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.