frequent reports
in older children {[}7, 36{]}.

Ferritin and D-Dimer are acute phase reactants and levels may also be
elevated in sepsis, a diagnosis of MIS-N was made in the clinical
context with other elevated relevant markers and negative blood
cultures. Pro BNP as a marker of cardiac dysfunction was elevated
significantly in all neonates with cardiac dysfunction, suggesting
immune-mediated myocarditis, similar to a case report of a 24-day-old
neonate by Kappanayil et al. {[}11{]}. Cardiac biomarker Pro BNP can be
raised in premature neonates {[}36{]} with patent ductus arteriosus, but
levels noted in this preterm cohort were exponentially high, suggesting
myocarditis. Pro BNP may be helpful as early predictors of cardiac
dysfunction in MIS-N. We did not find coronary aneurysm in any case as
reported in the pediatric population {[}26{]} except eight babies having
marginally dilated coronaries. There was also no report of any cardiac
arrhythmia same as that in a published neonatal cohort {[}5{]}.

SARS-CoV2 IgG antibodies were positive in all, indicating possible
transmission of transplacental of IgG. However, we couldn't confirm this
in some neonates presenting late who may have developed these antibodies
due to perinatally acquired infection.

Neonatologist managing our cohort of MIS-N cases used steroids
(Methylprednisolone or prednisolone) either alone or in combination with
IVIG as per recommendations by ICMR 2020.In the LATE MIS-N group, fever
in two babies responded only after starting steroids. In severely
affected neonates with associated cardiac dysfunction, most neonates
showed improvement in clinical and biochemical parameters after both
steroids and IVIG administration. All neonates in our cohort, except
two, recovered completely, without requiring prolonged ventilation.
Generally, environmentally acquired SARS- CoV2 infection in newborns
seems to be a severe disease {[}21{]}; but there was no significant
difference in morbidity or outcomes between early and late presenters.
In this pandemic, we would like to caution neonatologists, the
increasing number of pregnant mothers who are exposed to SARS-CoV-2
during pregnancy or who have received a COVID vaccine. Transfer of these
antibodies to the newborn may or may not cause MIS-N in the infant. It
could however result in over-diagnosis of MIS-N by treating clinicians
if these antibodies are incidentally detected during another illness.
Thus, typing antibodies for anti-nucleoprotein anti-bodies suggesting
past infection rather than anti-spike protein antibodies which shows
vaccination status can be considered to prevent confusion in situations
where there is no definite evidence of present and past maternal
SARS-CoV2infection.

\textbf{CONCLUSION:}

Our Cohort of MIS-N is the largest reported as per current literature
data. MIS-N occurs as a syndrome which occurs post-exposure to
SARS-CoV2, manifests with a variety of clinical symptoms. The diagnosis
of MIS-N can be challenging and needs a high index of suspicion, after
all other potential etiologies have been excluded. MIS-N can be
considered in a neonate presenting with two or more systems involvement,
in the presence of SARS-CoV2 antibodies, along with elevated
inflammatory markers. In such cases neonatologists should perform
specific investigations such as SARS-CoV2 antigen and antibodies,
inflammatory markers routinely along with cardiac biomarkers like Pro
BNP, LDH, and early ECHO screening to evaluate myocardial dysfunction
when needed. Immunomodulator therapy should be given only for severe
cases where definitive criteria of MIS-N are met.

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\end{enumerate}

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