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*Corresponding Author: Sandhya bandara, Consultant Paediatrician Incharge Neonatology unit Teaching Hospital, Peradeniya.
Citation: Bandara S, Bavanandan B, Karunarathna W.A.C.N, Attanayake J.C. (2022) Multisystem Inflammatory Syndrome in Neonates; a Real Diagnostic Dilemma!. J. Archives of Medical Case Reports and Case Study, 6(1); DOI: 10.31579/2692-9392/128
Copyright: © 2022 Balasubramaniyam Bavanandan, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 23 May 2022 | Accepted: 10 June 2022 | Published: 28 June 2022
Keywords: neonatal multisystem inflammatory syndrome; early onset sepsis; SARS-Co-2; immune dysregulation; immune modulatory therapy
Neonatal multisystem inflammatory syndrome is a potentially life threatening disease entity which was described following the global crisis of SARS-CoV-2 that still demands further evidence for a conclusive diagnosis. We report a group of neonates who admitted to our neonatal intensive care unit with predominantly cardiac manifestations were treated for early onset of sepsis and subsequently for Neonatal multisystem inflammatory syndrome ended up with a good survival outcome.
IgM – Immunoglobulins M
IgG – Immunoglobulins G
MIS-C – Multisystem inflammatory syndrome in children
RT-PCR – Reverse transcriptase polymerase chain reaction
QTc – Corrected QT interval
MOD – Mode of delivery
NVD –Normal vaginal delivery
LSCS – Lower segment caesarian section
EM – Emergency
EL – Elective
HVS – High vaginal swab
GBS – Group B streptococcus
UTI – Urinary tract infection
POA – Period of amenorrhea
IV IG – Intravenous immunoglobulins
IV MP – Intravenous Methyl prednisolone
MRSA – Methicillin resistant staphylococcus aureus
EF – Ejection fraction
Introduction
COVID-19 caused by SARS-CoV-2, is a global public health crisis with the significant surge in Sri Lanka. According to the figures from Health Promotion Bureau, Sri Lanka, as of 9 may 2022, 517 million individuals were infected worldwide and six hundred thousand were infected in Sri Lanka. Initial studies showed that children were spared of severe COVID-19 [1-3]. However, recently many case reports of children experiencing a potentially life threatening multisystem inflammatory syndrome in children (MIS-C) has been explained [4-6].
MIS-C is said to be due to immune dysregulation following exposure to SARS-CoV-2 though the exact mechanism is still unclear [7]. It presents with fever with multi organ involvement, with raised inflammatory markers weeks after exposure to SARS-CoV-2 (4,5,7). MIS-C has clinical and biochemical resemblance with Kawasaki disease and severe COVID-19 cytokine storm seen in adults [8]. However, its pathophysiology is somewhat different and may be mediated by autoantibodies formed following a COVID-19 infection [9]. More than 80% of children with MIS-C have positive serology (Specific IgM and IgG antibodies) against SARS-CoV-2, but only about one third are positive for SARS-CoV-2 by RT-PCR [4,10,11].
Unlike MIS-C, where the primary infection and multisystem inflammation occur in the same subject, few case reports suggest neonatal multisystem inflammation (MIS-N) occurs secondary to maternally derived antibodies against SARS-CoV-2 which were believed to occur in the newborn through trans-placental passage [13-16].
Maternal antibodies pass transplacentally is a well-known fact and maternal infection with SARS-CoV-2 is not different. Multiple studies are reported transplacental transfer of anti SARS-CoV-2 IgG antibodies to neonates [17-19]. The majority (87%) of infants born to seropositive mothers had detectable IgG antibodies at birth and there was a positive correlation with maternal and infant antibody titers, regardless of presence of symptoms in the mother [18].
Few Indian case series described that these neonates mainly presented with conduction system abnormalities with structurally normal hearts. Specifically prolonged QTc with atrioventricular block or thrombosis with in the 1st week after birth [20].
We present a case series of a group of newborns who admitted to our neonatal intensive care unit over the period of 6 months (1st October 2021 to 31st march 2022) with predominantly cardiac manifestations were treated for early onset of sepsis and subsequently for Neonatal multisystem inflammatory syndrome, ended up with a survival outcome of 87.5% without major comorbidities.
Case details are summarized in table 1.
| Case number | Sex | POA | Parity | MOD | Birth weight | Birth asphyxia | Antenatal history | Perinatal history | Fetal scan |
| 1 | Female | 37 | P2C1 | NVD | 2.5kg | No | No | No | Normal |
| 2 | Female | 39 | P5C3 | NVD | 3.3kg | No | No | No | Normal |
| 3 | Female | 41 | P3C2 | Assisted vaginal delivery | 3.1kg | No | No | Dribbling for unknown duration | Normal |
| 4 | Female | 40 | P1C0 | EM/LSCS | 3.2kg | No | No | Moderate meconium, dribbling for 14 hours, HVS – GBS positive | Normal |
| 5 | Female | 38 | P2C1 | EL/LSCS | 3.3kg | No | No | No | Normal |
| 6 | Female | 40 | P1C0 | NVD | 2.75kg | No | No | Moderate meconium | Normal |
| 7 | Male | 39 | P1C0 | EM/LSCS | 3.85kg | No | No | Dribbling 28 hours | Normal |
| 8 | Female | 30 | P1C0 | NVD | 1.4kg | No | UTI | No | Normal |
Of the eight mothers (all with singleton pregnancy), two (25%) were symptomatic for COVID-19 during pregnancy, six (75%) were asymptomatic. Both symptomatic mothers were tested positive for Rapid antigen test for COVID-19 during 3rd trimester. All mothers were tested for COVID – 19 Rapid antigen test during the admission for delivery and none of them detected positive. Antenatal scans were normal in all mothers and there were no antenatal complications were recorded either.
All mothers were vaccinated for COVID – 19 during pregnancy. The details of vaccination are shown in table 2.
(Table 2)
Case number | Maternal RT-PCR | Maternal RAT | Maternal Serology | Symptoms suggestive of COVID – 19 infection | Exposure History | Vaccination status during pregnancy | Serological evidence in the neonate | ||
1st dose | 2nd dose | Booster dose | |||||||
1 | Not done | Positive at 28 weeks | Not done | Yes | Yes | 6 weeks | 32 weeks | Not given | IgG positive (393AU/ml) |
2 | No | No | Not done | No | No | 19 weeks | 23 weeks | 33 weeks | IgG positive (>400AU/ml) |
3 | Not done | Positive at 40 weeks | Not done | Yes | Yes | 12 weeks | 16 weeks | Not given | IgG positive (362AU/ml) |
4 | No | No | Not done | No | No | 24 weeks | 28 weeks | Not given | IgG positive (Titer not available) |
5 | No | No | Not done | No | No | 18 weeks | 22 weeks | Not given | IgG positive (245AU/ml) |
6 | No | No | Not done | No | No | 22 weeks | 26 weeks | Not given | IgG positive (>100AU/ml) |
7 | No | No | Not done | No | No | 22 weeks | 26 weeks | Not given | IgG positive (274AU/ml) |
8 | No | No | Not done | No | No | 23 weeks | 27 weeks | Not given | IgG positive (Titer not available) |
Resuscitation at birth and post resuscitation period
Three neonates (37.5%) did not cry immediately after birth and two of them had significant respiratory distress in the delivery room. But none of them require any positive pressure ventilation in the delivery room. However all three required respiratory support in the form of nasal prong oxygen. Five neonates (62.5%) neither required resuscitation nor respiratory support in post resuscitation period.
The most common presentation involved the cardiovascular system. Three had rhythm disorders (37.5%) and all of them presented with prolonged QTc interval. One infant also had an episode of persistent unexplained tachycardia. Hypotension was seen in four neonates. Cardiac dysfunction (Septal hypokinesia, dilated cardiac chambers and low ejection fraction) in 2D Echocardiography was seen in 87.5% of neonates. One neonate had slightly prominent right coronary in the 2D Echocardiogram and another one had thin rim of pericardial effusion. One had normal 2D-Echocardiogram.
Table 3 summarizes the general characteristics and other clinical presentations
(Table 3)
Characteristic | Variables | Percentage | Total number of cases assessed |
Maternal symptoms | Symptomatic Asymptomatic
| 25% 75% | 8 |
Trimester when the mother had COVID | 1st trimester 2nd trimester 3rd trimester
| 0% 0% 100% | 2 |
Maternal exposure to COVID patients | Exposure No exposure Unknown
| 25% 0% 75% | 8 |
COVID Vaccination status 1st dose
2nd dose
Booster dose |
1st Trimester 2nd trimester 3rd trimester 1st Trimester 2nd trimester 3rd trimester 1st Trimester 2nd trimester 3rd trimester |
25% 75% 0% 0% 25% 75% 0% 0% 100%
|
8
8
1 |
Mode of delivery | NVD Assisted vaginal delivery EL/LSCS EM/LSCS | 50% 12.5% 12.5% 25%
| 8 |
Gestational age at birth | <28> 28 – 32 weeks 32+1 – 36+6 weeks >37 weeks | 0% 12.5% 0% 87.5%
| 8 |
Birth weight | >3.5Kg 2.5Kg – 3.5Kg 1.5Kg – 2.5Kg < 1> | 12.5% 75% 12.5% 0%
| 8 |
Multiplicity | Singleton Twin | 100% 0%
| 8 |
Age at presentation | <24hours> 1 – 5 days >5days | 37.5% 50% 12.5%
| 8 |
Organ system involvement | Cardiac Hematologic Respiratory Gastrointestinal Neurologic Cutaneous Renal Fever/Temperature instability Antenatal Complications
| 87.5% 75% 50% 25% 12.5% 0% 12.5% 50% 0%
| 8 8 8 8 8 8 8 8 8
|
Cardiac manifestations | Bradycardia Unexplained tachycardia Hypotension & shock Prolonged QT interval Dilated cardiac chambers Dilated coronary arteries Tricuspid regurgitation Mitral regurgitation Pericardial effusion Intracardiac thrombosis Persistent pulmonary hypertension | 0% 12.5% 50% 37.5% 75% 12.5% 0% 0% 12.5% 0% 12.5%
| 8 8 8 8 8 8 8 8 8 8 8 |
Respiratory manifestations | Respiratory distress Pleural effusion | 25% 12.5%
| 8 8 |
Gastrointestinal manifestations | Feed intolerance Ascites | 12.5% 25%
| 8 8
|
Renal manifestations | Acute renal failure | 12.5%
| 8 |
CNS manifestations
| Convulsions | 12.5% | 8 |
Four of eight neonates (50%) had at least one indication for intra partum antibiotic prophylaxis to prevent early onset sepsis (21,22). Two of them had dribbling for more than 18 hours, one had high vaginal swab positive for group B streptococcus in current pregnancy and one neonate born prematurely at 30 weeks of gestation in whom the mother had symptomatic culture negative urinary tract infection during antenatal period.
As five of eight neonates had positive blood cultures (one positive for MRSA and four positive for klebsiella pneumoniae – 62.5%) and all of them had blood pictures positive for possible early onset bacterial sepsis (left shift with neutrophil toxic changes) with elevated inflammatory markers we have considered early onset of sepsis as the primary diagnosis and commenced intravenous antibiotics according to the local guidelines. Neonates who developed circulatory compromise (50%) were effectively managed with intravenous inotropes.
The higher incidence of cardiac manifestations among this group of neonates which is quite unusual to explain only by early onset of sepsis, urged us to consider cardiac markers and 2D Echocardiography to exclude possible infectious or inflammatory myocarditis in them. Surprisingly all of them had elevated troponin I values for age related ranges with 2D Echocardiographic changes suggestive of ventricular dysfunction after the 1st week of life while on treatment with appropriate antibiotics according to the antibiotic sensitivity test.
As new cases with asymptomatic COVID-19 infections being soaring up during that period in our country we have also considered Multisystem inflammatory syndrome in new born (MIS-N) induced by trans placental passage of COVID-19 antibodies as an alternative diagnosis.
To further confirm the diagnosis, investigations done according to the current guidelines for MIS-N practiced in Sri Lanka (Table 4) [23].
(Table 4)
Investigations | Percentage | Total number cases assessed |
Neutrophilic leukocytosis | 0% | 8 |
Thrombocytopenia | 75% | 8 |
Elevated C reactive protein | 87.5% | 8 |
Elevated Serum ferritin | 50% | 2 |
Elevated Pro-calcitonin | 100% | 2 |
Elevated Lactate dehydrogenase | 87.5% | 8 |
Elevated D-dimers | 100% | 8 |
Elevated liver enzymes | 87.5% | 8 |
Elevated Creatinine | 12.5% | 8 |
Elevated INR | 75% | 8 |
Elevated troponin I | 100% | 8 |
Hyponatremia | 12.5% | 8 |
Positive blood culture | 62.5% | 8 |
Positive CSF analysis | 25% | 4 |
Blood picture compatible with sepsis | 100% | 8 |
Anti-SARS-CoV-2-IgM antibodies were not done in all the neonates because it is not readily available in Sri Lanka, and IgG antibodies (cut-off-index (COI) > 1 considered reactive) were positive in all neonates.
The neonates were treated with IVIG (2g/kg over 24 to 48 hours), methylprednisolone (10mg/kg over 30 minutes for 5 days), aspirin (1-5mg/kg/day) and anti-failure treatment (Furosemide and Captopril). The neonates have also been covered with 14 – 21 days of intravenous antibiotics. Normalization of QTc and remarkable improvements in ventricular functions on subsequent 2D Echocardiograms were observed following immune modulatory therapy.
Table 5 summarizes the cardiac manifestations and the treatment given.
(Table 5)
Case number | Clinical presentation | Day of presentation | Troponin I | QTc (>0.47 - prolonged) | 2-DECHO
| Treatment given |
1 | Persistent tachypnea since birth | Day 1 | 93pg/mL on day 10 | 0.40 seconds | Dilated left ventricle with mild septal hypokinesia (EF – 53%) | IVIG IV MP Captopril Furosemide Aspirin Prednisolone |
2 | Fever | Day 2 | 63.2pg/mL on day 15 | 0.50 seconds | Mildly prominent left ventricle (EF – 70%) | IVIG IV MP Aspirin Prednisolone |
3 | Fever | Day 8 | 93.9pg/mL on day 19 | 0.42 seconds | Mild fullness of left ventricle (EF – 65%)
| IVIG Aspirin Prednisolone |
4 | Poor feeding
| Day 2 | 195pg/mL on day 20
| 0.41 seconds | Fullness of left ventricle with mild septal hypokinesia (EF – 69%) Prominent right coronary artery | IVIG IV MP Aspirin Prednisolone Furosemide spironolactone |
5 | Persistent pulmonary hypertension | Day 2 | 75.5pg/mL on day 12 | 0.48 seconds | Mild fullness of left ventricle (EF-76%) | IVIG IV MP Aspirin Prednisolone |
6 | Respiratory distress | Day 1 | 89.2pg/mL on day 32 | 0.43 seconds | Global hypokinesia, mild ventricular dysfunction Thin rim of pericardial effusion (EF-45-50%)
| IVIG IV MP Captopril Furosemide Aspirin Prednisolone |
7 | Fever | Day 3 | 111.4pg/mL on day 24 | 0.48 seconds | Hypokinetic inter ventricular septum (EF – 48%) | IVIG IV MP Captopril Furosemide Aspirin Prednisolone |
8 | Very prematurity | Day 1 | 80.5pg/mL
| 0.42 seconds | No evidence of myocarditis and coronary arteritis (EF – not available) | IVIG IV MP |
The only premature baby in this group eventually succumbed due to acute kidney injury related complications. Those term neonates who survived (87.5%) were discharged with aspirin, oral prednisolone and anti-failures and put on follow up at clinic on regular intervals to modify the drug management according to the repeat 2D-Echocardiograms in liaison with pediatric cardiology team.
According to the proposed inclusion criteria for neonatal multisystem inflammatory response syndrome (MIS-N) secondary to maternal SARS-CoV-2 exposure or infection, presence of a positive blood culture excludes the diagnosis of MIS-N [23]. However there were no convincing evidence to describe the cardiac manifestations that we have observed in this group of neonates, caused by sepsis alone.
Presence of IgG antibodies against COVID-19 in high titers (>100AU/L) and significant improvement observed clinically, biochemically and in follow up 2D-Echocardiograms with immune modulatory therapy further suggest an underlying inflammatory process could be due to MIS-N caused by trans-placental passage of antibodies following symptomatic and asymptomatic COVID-19 infection in the mothers during pregnancy.
Thus, we believe that the immune dysregulation caused by multisystem inflammatory syndrome may increase the susceptibility to acquire early onset sepsis in newborns and both these entities may coexist in a given time. But we require further evidence to support our observation.
Conclusion
The diagnosis of neonatal multisystem inflammatory syndrome following SARS-CoV-2 infection or exposure during antenatal period, is a diagnostic dilemma that demands further studies to understand the underlying pathological mechanism and to decide on crucial immune modulatory therapy in mixed presentations as in our case.
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