Case Series of Multisystem Inflammatory Syndrome in Neonates (MIS-N) With a Link to Coagulopathy

Introduction Multisystem inflammatory syndrome in neonates (MIS-N) is an emerging clinical entity observed in neonates born to mothers with exposure to the SARS-CoV-2 virus before or during the antenatal period. Methods We report 18 neonates diagnosed with MIS-N from retrospectively collected data. A total of 18 neonates (13 term and five late-preterm; 10 males) admitted to the neonatal intensive care unit (NICU) of a tertiary care medical institute, between June 2021 to November 2022, were diagnosed with MIS-N. Results The median age of presentation of the 18 neonates was 1.5 days of life. All the neonates were positive for SARS-CoV-2 IgG antibodies and had elevated D-dimer levels. Respiratory system involvement was the most common (12 of 18 neonates: 66.67%). Ten out of 18 neonates (55.55%) had coagulopathy. Seven of the ten neonates with coagulopathy had central nervous system (CNS) involvement as seizures and/or intracerebral infarcts/bleeds. Cardiovascular and gastrointestinal system involvement was observed in nine (50%) and seven (38.89%) neonates, respectively. One out of 18 neonates died due to intraventricular and cerebral hemorrhage. The mortality rate was 5.55% (n=1). Ten of 18 neonates with coagulopathy required fresh frozen plasma along with repeated therapeutic doses of injection vitamin K. Eight neonates (44.44%) required human intravenous immunoglobulin (IVIG), and three neonates (16.67%) required steroids and IVIG for recovery along with supportive care. Conclusion Coagulopathy can be one of the salient features of presentation in MIS-N. In the immediate post-pandemic era, it is essential that MIS-N is considered in the differential diagnosis of neonates presenting with intracerebral bleeds/infarcts. IVIG and steroids might play an important role in the treatment of neonates with MIS-N.


Introduction
Multisystem inflammatory syndrome in neonates (MIS-N) is a recently observed clinical entity in neonates born to mothers who have had exposure to the SARS-CoV-2 virus during their antenatal period [1][2].Multiple case reports on MIS-N from different parts of the world have been published in 2021, but it is to be noted that the pathophysiology of MIS-N is not completely understood [3].This disease is hypothesized to be the result of certain antibodies formed in the mother as a defense against SARS-CoV-2 that crosses the placenta and acts against the antigens of the fetus/neonate.The clinical presentation, laboratory features, and diagnostic criteria for MIS-N are still evolving and need further research.
More et al. in 2022 provided a diagnostic criterion for MIS-N which is as follows: i) onset of symptoms anytime from birth to ≤28 days of life [2].ii) fever along with the involvement of ≥2 systems (i.e., cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, and neurological) requiring hospitalization (fever was not taken as a mandatory symptom as neonates do not commonly present with fever).iii) evidence of raised inflammatory markers including any one of the following: c-reactive protein (CRP), procalcitonin (PCT), ferritin, D-dimer, IL-6, and pro-BNP (brain natriuretic peptide).iv) evidence of SARS-CoV-2 antibodies (SARS-CoV-2 IgG) in the mother and neonate.v) exclusion of alternate diagnoses with similar clinical presentations, like perinatal asphyxia, sepsis confirmed by blood culture, and maternal lupus resulting in atrioventricular conduction abnormalities in the fetus and neonate.

Materials And Methods
A total of 18 neonates (13 term and five late-preterm; 10 males and eight females) admitted to the neonatal intensive care unit (NICU) of a tertiary care medical institute, between June 2021 and November 2022, were diagnosed with MIS-N.The demographic characteristics and clinical profile of the neonates are provided in Table 1.Various researchers have attempted to come up with diagnostic criteria for MIS-N based on the multisystem inflammatory syndrome in neonates (MIS-C) criteria [1][2].Based on the criteria mentioned by More et al., the neonates were diagnosed with MIS-N.After diagnosis of MIS-N, the neonates were classified into the following categories: most likely MIS-N, when all criteria mentioned above are present, and possible MIS-N, when there is an unusual clinical presentation, suspicious of MIS-N, not meeting all specified diagnostic criteria but there is no other explainable cause [2].

Results
The detailed clinical presentation and investigations are shown in Table 1.Investigations were carried out according to the presenting symptoms.Common clinical conditions like early onset sepsis and necrotizing enterocolitis were ruled out by relevant investigations like CRP, blood for culture and sensitivity, stool for occult blood, and chest and abdominal x-rays.
When the clinical scenario suggested multisystem involvement, quantitative immunoassay for SARS-CoV-2 IgG antibodies, to identify neutralizing antibodies against S1/S2 spike antigens of the virus, was done for all the neonates and 11/18 mothers.The antibodies were positive in all neonates and 11 mothers.Four mothers refused consent for the test and the rest three denied it due to affordability issues.The D-dimer assay done for all the neonates showed raised titers in all neonates [2,4].The other inflammatory markers like fibrin degradation product (FDP), fibrinogen, ferritin, and pro-BNP were done as per affordability.
Most of the neonates (14/18; 77.78%) presented with bleeding manifestations such as blood in nasogastric aspirates, melaena, intracranial bleeds (intracerebral, periventricular, subarachnoid, subdural bleed), and rash in the skin but with normal platelet count.The absence of laboratory parameters to support sepsis led us to evaluate coagulopathy with a coagulation profile.Among the 18 neonates, 10 neonates (55.56%, cases 2, 3, 6, 8, 10, 12 to 15, 17) had altered coagulation profiles with either prolonged prothrombin time (PT) or APTT (activated partial thromboplastin time) or both [5].Liver function test and renal function test were done as per clinical need.Trans-fontanelle ultrasonogram (USG or neurosonogram) was done for all neonates, while CT/MRI brain was done, where indicated (clinical presentation of seizures/encephalopathy/abnormal tone or when neurosonogram was abnormal).Seven neonates had central nervous system (CNS) involvement in the form of seizures due to intracerebral infarcts/bleeds (cases-1, 9, 10, 11, 12, 14, and 15).Neonates with cerebral infarcts were evaluated to rule out prothrombotic states like antiphospholipid antibodies (APLA), protein C, and protein S.
The neonates were provided with partial parenteral nutrition and supportive medications such as oxygen by nasal prongs (n=8; 44.44%) and/or continuous positive airway pressure (CPAP) (n=6; 33%).Six neonates (33%) received antiepileptics, namely, phenobarbitone and/or phenytoin/levetiracetam for seizures.All the 14 neonates with bleeding manifestations received therapeutic doses of vitamin K injection.Ten of these were transfused with fresh frozen plasma as they had major bleeds.Seven neonates (38.89%) with clinical features of delayed capillary refill time and/or hypotension received inotropes such as dobutamine and/or dopamine infusion at 5-10 mg/kg/min.One neonate (case 10) required ventilator support due to recurrent seizures, refractory to multiple antiepileptics (phenobarbitone, phenytoin, levetiracetam, and infusion of midazolam).This neonate had multiple intracerebral (parenchymal and ventricular) bleeds, developed disseminated intravascular coagulation (DIC) and succumbed to the illness on the 10th day of life.All other neonates survived and were discharged home.
Eight neonates (44.44%) (cases 1, 2, 3, 7, 9, 11, 13, 15) in this series received human intravenous immunoglobulin (IVIG) -2 g/kg over 48 hours as slow infusion.Three of these neonates (16.67%) (cases 1, 9, and 13) received intravenous dexamethasone 0.5 mg/kg/day in two divided doses for three days in addition to IVIG.The mean age at which IVIG was administered was 4.2±0.8days.There were no adverse drug reactions to IVIG in any of these neonates.All eight neonates who received IVIG showed clinical improvement and became stable by the end of 48-72 hours.The decision to treat neonates with IVIG and/or steroids was taken by the treating pediatrician on the grounds of inadequate or less-than-expected clinical improvement with supportive treatment alone.

Discussion
MIS-C was observed in children from across the globe as the first wave of COVID-19 infection started to decrease.The initial report was from the United Kingdom in April 2020 [6].A similar pattern of multisystem involvement with raised inflammatory markers in neonates was first reported in Qatar in November 2020 [7].The diagnosis of MIS-N was sought once the symptoms that the neonates presented with did not fit the common differential diagnosis.Clinical suspicion plays a strong role in the diagnosis of MIS-N as there are no set patterns or specific symptoms.The most common systems in the present case series included respiratory (12/18; 66.67%), hematological (10/18; 55.56%), cardiovascular system (CVS) (9/18; 50%), followed by gastrointestinal (7/18; 38.89%) and CNS (7/18; 38.89%).This pattern of cardiorespiratory system involvement is commonly observed in other studies too [1][2]8].In the present series, hematological system involvement is high, which could also explain the higher number of neonates (38.89%; n=7) presenting with CNS involvement (intracerebral bleeds/infarcts).When the neonates presented with intracerebral infarcts/bleeds, most of the common differential diagnoses like sepsis, DIC, APLA-induced vasculitis, and TORCH infections were ruled out, and evaluation for coagulopathy as a component of MIS-N presentation was sought.To the best of our knowledge, this case series has the highest number of neonates with coagulopathy (55.56%) and CNS involvement (38.89%) compared to the previously published literature.A comparison of published case series on MIS-N from India and abroad is provided in Table 2.As we searched the literature, (including literature search done till March 31, 2023), there were multiple case series and case reports reported since 2020.Among the neonates (n=98) reported in the literature (Table 2), most were preterm neonates (54.1%, n=54 out of 98 in Table 2); the majority of neonates had early MIS-N, that is, within the first 72 hours of life.The most common organ system involved was the respiratory and CVS in the literature (61.22%; n=60 and 55.1%; n=54, respectively).This was akin to the present case series where 12 out of the 18 neonates had respiratory symptoms.In the literature, 18 neonates (18.37%) had CNS involvement in the form of encephalopathy and seizures while the present series has 38.89%CNS involvement (n=7).Coagulopathy was observed in 15 neonates (15.31%) in the literature, while 55.56% (n=10/18) in the present case series had coagulopathy (altered coagulation profile).Fever was observed only in 42 (42.8%)neonates in the literature.There are at present no standard guidelines for the treatment of neonates with MIS-N.The experiences and treatment regimens applied to MIS-C patients have been used and extrapolated for neonates [7][8][9][10].Apart from the supportive treatment, IVIG and steroids were used in 67 (68.36%) and 75 (75.31%)neonates, respectively, in the literature.The majority of neonates had favorable outcomes and were discharged home and only 7 (7.14%)neonates died among the 98 in the literature.In the present case series, eight out of 18 neonates (44.44%) received IVIG.In our institute, IVIG was the initial choice of treatment, when supportive treatment alone was not helpful.The pathophysiology of MIS-N is postulated to be caused due to exposure to maternal antibodies in utero or transplacental transfer of infection resulting in endogenous production of antibodies or postinfectious immune response to infection in the neonate itself [34].It is hypothesized that certain antibodies might act against autoantigens and initiate MIS-N in neonates [3].Hence, it is expected that IVIG or steroids could probably help in the treatment of these neonates.However, it is to be noted that there are no standard recommendations for the use of these drugs in MIS-N.

Conclusions
MIS-N presents in myriad ways and needs further attention and studies to understand it better.This case series does help us to speculate that coagulopathy can be one of the salient presenting features of MIS-N.With this knowledge, in the immediate post-pandemic era, it is essential that MIS-N be considered in the differential diagnosis of neonates presenting with intracerebral bleeds/infarcts.Since MIS-N is expected to result in immunomodulation with attendant antibodies to self-antigens, the role of human IVIG and steroids needs to be analyzed in more detailed studies.
interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

TABLE 2 : Comparison of case series of MIS-N from India and abroad
DOL, day of life; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin; CNS, central nervous system; r-TPA, recombinant tissue plasminogen activators; GI, gastrointestinal; MP, methyl prednisolone; CVS, cardiovascular system; MIS-N, multisystem inflammatory syndrome in neonates