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Kumar M, Swarnim S, Pallavi P. Clinical Characteristics of Multisystem Inflammatory Syndrome in Children and Young Adults With COVID-19: A Rapid Systematic Review. J. Pediatr. Rev. 2022; 10 :367-388
URL: http://jpr.mazums.ac.ir/article-1-432-en.html
1- Department of Pediatrics, All India Institute of Medical Sciences, Gorakhpur, India.
2- Department of Pediatrics, Maulana Azad Medical College, New Delhi, India.
3- Department of Pediatrics, Maulana Azad Medical College, New Delhi, India. , pallavi86.delhi@gmail.com
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1. Introduction
Several cases of a new kind of pneumonia were identified in Wuhan City, China, in 2019. This new disease is now a pandemic and a global health catastrophe. The World Health Organization (WHO) designated the disease as coronavirus disease (COVID-19), caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). In initial reports, the morbidity of this disease was relatively mild in children and adolescents compared to the adult population (2). However, since late April 2020, several cases have been reported of children presenting with circulatory shock and systemic inflammation, with phenotypic similarity to Kawasaki disease (KD) and toxic shock syndrome (TSS). The first cases were reported from the United Kingdom as a series of eight previously healthy children presenting with hyperinflammation and cardiovascular shock (3), followed by similar reports from other parts of Europe and the United States of America. 
A case definition for this emerging hyperinflammatory disorder was formulated by The Royal College of Pediatrics and Child Health (RCPCH) in late April and was provisionally named pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) (4). Later, in May 2020, following a health alert issued by the New York State Department of Health, the Centers for Disease Control and Prevention (CDC) issued a clinical case definition and designated this syndrome as the multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 (5). WHO has also developed a preliminary case definition and case report form for this multisystem inflammatory disorder in children and adolescents (6). Case definitions of this pediatric inflammatory disorder, given by RCPCH, CDC, and WHO, have been summarized in supplementary Table 1.

There have been heterogeneous reports of MIS-C in the form of case reports or small case series. The lack of comprehensive clinical data describing the complete clinical spectrum, treatment options, and outcome of children and young adults under 21 years of age suffering from MIS-C has prompted this review.

2. Materials and Methods
This rapid review was initiated after registering the protocol in the International Prospective Register of Systematic Reviews (PROSPERO) database with registration No. CRD42020190751. This review was conducted following Cochrane guidance on Rapid Reviews (7) and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (8) (Table 2).


Study objectives
The primary objective of this review was to systematically review the clinical characteristics, treatment options, and outcomes of MIS-C or KD-like hyperinflammatory states in children and young adults with COVID-19 infection.

Search strategy
Two authors independently searched PubMed and Embase databases from inception to July 3, 2020. The search was limited to publications in the English language. The search strategy consisted of CDC suggested COVID-19 search terms (9) along with a combination (using Boolean operator AND) of keywords and their corresponding Medical Subject Headings (MeSH). 

Novel coronavirus
Multisystem inflammatory syndrome in children

Kawasaki disease
Details of the search strategy used for PubMed and Embase databases are presented in supplementary Table 3.

Eligibility criteria
Search results were uploaded to Rayyan web applicationand no single method fulfills the principal requirements of speed with accuracy. Automation of systematic reviews is driven by a necessity to expedite the availability of current best evidence for policy and clinical decision-making., We developed Rayyan (http://rayyan.qcri.org (10) for screening by two authors independently. We included all types of studies, including longitudinal studies, case series, case reports, or correspondences from all clinical settings reporting clinical-epidemiologic characteristics of MIS-C or KD-like illness in children and young adults up to the age of 21 years in the review. A third author screened all excluded records. Any disagreements regarding eligibility for inclusion were resolved by consensus.

Critical appraisal 
Critical appraisal and assessment of the risk bias in included studies were done by all authors independently using Joanna Briggs Institute Critical Appraisal Checklist for studies reporting prevalence data (11).

Data extraction 
Individual study data were extracted in a pre-designed format in Microsoft Excel by two authors independently. Study details included first author, location of study, study design, study period, demographic variables, clinical features, details of laboratory, radiological and other investigations, treatment details, and outcomes. Any disagreements related to collated data were resolved by consensus after discussion with the third author.

Data synthesis
Synthesis of included studies was performed through descriptive summaries (usually as a percentage) of demographic variables, clinical features, investigations performed, treatment details, and clinical outcomes.

3. Results 
Search results and critical appraisal
A total of 408 records were identified using the search mentioned above strategy. After excluding duplicate records, the title and abstracts of 301 articles were screened. In the initial screening of title and abstracts, 94 full-text articles were assessed for eligibility, and 55 articles were excluded. Of these rejected studies, 41 were reviews, correspondences, or editorials with no individual patient data; 13 studies did not meet the inclusion criteria for this review, and one study was excluded because it was in the Swedish language. Then, 39 remaining articles (3, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) were subjected to critical appraisal using Joanna Briggs Institute Checklists and were included for qualitative synthesis after confirming their methodological rigor.

Included studies
Twenty out of 39 included studies were from Europe, 7 studies from the UK and 7 from France, and 16 studies from the USA. Three case reports from India and 1 case report from Israel were also included. Of the 39 included studies, 16 were case reports, 9 case series, 10 retrospective observational studies, and 4 prospective observational studies or surveillance studies. The study period of most of the included studies ranged from March to April 2020, with Verdoni et al. (38) reporting data from as early as February 2020 (Table 1). 

Demography
A total of 39 studies were included in this rapid review, constituting 799 participants with 446 males (55.8%). Feldstein et al. (44) and Belot et al. (26) studies were the largest studies in terms of participants, with 186 and 108 participants, respectively. The median age of participants in both studies was 8 years. Similar median age was reported by other included studies (3, 16, 23, 34). The youngest participant was a 4-month-old baby reported by Acharyya et al. (36), while in studies by Miller et al. (32) and Riollano-Cruz et al. (49), the maximum age of included participants was 20 years. Ancestry or racial characteristics were reported in 16 of 39 studies. Many studies from the USA and the UK documented an increased incidence of MIS-C in Black/Afro-American/Non-Hispanic races compared to other races or ethnicities (3, 13, 17, 24, 28, 34, 39, 44, 45).

Clinical features
Fever was a ubiquitous presenting feature in 96.4% (667/692) of patients. Respiratory symptoms were reported in 28 studies comprising 589 patients. Runny nose, sore throat, or cough was reported in 10% (59/589) of patients, while dyspnea was relatively more common and affected 33% of the patients (194/589). Gastrointestinal symptoms were the most common extra-pulmonary systemic feature of MIS-C. More than 50% of the participants in 25 of the 39 included studies presented with either abdominal pain, vomiting, or diarrhea. Neurocognitive features were present in 27.1 % of patients (162/597).
Amongst the symptoms characteristic of KD, rash and non-purulent conjunctivitis were most common, seen in 58.8% (374/635) and 59.9% (377/629), respectively. Other KD-like symptoms were lip/oral changes in 42.4% (242/570) of patients, extremity changes in 32.3% (135/417) of patients, and cervical lymphadenopathy in 17.95% (88/490) patients. More than half of the children in the hyperinflammatory state developed circulatory insufficiency, as 53% (358/668) of patients developed shock.
Comorbidities were reported in the participants of 12 of the 39 included studies. Obesity was the commonest comorbidity, seen in 113/581 (19.4%), asthma in 54/581 (9.2%), and various comorbidities in 49/581 (8.4%) patients.

Laboratory investigations
Table 3 summarizes the median values of laboratory investigations. Blood counts trends were non-specific. Out of 25 studies reporting median white cell counts, 14 showed trend towards leukocytosis (13, 14, 16, 17, 18, 19, 21, 23, 24, 34, 36, 39, 43, 46). All 22 studies reporting median lymphocyte count had lymphopenia except 3 studies (15, 30, 46). In 6 case reports, children with features of MIS-C were anemic (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 33, 36, 43) while median hemoglobin value was less than 11 g/dL in 3 other studies (24, 34, 46).
For documenting the underlying hyperinflammatory state, 35 studies reported median C-reactive protein (CRP) values raised in all except the French study by Leon et al. (15). The median value of other inflammatory markers was reported high in all reporting studies. These markers included procalcitonin (PCT) (19 studies), serum ferritin (28 studies), D-dimer (25 studies), and Interleukin (IL)- 6 (12 studies). 
Underlying cardiac dysfunction associated with MIS-C was documented through measurement of cardiac markers like troponin (25 studies) and pro-BNP (pro-brain natriuretic peptide) (21 studies). Median values of these cardiac markers were raised in all the reporting studies.
Underlying SARS-CoV-2 infection was more often documented through serology. Of all patients included in this review, 212 of 560 (37.8%) had positive nasopharyngeal reverse transcription-polymerase chain reaction (RT-PCR), while 79.15% (410/518) had antibodies against SARS-CoV-2.

Radiological investigations
Chest x-ray abnormality was found in 161 of 369 (43.6%) patients. Very few studies reported imaging findings of chest computed tomography (CT). Hameed et al. (48) performed a chest CT scan on 33 of 35 patients. The main findings were basal consolidation with the collapse in 39% and pleural effusion in 30% of the patients. Three children had bilateral diffuse ground-glass opacities along with patchy dense consolidation. Dufort et al. reported either abnormal chest x-ray or abnormal chest CT in 35% of the patients (35) (Table 4).

In echocardiography, ventricular dysfunction was the major abnormality found in 50.2% (284/565) of the patients, while coronary dilatation was seen in only 15% (87/577) of the cases. Other findings like valvular involvement and pericardial effusion were documented in around 33% (148/446) of the cases.

Treatment and outcomes
About 77% (571/741) of patients in this review required admission to the intensive care unit (ICU). Mechanical ventilation was required in 211 of 773 (27.2%) patients, while 56.35% (448/795) required inotropic support to maintain hemodynamic stability (Table 5).

Amongst treatment modalities used to manage MIS-C, intravenous immunoglobulins (IVIG) was the most common modality, which was used in 510 of 653 patients (78.1%), followed by steroids which were administered to 357 of 639 (55.8%) patients. In refractory cases, immunomodulators were used. Anti-IL-1 (anakinra and others) use was reported in 10.8% (54/500), anti-IL-6 (tocilizumab and others) in 10.2% (51/500), and infliximab in 2% (10/500) of patients. Very few studies reported the use of aspirin and anticoagulants. Aspirin was given in 80 of 108 (74%), while anticoagulants were used in 234 of 380 (61.5%) patients. The mortality rate of MIS-C documented in this review was 1.5%, with only 12 out of 797 participants succumbing to it. Median duration of hospital admission was 7-8 days in many studies (23, 31, 34, 41, 46, 49).

4. Discussion 
There is significant scope and need for studies defining the clinical characteristics of MIS-C in children and young adults because most of the 39 studies in this review were either case reports or case series with small sample sizes. However, their results provide a sneak peek into this previously unrecognized clinical syndrome associated with COVID-19 with KD-like presentation.
Although initial reports of MIS-C reported a phenotypic resemblance to KD, our review emphasizes specific important demographic differences. The median age of MIS-C presentation appears to be higher than that for KD. There is an increased incidence of this clinical entity in Black/Afro-American races than KD, which is more common in Asian ethnicities. Barring 3 case reports from India, none of the studies in this review hailed from Asia despite the COVID-19 pandemic having its origin in China. This racial predilection may emanate from genetic differences, mutations in the virus, or undetermined factors.
Certain manifestations of MIS-C are worth mentioning. As documented in this review, unlike KD, gastrointestinal symptoms are predominant in MIS-C. Similarly, circulatory insufficiency and myocardial dysfunction are distinctly more common than KD, affecting more than half of patients with MIS-C, as evident from clinical manifestations and increased cardiac markers reported by studies included in this review.
The hyperinflammatory state of MIS-C is well established through laboratory evidence synthesized in this review. This hyperinflammation is similar to cytokine storm syndrome associated with acute COVID-19 infection in adults, albeit delayed. Delay in interferon response and slow viral clearing has been putatively implicated in the pathogenesis of MIS-C (51).
Feldstein et al. have documented a temporal association between MIS-C and preceding SARS-CoV-2 infection (44). Also, based on the results of this review, the serological evidence of a preceding SARS-CoV-2 infection is more common than positive nasopharyngeal RT-PCR for viral nucleic acid, which probably suggests that these hyperinflammatory states are post-infectious phenomena brought about by a dysregulated immune response. However, given the lack of definitive data regarding causality other than the temporal association, an evolving body of evidence describing this clinical syndrome, and a myriad of clinical mimickers of its presentation, it is pertinent that the scientific community adopts a meticulous as well as the cautious approach in attributing these hyperinflammatory states to COVID-19.
The collated echocardiographic findings in this review show that ventricular dysfunction was more common than coronary changes in MIS-C. This pattern is distinct from KD, where coronary artery abnormalities are reported in about one-fourth of cases (52). Also, given the lack of follow-up data, the long-term cardiac sequel of MIS-C is still unknown.
Intravenous immunoglobulin (IVIG) was used as the primary treatment modality in 78.1% of participants included in this review. The indirect evidence for the use of IVIG in MIS-C stems from its use in other conditions with phenotypic similarities, such as KD or toxic shock syndrome (TSS). Adjunctive therapy has been used in the form of steroids and, in some studies, immunomodulators of IL-1 and IL-6. Their use, with a mostly favorable response, lends credence to the putative theory of MIS-C being a diffusely hyperinflammatory state of the dysregulated immune response. 
Another important finding of this review is that 77% of children required intensive care with a need for mechanical ventilation in about a quarter of included participants. Hence, early recognition and treatment in an appropriate setting are necessary to decrease mortality which in this review was 1.5%.

5. Conclusion
MIS-C is a clinical mimic of hyperinflammatory states such as KD and TSS. However, evidence collated in this review show notable clinical and epidemiological differences compared to KD, like an increased median age of presentation, a higher incidence in Afro-Americans, the preponderance of gastrointestinal manifestations, and ventricular dysfunction. More extensive epidemiological studies will help in better defining this entity and delineating its phenotypic subtypes
There are inherent limitations of our rapid review. Our search strategy had a selection bias as only articles in English were included. Despite the systematic search of two major databases of PubMed and Embase, the data from studies indexed in the Chinese database of China National Knowledge Infrastructure (CNKI) has not been included. In the absence of a consensus clinical definition, this review includes all studies which have reported a hyperinflammatory state resembling KD, which brings heterogeneity and inadequate generalizability to its findings. This rapid review lacks follow-up data to characterize squeal and reflect the evolving nature of both the pandemic and our understanding of it.

Ethical Considerations
Compliance with ethical guidelines

There were no ethical considerations to be considered in this research.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
Conceptualized and Methodology: Manish Kumar; Data collection: Swarnim Swarnim and Pallavi Pallavi; Investigation: Manish Kumar; Writing – original draft, and Writing – review & editing: All authors.

Conflicts of interest
The authors declared no conflict of interest.



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Type of Study: Systematic Review | Subject: Pediatric Infectious Diseases
Received: 2021/09/2 | Accepted: 2021/11/27 | Published: 2022/01/1

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