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Neonatal MIS-C
Introduction
World Health Organization declared a COVID-19 pandemic in March 2020. SARS-CoV-2 causes COVID-19 infection. It presents as acute respiratory distress syndrome and infects all age groups. In adults, COVID-19 causes acute respiratory failure. In children, COVID-19 usually has a milder clinical course and more favorable outcome than in adults. In contrast to adults and older children, covid-19 infection is uncommon in neonates.[1]
The low incidence of COVID-19 infection in neonates is attributed to the low availability of angiotensin-converting enzyme two receptors in the nasal epithelium, which is thought to be the principal point of access for COVID-19 in the human body. However, hyperinflammatory shock and organ failure cases were reported in neonates and older children with previous COVID-19 and positive antibodies. Following this, a different disease entity associated with COVID-19 in children was described as a multisystem inflammatory syndrome associated with covid-19 (MIS-C).
This condition has also been referred to as pediatric multisystem inflammatory syndrome (PMIS) or pediatric inflammatory,y multisystem syndrome (PIMS). Multisystem inflammatory syndrome associated with COVID-19 (MIS-C) in children is defined as persistent fever, evidence of inflammation, and signs of multiorgan dysfunction with or without confirmation of previous COVID-19 infection.[2]
Other infectious and inflammatory causes with similar signs and symptoms must be excluded before diagnosing MIS-C. MIS-C is considered an immune sequela of COVID-19. MIS-C is typically known to occur after a latency period of 4 to 5 weeks following COVID-19 exposure. MIS-C has broad evolving symptomatology and severity, ranging from asymptomatic to a life-threatening multiorgan failure. Although rare, MISC is known to affect neonates and infants as well.[3]
Etiology
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Etiology
Neonatal cases of COVID-19 infection are mostly due to horizontal transmission. Vertical transmissions have been reported.[4] However, recent evidence suggests that vertical transmission is infrequent, which is thought to be due to low placental expression of the canonical receptors required for the entry of the virus.[5]
Even though the exact etiology of MIS-C is speculative, it is postulated that MIS-C occurs due to a hyperinflammatory response after symptomatic or asymptomatic COVID-19 infection rather than direct cell injury from the virus. Hence, there are a few possible etiologies:
- Maternal covid-19 infection and transplacental transfer of maternal antibodies
- Transplacental transfer of maternal infection and endogenous production of antibodies
- Neonatal COVID-19 infection and post-infectious immune response.[6]
Epidemiology
There is a paucity of data on the incidence of COVID-19 and MIS-C in neonates. MIS-C is estimated to occur only in less than 1 percent of children exposed to COVID-19 infection. Associated risk factors included a history of asthma and obesity. However, the exact incidence of MIS-C in neonates is unknown.
According to the reported data from CDC, only 4% of the total MIS-C cases occurred in infants < 1 year.[7] Most neonatal MIS-C data are from case reports and case series.[8][9] Overall, neonates seem to have a lesser incidence of COVID-19 infection and MIS-C than older children.[10]
Pathophysiology
The exact pathophysiology of MIS-C is unknown. It is speculated that MIS-C occurs due to an immune-mediated mechanism leading to a cytokine storm and oxidative stress. The cause of immune dysregulation and cytokine storm after COVID-19 infection in children and neonates remains unclear.
Maternal COVID-19 infection during pregnancy can impact the developing fetal immune system. Evidence from case reports shows increased inflammatory markers and cytokine functionality in fetuses of mothers with active COVID-19 infection during pregnancy. Less is known regarding the impact of the timing of the exposure and if these inflammatory responses are transient.[11]
Evidence from the placental studies of the mothers exposed to covid-19 infection during the pregnancy reveals thrombotic and vascular changes,[12]which suggests fetal inflammatory risk even in the absence of an active viral infection in the fetus or neonate.[13]
During maternal COVID-19 infection, protective maternal IgG antibodies are transferred to the fetus via the transplacental route. In some neonates, this may cause an autoantibody reaction that binds to neutrophil and macrophage receptors and cause cytokine response which leads to MIS-C.[14][15]
Depending on the timing of COVID-19 exposure in the mother, this reaction can occur prenatally or postnatally. Thus, neonates exposed to the covid-19 infection in the mother during the antenatal period can also trigger an inflammatory response postnatally, leading to the development of MIS-C.
Thus, MIS-C in neonates can develop due to immune-mediated multisystem injury either due to transplacental transfer of antibodies or antibodies from a neonatal covid-19 infection.[14][16]
History and Physical
Signs and symptoms of MIS-C are highly variable. The time of onset of the symptom of COVID-19 exposure is essential. Since MIS-C is a post-infectious immune sequela of COVID-19, there usually is a latency period of 4 or 5 weeks following the COVID-19 exposure to the development of MIS-C symptoms. It is important to note that infants with a maternal history of COVID-19 exposure may present earlier than 4 to 6 weeks of life due to the placental transfer of antibodies in fetal life. The presentation can range from asymptomatic infection to multiorgan failure. Infants can present with or without fever. Signs of inflammation and multiorgan dysfunction aid the diagnosis.[17]
Symptoms may include fever, rash, conjunctivitis, gastrointestinal symptoms such as emesis, diarrhea, and abdominal tenderness. It is important to note that fever may be absent in infants even with the signs of inflammation and multiorgan dysfunction.[6] In neonates, symptoms can vary from older children due to the developmentally immature immune system. The clinical presentation in neonates can be predominantly gastrointestinal and poor feeding.[17]
Other clinical signs and symptoms include:
- Bilateral non-suppurative rash, conjunctivitis, or mucocutaneous involvement
- Hypotension, shock, or signs of cardiovascular dysfunction
- Gastrointestinal involvement such as emesis, diarrhea, abdominal tenderness
- Respiratory distress or pneumonia
- Neurological impairment, seizures, signs of meningitis
- Signs of acute kidney injury
- Signs of coagulopathy[18]
Evaluation
Diagnosis of MIS-C is based on the characteristic clinical presentation, history of exposure to COVID-19, and characteristic laboratory abnormalities. Exclusion of other diagnoses with similar presentation and evidence of COVID-19 exposure (prior maternal SARS-CoV-2 exposure, positive neonatal RT-PCR, or positive serology) is also essential while diagnosing MIS-C. The CDC and WHO have published criteria for diagnosing MIS-C in children. However, these criteria may not always be ideal for the neonatal population. Currently, there is no widely agreed definition for diagnosing MIS-C exclusively in neonates.[16]
Laboratory findings may include the following:
- Leukocytosis or leukopenia, neutrophilia, anemia, thrombocytopenia
- Elevation of inflammatory markers including C- reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, interleukin-6 (IL-6)
- Elevation of cardiac markers such as troponin or Pro-BNP
- Coagulopathy as evidenced by prolonged prothrombin time, D-dimer elevation
- Hypoalbuminemia and hyponatremia
- Elevated liver and renal function tests
- Metabolic acidosis and elevated lactate
Laboratory findings are variable, especially in the neonatal population. Therefore, high suspicion is required for the diagnosis of MIS-C in neonates. Laboratory work-up must be done in cases of suspected MIS-C to evaluate the degree of inflammation and end-organ dysfunction. Positive neonatal real-time polymerase chain reaction (RT-PCR) or positive serology for SARS-CoV-2 can be considered evidence of prior COVID-19 exposure. A history of maternal SARS-CoV-2 exposure should be obtained in infants with negative testing.
To rule out cardiac dysfunction, an electrocardiogram and echocardiographic evaluation must be obtained in all neonates with suspected MIS-C.[18] Infants with elevated troponins, pro-BNP, or signs of cardiac dysfunction such as hypotension, shock, or need for inotropic support are at a higher risk for myocardial involvement.[19] Myocardial dysfunction, pericarditis, pericardial effusion, valvulitis, and coronary arterial abnormalities have been reported in children and neonates with MIS-C.[20]
A Chest X-ray or computed tomography (CT) of the chest may show findings of pulmonary involvement, including interstitial pneumonia, pleural effusion, etc. The abdominal ultrasound should be done in infants with gastrointestinal symptoms to look for organomegaly and gall bladder hydrops and rule out other possible differential diagnoses—cases of neurological impairment warrants a brain ultrasound or magnetic resonance imaging (MRI) of the brain.
Treatment / Management
Treatment for neonatal MIS-C is largely extrapolated from the evidence from the treatment of adults and older children.[21] Intravenous immunoglobulin and corticosteroids are used to manage MIS-C to improve symptoms related to the increased inflammatory response.[18] (A1)
Studies have shown that the combination of IVIG and steroids is more effective than IVIG alone. Inotropic support may be required in cases of cardiovascular dysfunction. Biological agents such as tocilizumab, infliximab, anakinra, and interferons have been used for children and neonates with refractory disease unresponsive to corticosteroids and IVIG. However, data supporting the use of such medications is sparse.[1]
Broad-spectrum antibiotics are mostly used during presentation due to the clinical presentation mimicking sepsis. Antibiotic treatment should be discontinued once the diagnosis is confirmed and the blood cultures are resulted to be negative. Thromboprophylaxis is indicated in cases of high pro-thrombotic risk factors.[22][23]
The ideal treatment approach must be tailored based on the clinical presentation. More clinical trials are necessary to study the efficacy of various treatment modalities. Long-term follow-up is necessary to elucidate potential sequelae.
Differential Diagnosis
The signs and symptoms of MIS-C can mimic several other conditions. Important differential diagnoses to consider include:
- Toxic shock syndrome
- Macrophage activation syndrome
- Kawasaki disease
- Hemophagocytic lymphohistiocytosis[24]
Prognosis
Short-term outcomes of MIS-C depend on the severity and extent of cardiovascular and respiratory involvement.[25] Various studies have reported mortality ranging from 1 to 11%.[26][27][28] With timely diagnosis and management, outcomes are favorable. Long-term follow-up in infants exposed to COVID-19 antenatally or in the neonatal period is necessary to elucidate potential sequelae.
Complications
The most common complications of MIS-C include respiratory distress and cardiovascular dysfunction. Infants with MIS-C also have an increased risk for prothrombotic coagulopathy and thromboembolic complications, including pulmonary thromboembolism.[29]
Case reports have described complications such as deep vein thrombosis, limb ischemia, and intracranial hemorrhage.[30]Other complications, such as pericardial effusion and acute renal failure, have been reported.[31]
Consultations
Often, these infants are managed in the neonatal or pediatric ICUs, and the following consultations may be utilized:
- Pediatric rheumatology for the recommendations regarding the use of biological medications
- Pediatric hematology for the anticoagulation recommendations
- Pediatric infectious diseases to rule out infectious etiology
- Pediatric cardiology in cases with cardiovascular involvement and/or requiring inotropic support
Deterrence and Patient Education
MIS-C is a disease entity associated with COVID-19 and has evolving symptomatology and severity. A deeper understanding of the pathophysiology of MIS-C may lead to better treatment strategies. Due to rapid mutations and the contagious nature of the viral infection, covid-19 infection and associated sequelae remain a threat, and better preventative strategies are needed.
Pearls and Other Issues
MIS-C in neonates, although rare, is associated with morbidity and mortality. MIS-C in neonates may present with a wide variety of signs and symptoms. Early recognition is paramount. The mainstay of treatment involves IVIG and corticosteroids. More clinical trials are necessary to study the efficacy of various treatment modalities. Long-term follow-up is necessary to elucidate potential sequelae.
Enhancing Healthcare Team Outcomes
The diagnosis and management of MIS-C require an interprofessional team approach. Diagnosis is based on clinical presentation and is often a diagnosis of exclusion in patients with known COVID-19 exposure. Neonatal intensivists need to consider the possibility of MIS-C in neonates with in-utero exposure to COVID-19.
The initial evaluation is often by a neonatologist or pediatric intensivist. Once the diagnosis is made, a multidisciplinary approach involving pediatric or neonatal intensivist, pediatric cardiology, pediatric infectious disease, pediatric rheumatology, and pediatric hematology is essential for the management of the presentation as well as the potential complications. The interprofessional team approach is vital to improve the outcomes for patients.
Current evidence on the pathophysiology of neonatal MIS-C is scarce and contradicting. Therefore, well-structured diagnostic criteria and management approaches are needed. A deeper understanding of pathophysiology may lead to better treatment strategies. Data sharing is crucial to formulate optimal treatment approaches.
References
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