|Year : 2022 | Volume
| Issue : 2 | Page : 65-70
Clinical profile, laboratory parameters, management and outcomes of newborns with multisystem inflammatory syndrome (mis-n) due to transplacental transfer of SARS-CoV 2 antibodies: A study from a tertiary care institute
Lokeswari Balleda1, Saikiran Pasupula2, Sravani Kolla1, Chandrasekhara Reddy Thimmapuram1
1 Department of Paediatrics and Neonatology, Sri Ramachandra Children's and Dental Hospital, Guntur, Andhra Pradesh, India
2 Department of Psychiatry, Guntur Medical College, Guntur, Andhra Pradesh, India
|Date of Submission||03-Jan-2022|
|Date of Decision||02-Feb-2022|
|Date of Acceptance||05-Feb-2022|
|Date of Web Publication||20-Apr-2022|
Sri Ramachandra Children's and Dental Hospital, Guntur, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: Multisystem inflammatory syndrome in children (MIS-C) is a well-known entity that occurs 3–4 weeks after COVID-19. A similar entity in newborns, known as Multisystem Inflammatory Syndrome in Newborns (MIS-N), is also described. However, the epidemiology, case definition, clinical presentations, and outcomes of MIS-N are still being updated. The presence of SARS CoV 2 antibodies in both the mother and the neonate suggests transplacental transfer of IgG antibodies causing cytokine storm and multisystem inflammatory syndrome in newborns (MIS-N). Aims and Objectives: To investigate the clinical characteristics, laboratory parameters, outcomes, and treatment modalities of neonates with multisystem inflammatory syndrome due to transplacental transfer of SARS CoV 2 antibodies. Materials and Methods: The study included eighteen consecutive neonates who met the MIS-C criteria. Following prior ethical clearance and consent from parents or guardians, socio-demographic data, lab parameters, clinical parameters, and treatment given were documented, tabulated, and analysed. Results: All of the 18 neonates had fever. The most common system involved was the respiratory system (15/18), followed by the cardiovascular system with coronary artery dilatations (10/18) and persistent pulmonary hypertension (4/18). All 17 cases (17/18) responded favourably to intravenous immunoglobulins (2 gm/kg) and intravenous dexamethasone (0.15 mg/kg). D-Dimers decreased significantly after treatment, with a p value of 0.01. One case with more than three systems involved (respiratory, CVS, CNS, and renal involvement) (1/18) resulted in death. Conclusion: A high index of suspicion is warranted in critically ill neonates, especially with fever, multisystem involvement and positive SARS CoV 2 antibodies. Fever may be a soft pointer to the diagnosis as fever is rare in neonates with other illnesses. Followup antibody titres are needed to document if there is any relationship between level of antibodies and disease. Safety of vaccination also needs to be addressed as antibodies are implicated in the etiopathogenesis of MIS-N.
Keywords: Coronary dilatation, fever, inflammatory markers, intravenous immunoglobulins, pulmonary hypertension, respiratory distress, seizures
|How to cite this article:|
Balleda L, Pasupula S, Kolla S, Thimmapuram CR. Clinical profile, laboratory parameters, management and outcomes of newborns with multisystem inflammatory syndrome (mis-n) due to transplacental transfer of SARS-CoV 2 antibodies: A study from a tertiary care institute. J Clin Neonatol 2022;11:65-70
|How to cite this URL:|
Balleda L, Pasupula S, Kolla S, Thimmapuram CR. Clinical profile, laboratory parameters, management and outcomes of newborns with multisystem inflammatory syndrome (mis-n) due to transplacental transfer of SARS-CoV 2 antibodies: A study from a tertiary care institute. J Clin Neonatol [serial online] 2022 [cited 2022 Aug 9];11:65-70. Available from: https://www.jcnonweb.com/text.asp?2022/11/2/65/343412
| Introduction|| |
Multisystem inflammatory syndrome in children (MIS-C), which occurs 3–4 weeks after coronavirus disease (COVID-19), has been recognized globally since the first case was discovered in the United Kingdom in May 2020., The precise pathogenesis of MIS-C is unknown. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies cause a cytokine storm and immune dysregulation, resulting in postinfectious inflammatory syndrome (MIS-C).
There is no information on the SARS-CoV-2 virus vertical transmission from the mother to the baby. Furthermore, newborns' immune systems are not well developed, and hence, they may not produce enough SARS CoV-2 antibodies. Transplacental transfer of maternal SARS CoV-2 antibodies, on the other hand, may play an important role in the pathogenesis of multisystem inflammatory syndrome in neonates (MIS-N).
Recent research has shed light on the transplacental transfer of SARS-CoV-2 IgG antibodies from the mother to the fetus., This multisystem inflammatory syndrome has been reported in the newborn population, presenting as myocarditis, left ventricular dysfunction with or without elevated biomarkers such as troponin and pro-B natriuretic peptide.
The clinical spectrum and management of MIS-C in children are now better understood. However, in a few case reports, a similar spectrum of possible manifestations and management protocols in neonates with MIS-N have been reported but need to be better understood.,,, This study of 18 neonates with MIS-N after transplacental transmission of SARS-CoV-2 antibodies is described, with emphasis on clinical characteristics, laboratory parameters, management, and outcomes.
Aims and objectives
This study aimed to investigate the clinical characteristics, laboratory parameters, outcomes, and treatment modalities of neonates with multisystem inflammatory syndrome due to transplacental transfer SARS CoV-2 antibodies.
| Methodology|| |
Neonates who presented to our tertiary care neonatal intensive care units (NICU) at Sri Rama Chandra Children's and Dental Hospital, Guntur, Andhra Pradesh, India between 1st June and 30th September 2021, with multisystem involvement without a known etiology and the presence of SARS CoV-2 IgG antibodies in the mother and baby were studied. Clinical presentations, laboratory parameters, the need for respiratory support (such as oxygen support, high-flow nasal cannula, continuous positive airway pressure support, invasive ventilatory support), ICU stay, hospital stay, treatment, and mortality were all collected retrospectively. The data was organized and analyzed on an Excel worksheet.
- Neonate <28 days at the time of presentation
- Serological evidence of SARS CoV-2 IgG antibodies in the mother and baby
- Neonates who met the clinical criteria listed below.
- Severe illness requiring hospitalization and the involvement of two or more organ systems (i.e., cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurological, and temperature instability [fever or hypothermia])
- Abnormalities in cardiac Atrioventricular conduction, coronary dilation, or aneurysms (without involvement of a second organ system)
- Laboratory evidence of inflammation, including one or more of the following: increased C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase (LDH), or IL-6; increased neutrophils or decreased lymphocytes; and low albumin
- No other diagnosis (such as birth asphyxia, viral or bacterial sepsis by confirmed blood culture; maternal lupus resulting in neonatal AV conduction abnormalities).
Patients with earlier medical problems and congenital anomalies were excluded from the study.
The categorical variables were presented in the form of numbers and percentages (percent). The quantitative data, on the other hand, were presented as means standard deviation and medians with 25th and 75th percentiles (interquartile range). The Kolmogorov–Smirnov test was used to determine the normality of the data. Nonparametric tests were used in cases where the data were not normal. The paired t-test was used to compare pre- and post-D-dimers (ng/mL), and the Wilcoxon signed-rank test was used to compare pre- and post-CRP (mg/L). The data were entered into a Microsoft EXCEL spreadsheet, and the final analysis was performed using International Business Machines corporation(IBM) United States of America (USA) Statistical Package for Social Sciences (SPSS) software, version 21.0, Chicago, USA. In terms of statistical significance, P < 0.05 was deemed statistically significant.
| Results|| |
From 1st June to 30th September, 2021, we studied 18 neonates admitted to our NICU with multisystem involvement without a known cause and evidence of transplacental transfer of SARS CoV-2 IgG antibodies.
Demographic data from the study subjects revealed a total of eighteen cases, with a male predominance. Male babies were 11 (61.10%) of the total, while female babies were 7 (38.90%) [Figure 1]. The study subjects' gestational age of presentation revealed a greater involvement of near-term babies, with 11 (61.10%) being 36 weekers, 6 (33.30%) being 38 weekers, and 1 case (5.60%) being 35 weekers [Figure 2].
The clinical presentation of the study subjects revealed fever as the most prominent feature. The total duration of fever ranged from 2 to 10 days, with a mean of 3.82 days. All patients had fever at the time of presentation or during their hospital stay. Seventeen cases (94.40%) had breathing difficulty, 8 cases (44.40%) had seizures, 3 cases (16.70%) had abdominal distension, and 2 cases (11.10%) had skin rash [Table 1].
The respiratory system was the most commonly involved primary system, accounting for 15 cases (83.30%), followed by the central nervous system (CNS) in 2 cases (11.10%), and the hematological system in 1 case (5.60%) [Table 2].
In terms of laboratory parameters, hemoglobin ranged from 12.5 g/dl to 21.6 g/dl, with a mean of 17.06 g/dl. The total leukocyte count ranged between 4600/mm3 and 32,500/mm3, with a mean of 15,117/mm3. The neutrophil count ranged from 22% to 90%, with 58.33% being the mean. The number of lymphocytes ranged from 7% to 75%, with a mean of 38.72%. The neutrophil/lymphocyte (N/L) ratio ranged from 0.3 to 3.6, with a mean of 1.63. ESR measurements ranged from 5 mm/h to 50 mm/h, with a mean of 14.62 mm/h. The platelet count ranged between 51,000/mm3 and 548,000/mm3, with a mean of 266,722/mm3. Albumin concentrations ranged from 2.6 to 4.7 g/dl, with a mean of 3.86 g/dl. Serum creatinine levels ranged from 0.5 mg/dl to 2.5 mg/dl, with a mean value of 0.91 mg/dl. The Prothrombin time (PT) ranged from 8.82 s to 22.4 s, with of 16.52 s. The activated partial thromboplastin time (aPTT)) ranged from 31 to 44.6 s, with a mean of 40.35 s. The international normalized ratio ranged between 0.5 and 2.2, with a mean of 1.27.
Pretreatment CRP levels ranged from 0.3 to 113.9 mg/L, with a mean of 19.13 mg/L. The D-dimers ranged from 670 ng/ml to 10,000 ng/ml, with a mean of 4740.4 ng/ml. Ferritin levels ranged from 68 ng/ml to 607.32 ng/ml, with a mean of 300.81 ng/ml. Procalcitonin levels ranged from 0.1 to 85 ng/ml, with a mean of 15.04 ng/ml. The LDH levels ranged from 607 IU/L to 1855 IU/L, with a mean of 998.44 IU/L.
While considering the pretreatment inflammatory markers, D-Dimers and LDH were elevated in 100% of cases followed by procalcitonin which was elevated in 72.40% of cases. Ferritin, CRP, and N/L ratio were elevated in 67.00%, 66%, and 16.3% of cases, respectively [Table 3].
The 2D ECHO findings showed coronary dilatations and pulmonary hypertension. Most common 2D ECHO finding was coronary dilatations seen in ten out of the 18 cases. The diameters of the left coronary artery disease (CAD) ranged from 1.4 mm to 3.5 mm, with a mean of 2.14 mm with corresponding Z scores of 0.56–6.47, with a mean of 3.45. The diameters of the right CAD ranged from 1 mm to 2.4 mm, with a mean of 1.86 mm with corresponding Z scores of-0.08–6.31, with a mean of 3.76. The pulmonary hypertensions were seen in 4 out of 18 cases. The right ventricular systolic pressure ranged from 23.7 to 64.6 mmHg, with a mean value of 41.67 mmHg [Table 4].
In 17/18 cases, respiratory support was required in the form of a ventilator/CPAP/HFNC/nasal oxygen. The required length of ICU stay ranged from 4 to 18 days, with a mean of 8.76 days. The total length of hospital stay required ranged from 4 to 21 days, with a mean of 10.17 days [Table 5].
|Table 5: Duration of hospital stay and respiratory support of the patients|
Click here to view
Statistically significant reduction was observed only for D-dimer levels. D-dimer levels after treatment ranged from 640 ng/ml to 8550 ng/ml, with a mean of 2462.25 ng/ml and a statistically significant P = 0.01.
Posttreatment CRP levels ranged from 0.4 to 42.5 mg/L, with a mean of 5.36 mg/L. Posttreatment LDH concentrations ranged from 106 to 964 IU/L, with a mean of 413.87 IU/L. Posttreatment ferritin levels ranged from 97 to 524 ng/ml, with a mean of 280.75 ng/ml [Table 6].
All newborns received intravenous immunoglobulins (IVIG) (2 g/kg) and intravenous dexamethasone (0.15 mg/kg). In 9/18 cases, low-molecular heparin (1 unit/kg) was used. In 15/18 of the cases, aspirin (3 mg/kg) was administered [Figure 3].
Out of the 18 cases, 17 (94.40%) were discharged, while one (5.60%) died. This case involved more than three systems (RS, cardiovascular system [CVS], CNS, and renal), and it was the only case with renal involvement [Figure 4].
| Discussion|| |
Following 3–4 weeks of SARS-CoV-2 virus infection, the MIS-C is a well-defined entity, but for newborns, this same entity is not well established. Only a few case reports were described. This MIS-N is mainly caused by either perinatal infection or transplacental transfer of SARS-CoV-2 antibodies. In our study, it is mainly because of transplacental transfer of SARS-CoV-2 antibodies as evidenced by the presence of SARS-CoV-2 IgG antibodies in the mother and baby and negative antigen test in the baby.
SARS-CoV-2 infection in the mother produces IgG antibodies against spike protein of the virus which is similar to IgG produced by vaccination. These antibodies can cross placenta and protect the newborn. However, these autoantibodies produced by SARS-CoV-2 may attach to the receptors in neutrophils and macrophages, and activate the immune system of the newborn to produce inflammatory cytokines and thus the MIS-N.
Several studies and case reports have described the transplacental transfer of SARS-CoV-2 IgG antibodies to neonates.,, In our study also, multisystem inflammatory syndrome in newborns is probably caused by transplacental transfer of SARS CoV IgG antibodies.
In our study, there was a male preponderance (61.10%), and near-term babies were the most commonly involved (61.1%). According to the NICHD Maternal–Fetal Medicine Units network, COVID-19-positive mothers showed more of premature deliveries.
In our study, fever was the most common clinical manifestation (at presentation or during the hospital stay) and was observed in all 18 neonates. According to the study by Piersigilli et al., neonates presented with fever, cough, and cold with SARS-CoV-2 infection and responded well to symptomatic treatment.
The respiratory system was the primary system involved in our study (15 cases out of 18). The maximum number of systems involved was four. Mortality was observed in one case in which three systems with renal involvement were seen. According to Orlanski-Meyer et al., the predominant system involved was gastrointestinal in a neonate of 8 weeks of age. According to Pawar et al., six neonates (30%) presented with gastrointestinal features. According to Shivshankar Diggikar et al., the main system involved was CNS with seizures followed by CVS with dilated coronary arteries.
The inflammatory markers such as CRP, D-dimers, ferritin, and LDH were all elevated in our study. D-dimers showed a statistically significant reduction after treatment (posttreatment D-dimers mean value of 2462.25 ng/ml vs. initial D-dimers mean value of 4740.4 ng/ml with a P = 0.01). Iroh Tam and Bendel discovered that inflammatory markers such as CRP, D-dimer, and lactate dehydrogenase were elevated in sick and septic babies., Hence, these inflammatory markers are not specific to MIS-N.
The mainstay of MIS-N therapy is supportive. In our case study, all patients received immunomodulatory therapies (IVIG and IV dexamethasone), 15 babies received antiplatelet agents (aspirin), and 9 babies received anticoagulants (low-molecular weight heparin). However, risks and benefits of these medications need to be addressed in babies with MIS-N., It is already known that there is no proven benefit of corticosteroids in similar viral infections such as SARS, Middle East respiratory syndrome, respiratory syncytial virus, and influenza.,, But as of now, the majority of case reports and case series used the aforementioned drugs and demonstrated good clinical response in babies with MIS-N. All newborns in our case study responded very well to the aforementioned drugs as well. However, more research in this age group is required to prove their efficacy.
To the best of our knowledge, this is one of the first studies to describe the clinical features, laboratory parameters, management, and outcomes of neonates with multisystem inflammatory syndrome caused by SARS CoV-2 IgG antibody transplacental transfer. However, due to a scarcity of cases and clinical evidence, larger studies are required to develop new criteria for the diagnosis of MIS-N and to establish treatment protocols. More research is needed to document long-term effects and cardiovascular prognosis.
| Conclusion|| |
In neonates, a disease similar to MIS-C has not been well described. As typical clinical features and laboratory parameters may not be present, a high index of suspicion is warranted, particularly in neonates with fever, multisystem involvement, and positive SARS CoV-2 antibodies. There are no specific clinical manifestations of MIS-N because the clinical features as well as laboratory parameters mimic the majority of common neonatal illnesses such as sepsis. As fever is uncommon in neonates with other illnesses, it may be a soft pointer to the diagnosis. Echocardiography can provide important diagnostic information and help to narrow the differential diagnosis. Serial antibody level estimations are warranted to document antibody waning and establish a transplacental transfer. Since antibodies are implicated in the etiopathogenesis of MIS-N, the safety of vaccination in the mother and baby must also be addressed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]