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.