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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 101-106

Multisystem inflammatory syndrome in children associated with Coronavirus Disease-2019: An overview


1 Department of Pediatrics, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates
2 Department of Obstetrics and Gynaecology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates

Date of Submission14-Oct-2020
Date of Decision28-Feb-2021
Date of Acceptance03-Mar-2021
Date of Web Publication26-Jun-2021

Correspondence Address:
Dr. Subhranshu Sekhar Kar
Department of Pediatrics, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras al Khaimah
United Arab Emirates
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_273_20

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  Abstract 


Coronavirus disease-2019 has been ravaging the world since the past several months with devastating consequences. Although it is seen that specific categories of patients with comorbidities are especially vulnerable, the risks from the acute disease in pediatric population have been consistently lower. However, the alarming rise in pediatric admissions in intensive care units with varied clinical presentation during this pandemic gave an insight to a new hyperinflammatory response called as multisystem inflammatory syndrome in children. Although overlapping symptoms may mimic toxic shock syndrome, macrophage activation syndrome, secondary hemophagocytic lymphohistiocytosis, myocarditis, or Kawasaki-like illness, clinical findings are relatively consistent across geographically distinct regions. Diagnosis is essentially clinical, and laboratory investigations are suggestive of increased inflammatory markers. Early recognition and appropriate institution of inotropes, intravenous immunoglobulins, corticosteroids, and antibiotics apart from general supportive treatment are required for a favorable outcome.

Keywords: Coronavirus disease-2019, Kawasaki-like illness, multisystem inflammatory syndrome in children, pediatric multisystem inflammatory syndrome temporally associated with coronavirus disease-2019, severe acute respiratory syndrome coronavirus 2


How to cite this article:
Kar SS, Dube R. Multisystem inflammatory syndrome in children associated with Coronavirus Disease-2019: An overview. Arch Med Health Sci 2021;9:101-6

How to cite this URL:
Kar SS, Dube R. Multisystem inflammatory syndrome in children associated with Coronavirus Disease-2019: An overview. Arch Med Health Sci [serial online] 2021 [cited 2021 Nov 30];9:101-6. Available from: https://www.amhsjournal.org/text.asp?2021/9/1/101/319387




  Introduction Top


The major global challenges for public health in recent times have been the reemerging pathogens. Coronaviruses are positively stranded enveloped RNA viruses widely distributed in humans, other animals, and birds. In late 2019, in Wuhan city of the Hubei Province of China, the novel coronavirus was attributed as the cause in cluster of pneumonia patients. In no time, due to its extremely rapid spread, it reached to epidemic proportion in China, followed by spread to other neighboring countries and beyond. In February 2020, the World Health Organization designated the disease as coronavirus disease-2019 (COVID-19), which stands for coronavirus disease 2019.[1] The virus causing COVID-19 is designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was previously referred to as 2019-nCoV. These pathogens commonly cause respiratory, gastrointestinal, and neurologic diseases. Seven strains of the virus are known to cause diseases in humans. The four strains, namely, 229E9 (alphacoronavirus), NL 63 (alphacoronavirus), OC43 (betacoronavirus), and HKU1 (betacoronavirus) normally cause self-limiting upper respiratory tract infection in immunocompetent individuals. The rest three zoonotic coronavirus diseases have caused epidemics with fatal outcomes. They are Middle Eastern Respiratory Syndrome coronavirus causing Middle Eastern Respiratory Syndrome (betacoronavirus), SARS-CoV causing severe acute respiratory syndrome (SARS) (betacoronavirus), and SARS-CoV2 (the novel coronavirus that causes coronavirus disease-COVID-19). The worrisome fact is that a large number of SARS-related potentially mutagenic strains of coronaviruses have been discovered in their natural reservoir in bats and also SARS-CoV-2 isolates encoding a D614G mutation in the viral spike (S) protein predominate over time in locales where it is found, implying that this change enhances viral transmission.[2],[3]

Till date, COVID-19 has caused >22 million infections globally with over 795,000 deaths. However, there is less information about epidemiology and clinical impact of COVID-19 in children. Younger population under 18 years of age are less involved (attack rate 2.4%).[4],[5] Furthermore, the clinical manifestations are generally milder in infants and children compared to adults.[6],[7],[8] Multisystem inflammatory syndrome in children (MIS-C) was first recognized in late April 2020, where clinicians in the United Kingdom reported a cluster of eight previously healthy children presenting with cardiovascular shock, fever, and hyperinflammation similar to presentations of incomplete Kawasaki disease (KD) or toxic shock syndrome (TSS).[9] On May 14, 2020, the Centers for Disease Control and Prevention (CDC) issued a national health advisory to report on cases meeting the criteria for MIS-C.[10] Thereafter, many case series of MIS-C were reported requiring admissions in intensive care from across the globe, especially from the USA, Italy, France, United Kingdom, and Spain.[11],[12],[13] Alternatively, MIS-C is also referred as pediatric hyperinflammatory shock, pediatric multisystem inflammatory syndrome, or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). The true prevalence of this condition is difficult to estimate as the disease is still evolving at this point of time.


  Epidemiology Top


Like any other pandemic situation, the reported case counts hugely underestimate the overall burden of COVID-19, as only a minor fraction of acute infections are diagnosed and reported. Seroprevalence surveys in the United States and Europe did point to the fact that, after accounting for potential false positives or negatives, the rate of prior exposure to SARS-CoV-2, as reflected by seropositivity, exceeds the incidence of reported cases by approximately 10-fold or more.[14],[15],[16] While the incidence of MIS-C is uncertain, evidences suggest that this phenomenon appears to be relatively rare in COVID-19 in children. In one report, the estimated incidence of laboratory-confirmed SARS-CoV-2 infection in individuals <21 years old was 322/100,000 and the incidence of MIS-C was 2/100,000.[17] Like KD, where the cause is entirely not known, MIS-C is also a syndrome having wide range of clinical manifestations without any pathognomonic findings or specific diagnostic tests.[9],[12],[18],[19],[20],[21],[22],[23],[24] However, the predominant affection of children older than 5 years of age and adolescents with more frequent cardiovascular involvement are clinical differentiating features of MIS-C from KD.[9],[12],[20] With time, the epidemiologic association of MIS-C with COVID-19 is now well established. Regions heavily affected by SARS-CoV-2, all over the world, are reporting many cases of MIS-C. From these reports, it has been clearly shown that the clinical findings are relatively consistent across geographically distinct regions. The timing of MIS-C is also consistent with a mechanism related to host response and hyperinflammation. Prospective reporting of this condition has now been initiated by agencies worldwide to capture prevalence, early clinical course, and outcome.[25]


  Pathophysiology Top


The host receptor for SARS-CoV-2 cell entry is the same as for SARS-CoV, the angiotensin-converting enzyme 2 (ACE2).[26] ACE2 is a membrane-bound protein commonly found in vascular endothelia, cardiovascular tissue, renal, and small intestine. The cellular protease TMPRSS2 also appears important for SARS-CoV-2 cell entry.[27]

Immune response to SARS-CoV-2 seems to involve both cell-mediated immunity and antibody production. Invasion of the cardiac myocytes by virus or hypoxemia resulting from respiratory failure, results in oxidative stress and myocardial damage.[28] Sudden and excessive release of cytokines cause acute respiratory distress syndrome and rapid progress to multiorgan dysfunction. MIS-C is also a possible consequence of cytokine storm (CS) and interleukin-6 (IL-6) is the major cytokine implicated. Its level correlates well with disease severity. The exact pathophysiology of MIS-C is not yet fully understood. Negative polymerase chain reaction (PCR) testing for SARS-CoV-2 but positive serology has been documented in many affected children. This observation supports the hypothesis that MIS-C is related to immune dysregulation occurring after acute infection has passed, usually 2–4 weeks post-COVID-19 infection.[29] The low levels of antibodies in these children may prevent further spread of the SARS-CoV-2 infection, but antibody-dependent enhancement might be responsible for MIS-C.[30] However, some children do have positive PCR testing.[12],[13],[20] A postinfectious process is also postulated, based on the timing of the rise of these cases relative to the peak of COVID-19 cases in communities.[20]


  Clinical Presentation Top


Varied clinical presentation in the young is reported in many case series, encompassing the features of TSS, myocarditis, macrophage activation syndrome (MAS), and KD-like syndrome.[9],[31] The usual features are prolonged history of fever, gastrointestinal symptoms including abdominal pain, cardiovascular involvement, conjunctivitis, rash, irritability, peripheral edema, neurocognitive problems, lymphadenopathy, and generalized myalgia.[12],[13],[21],[32] Acutely, due to the development of pleural effusion, pericardial effusion, or ascites, they can have severe respiratory symptoms. More than half of these children present with significant gastrointestinal symptoms. In relation to the cardiovascular involvement, the patients may present with distinct yet overlapping features [Table 1] and [Table 2].[19],[32]
Table 1: Criteria for diagnosis of complete and incomplete Kawasaki disease[19]

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Table 2: Clinical presentation of toxic shock syndrome[32]

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However, the hallmark feature of MIS-C is the presence of high and persistent fever (≥3 days), unexplained by other causes. Fever together with laboratory evidence of marked systemic inflammation and temporal association with COVID-19 having been present in the community should raise the index of suspicion for MIS-C.[33] They can even experience KD shock syndrome (KDSS), which is defined by systemic hypotension and hypoperfusion, and/or MAS.[24],[34],[35],[36],[37] MAS is a potentially life-threatening complication that presents with persistent fever, rash, lymphadenopathy, hepatosplenomegaly, and occasionally with neurological complications. Affected individuals have characteristic laboratory features including marked increases in C-reactive protein, ferritin, lactate dehydrogenase (LDH), aspartate transaminase, alanine transaminase, triglycerides, and D-dimers, as well as progressive cytopenias.[24],[35]


  Spectrum of the Disease Top


Initially, MIS-C was reported mostly in severely affected children. Subsequently, it is found that the spectrum of disease ranges from mild to severe. Subphenotypes of the syndrome are also gradually evolving [Table 3].[13] The case definitions are likely to change with the availability of more information.
Table 3: Corona virus disease-19 spectrum[13]

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  Case Definitions for Multisystem Inflammatory Syndrome in Children Top


MIS-C cases are defined differently by the US CDC,[10] the UK Royal College of Paediatrics and Child Health,[38] Canadian Pediatric Surveillance Program,[33] and also by the World Health Organization.[39] These case definitions include association with COVID-19 [Table 4], as defined by a positive test for SARS-CoV-2 or exposure to others with COVID-19 within 4 weeks before the onset of symptoms.
Table 4: Case definitions for multi-system inflammatory syndrome in children[10],[33],[38],[39]

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  Laboratory Investigations Top


As MIS-C has only recently been recognized, evidence-based recommendations for laboratory testing is difficult at this moment. However, as children with MIS-C deteriorate quickly, certain principles must be kept in mind for successful management. Positive test for SARS-CoV-2 by reverse transcriptase PCR for viral RNA (RT-PCR), antigen, or antibody establishes the diagnosis of COVID-19. When a patient presents with otherwise unexplained, isolated high fever ≥3 days and a history of or potential exposure to COVID-19 based on local epidemiology, screening laboratory tests for hyperinflammation should be considered [Table 5].[33] When laboratory evidence of significant hyperinflammation is present, additional workup is needed for an evolving picture of CS (ferritin, LDH, fibrinogen, D-dimers, partial thromboplastin time, international normalized ratio, and triglycerides), and for myocarditis (troponin, N-terminal-pro-B-type natriuretic peptide [NT-proBNP], and electrocardiogram [ECG]).[33]
Table 5: Investigations for multi-system inflammatory syndrome in children[33]

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The common laboratory abnormalities found in MIS-C are summarized in [Table 6].[33],[40]
Table 6: Laboratory abnormalities seen in multi-system inflammatory syndrome in children[33],[40]

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  Management Top


As the spectrum of patients is highly variable, treatment mostly is supportive and includes maintenance of fluid and electrolyte balance. Urgent admission is indicated if the child appears sick and investigation parameters are suggestive of high inflammatory markers with abnormal values of troponin or NT-proBNP. Treatment in the line of KD should be instituted after doing a thorough cardiac evaluation. Pediatric rheumatology and pediatric cardiology consultation should be ought. In case of deferred admission in apparently well looking child with underlying hyper-inflammation, a close follow-up is warranted with repeat laboratory investigations in next 24–48 h. Children presenting with KD such as symptoms should be managed with Intravenous Immunoglobulin- IVIG-2 g/kg, to a maximum of 70 g/day and acetylsalicylic acid. ECG and echocardiogram are advised at admission and again repeated as needed. Pediatric rheumatology and if possible, pediatric infectious disease specialist consultation might be needed.[12],[19],[21] At diagnosis, corticosteroids are started along with IVIG in high-risk cases. Patients <1 year of age at presentation, fever for ≥10 days, KDSS, MAS, or coronary artery dilatations on baseline echocardiogram are considered as high-risk cases.[19],[41],[42] In case of nonresponders to IVIG, corticosteroids may be considered, either oral prednisolone at 2 mg/kg/day in 2–3 divided doses or pulse intravenous (IV) methylprednisolone infusion at a dose of 20–30 mg/kg/day (maximum 1 g) over 1–3 h.[19] In complicated cases, for patients with KD with refractory MAS or shock and with inadequate response to IV pulse methylprednisolone treatment, biologic therapy with anakinra is indicated. In these cases, it is better to consult with a pediatric rheumatologist before starting therapy. In serious cases, presenting severe myocardial dysfunction and cardiogenic shock (with abnormal ECG, elevated markers such as troponin, and NT-proBNP), urgent intensive care unit management is indicated as these subsets of patients can deteriorate very quickly and require judicious and controlled administration of fluid, inotropes, and ventilation. Broad-spectrum antibiotics are started at the beginning as its difficult to rule out severe bacterial sepsis based on only overlapping symptoms. Multispecialty consultation especially cardiology and critical care consultation are required before shifting the patient for tertiary care.[33] Use of hydroxychloroquine and azithromycin is purely based on the institutional guidelines. Heparin may be advised in mechanically ventilated patients or with thromboembolic phenomena.[12],[43] Anti-inflammatory agents such as tocilizumab (8 mg/kg IV over 2 h), an IL-6 receptor antagonist approved by US FDA for treating CS may be useful in selected cases.[31] Extracorporeal membranous oxygenation is generally reserved for the very severe cases with pulmonary involvement and hypotensive shock.


  Conclusion Top


Although COVID-19 affects children less commonly with milder symptoms than adults, MIS-C associated with SARS-CoV-2 has led to serious and life-threatening illness in previously healthy children and adolescents. It appears to be a late manifestation as a result of immune dysregulation to pathogen. This rare syndrome shares common features with other pediatric inflammatory conditions including KD, TSSs, bacterial sepsis, and MASs. Patients may have abdominal symptoms with excessive inflammatory markers. Early recognition and multidisciplinary specialist consultation including referral to critical care are essential. Treatment regimens are individualized depending on the clinical presentation.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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Introduction
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