Neonatal Multi-System Inammatory Syndrome Associated With Covid-19 Exposure in Two Cases From Iran

Introduction: Immune dysregulation following exposure to Covid-19 results in MIS-N (Multi-system Inammatory Syndrome in Neonates). MIS-N affects various systems in the body and is diagnosed with a positive history of PCR test, positive serologic test, and a history of contact with those vectors of COVID-19 infection. This case series aimed to differentiate from possible misdiagnosis about MIS-N. Case Presentation: Both cases are term neonates with positive serology of COVID -19 and the 2nd case with a mother's positive history of Covid-19 PCR at 30 weeks of pregnancy. The rst case was admitted with diarrhea, dehydration, fever for three days, and rash on the 3rd day of hospitalization. We admitted the 2nd case on the 22nd day of birth with a cough, rashes on the head, palms, and soles for two days. Both cases responded to corticosteroid treatment that conrmed MIS-N. Finally, we discharged them with a stable and normal condition in follow-ups. Conclusions:


Introduction
Neonatal multi-system in ammatory syndrome (MIS-N) is an in ammatory and immunologic reaction that appears three to ve weeks after exposure to coronavirus (1). MIS-N affects various systems in the body and is diagnosed with a positive history of PCR test, positive serologic test, or the history of contact with those who are a vector for COVID-19 infection (1). The condition is con rmed in the case of a positive COVID-19 test result for the infant or relatives, fever that lasts three to four days, and the involvement of two or more organs (e.g., heart, lung, gastrointestinal tract, skin, kidney, joints) (2). Some mild symptoms manifest in rare cases without severe multi-organ involvement, including fever, cutaneous rashes, alterations in blood cells, blood ferritin concentration, and high C-reactive protein (CRP) levels (3). By intensity, the disease is categorized into mild, moderate, and severe conditions. In the mild type, symptoms may not appear, and the in ammatory reaction recedes with no intervention. In the intermediate class, oral corticosteroids control the disease. In severe cases with a high fever, the patient must be hospitalized in the intensive care unit and receive higher doses of corticosteroids. MIS is hard to diagnose, especially in neonates, because fever is less common in neonates.
We present two neonates with mild manifestations and variations in blood tests. They were diagnosed with MIS-N and underwent subsequent treatment and follow-up.

Case Presentation
Case I The rst case was a male neonate (GA: 39 weeks) born through elective C-section from a 23-year-old mother with G1L1 and a good APGAR score. He presented diarrhea, dehydration, and fever for three days, and we admitted him for suspicious neonatal sepsis on his 20th day after birth. Initially, considering the high CRP, we administered antibiotics and treated the dehydration. Thorax, brain, and abdominal images were normal in radiologic assessments. Due to the pandemic, We performed the COVID-19 PCR test. All the results were negative. The fever was relieved for a period but appeared again. On the fth day of admission, multi-form rashes appeared on the trunk and limbs ( Figure 1). Skin consultation results increased the probability of drug reaction and viral infection, with the possibility of alleviation straightaway. In ammatory markers and serologic tests for COVID-19 (IgG: 5; IgM: 0.1) were requested due to high fever recurrence and elevated Fibrinogen and D Dimer levels. Rheumatologic consultation results brought up the likelihood of MIS-N. We administrated Methylprednisolone 30 mg/kg stat intravenous, followed by 1mg/kg oral prednisolone for ve days because of patient limitation for staying in the hospital. The neonate became stable after corticosteroid pulse therapy. Fever did not appear during follow-ups after discharge, and the neonate ultimately regained his normal condition (Table 1).

Case II
The second case was a C-section-born female neonate (GA: 38 weeks). The neonate presented cough and rashes on the head, palms, and soles for two days ( Figure 2) and was admitted on her 22nd day of birth.
An outpatient center injected a single dose of hydrocortisone with the diagnosis of allergic reactions.
Mother was infected with COVID-19 on her 30th week of pregnancy. Physical examination, lab data, CXR of the neonate was normal except for rash and a high level of Covid-19 antibody. The neonate was negative for the COVID-19 test. We could not con rm any infectious disease. Cutaneous conditions were relieved, and coughs were disappeared after a single dose of hydrocortisone. Rheumatologic consult con rmed mild MIS-N and recommended no aggressive intervention due to receiving a single dose of hydrocortisone and alleviating the symptoms. The case was discharged with a stable condition after two days and recommended for undergoing cardiac and cutaneous follow-ups (Table1).In follow up the neonate had a normal state.

Discussion
MIS-C (Multisystem In ammatory Syndrome in Children) is more prevalent in children and infants (4), but some studies report cases of MIS in newborns (5). A study further reported MIS-F during the fetal period, where the infection starts during the fetal period, and symptoms appear after birth (6), as in case 2 in this study.
The serum IgG concentration was ve g/L in Case I, according to the Borderline kit results. The level could rise overtime at subsequent titrations, but we could not check it because of time limitations. Serum IgG was high level in Case II. In a study in India (1), the serologic test results were positive for 20 neonates. Since the immune system is immature and non-developed in newborns, positive IgM results are unexpected, though positive maternal IgGs and a history of positive PCR results can be a criterion for detecting MIS-N in newborns(1).
In Case II, the mother con rmed infection with COVID-19 on her 30th week of pregnancy. This history is essential, especially during the last trimester of pregnancy (1). In cases with no history of maternal infections, mothers must undergo serologic tests to nd any clue of infection in newborns. In these cases, positive IgM and IgG results are a criterion for MIS-N diagnosis. As clinically established, the neonate's infection can occur two months from their relatives' infections (7). When there is no evidence of the history of disease and/or positive serologic test results while the infant develops symptoms in the second or third week, then infection through carriers who are in contact with the infant can be expected.
Diagnosis criteria for MIS-C are not considerably different in studies. In general, MIS-C is diagnosed with positive PCR test results, positive serologic test results, and a history of contact with those infected or carrying infections.
Various case series show the involvement of multiple systems (e.g., skin involvements), spanning children from multi-form to maculopapular rashes and severe lesions such as allergic lesions, urticaria, and even gangrene infection(4). In both cases, lesions were mild and disappeared after corticosteroid treatment. There are some criteria for MIS in children (9). However, we cannot use MIS-C criteria for neonates as fever is less common compared to children. We suggest combination criteria as exposure to COVID-19, systemic symptoms with increased in ammatory lab data are enough in neonates.
MIS-C does not occur in the active phase of the coronavirus disease. Symptoms of in amed systems usually appear two to three weeks after cytokine storm (8) (severe cytokine release syndrome (CRS)). The rst-line treatment for this case is corticosteroid pulse therapy (e.g., using methylprednisolone). This technique has been successful in older babies (9) and, thereby, can treat newborns. In Case I, we did not start treatment because of alleviated fever and CRP concentrations, but in ammation was not e ciently controlled given the fever recurrence and increased CRP level. The corticosteroid pulse therapy was, therefore, started for suppressing the in ammation. Advantages of using corticosteroid pulse therapy are diminished hospitalization period, rapid in ammatory reaction alleviation in the in ammatory phase, and no need for the simultaneous use of non-steroidal anti-in ammatory drugs. In this condition, methylprednisolone is a potent medication for suppressing in ammation (10).
Intravenous Immunoglobulin Therapy (IVIG) (11), used for cardiogenic shocks in patients infected with COVID, is not well accepted due to high expenses, limited availability, and uid restriction during shocks. The standard dose for methylprednisolone in children is 10 to 30 mg/kg as a 2-to-3-hour infusion for three days (and ve days in severe cases) (9). In case I, 30 mg/kg was administrated one day and followed by 1mg/kg oral prednisolone for ve days because of patient limitation for staying in the hospital.
Studies have reported up to 90% cardiac involvement, particularly myocardial involvement as cardiac block or even cardiogenic shock, in patients with MIS-C. For this, both cases underwent echocardiography. In the case of cardiac involvement, proper interventions and regular cardiac follow-ups are required, especially at lower ages (12). Establishing at least two follow-up sessions and checking in ammatory markers within two weeks to two months (1).
In case I, the neonate had a high D-Dimer level for thrombosis, though it decreased in subsequent tests without using anticoagulant medication. Anticoagulants, such as enoxaparin (in urgent cases for patients admitted to the intensive care unit) and aspirin (dosage: 3-5 mg per kg of weight, for less severe conditions and patients not admitted to the intensive care unit), have been advised for COVID infection with a high risk of thrombosis and coagulopathy. Such medications are administrated depending on the infant's conditions because the risk of thrombosis is low at lower ages and newborns (1).

Mc Carty et al. (6) reported MIS-N manifestations as Persistent Pulmonary Hypertension in the Neonate
(PPHN), which are alleviated using dexamethasone. Some studies have rarely worked with the DART (Dexamethasone: A Randomized Trial) (13) protocol for dexamethasone. Dexamethasone varies from methylprednisolone in the drug's e cacy. The former is a long-action drug, while the latter is a shortaction medication. High doses of methylprednisolone suppress and restart the immune system by rapid and short-term operating, while dexamethasone's half-life in blood is longer and can cause long-term immune system suppression implications (14).

Conclusion
In in ammatory syndromes, especially in delayed phases of COVID cytokine storms, considering clinical manifestations in newborns, if we consider appropriate and on-time interventions to inhibit cytokine cascade in ammations, mortality and morbidity caused by in ammation and relative complications can diminish. Furthermore, using corticosteroids in newborns to cope with such reactions demands additional trials. -Acknowledgements :The authors would like to thank the parents of the infant for written informed parental consent and special thank from Dr Fatemeh Tahghighi pediatric rheumatologist for her consults. Multi-form rashes on the 3rd day of admission for Case I Figure 2 Cutaneous rashes in Case II