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Abstract
Background Knowledge about multisystem inflammatory syndrome in children (MIS-C) is evolving, and evidence-based standardised diagnostic and management protocols are lacking. Our review aims to summarise the clinical and diagnostic features, management strategies and outcomes of MIS-C and evaluate the variances in disease parameters and outcomes between high-income countries (HIC) and middle-income countries (MIC).
Methods We searched four databases from December 2019 to March 2023. Observational studies with a sample size of 10 or more patients were included. Mean and prevalence ratios for various variables were pooled by random effects model using R. A mixed generalised linear model was employed to account for the heterogeneity, and publication bias was assessed via funnel and Doi plots. The primary outcome was pooled mean mortality among patients with MIS-C. Subgroup analysis was conducted based on the income status of the country of study.
Results A total of 120 studies (20 881 cases) were included in the review. The most common clinical presentations were fever (99%; 95% CI 99.6% to 100%), gastrointestinal symptoms (76.7%; 95% CI 73.1% to 79.9%) and dermatological symptoms (63.3%; 95% CI 58.7% to 67.7%). Laboratory investigations suggested raised inflammatory, coagulation and cardiac markers. The most common management strategies were intravenous immunoglobulins (87.5%; 95% CI 82.9% to 91%) and steroids (74.7%; 95% CI 68.7% to 79.9%). Around 53.1% (95% CI 47.3% to 58.9%) required paediatric intensive care unit admissions, and overall mortality was 3.9% (95% CI 2.7% to 5.6%). Patients in MIC were younger, had a higher frequency of respiratory distress and evidence of cardiac dysfunction, with a longer hospital and intensive care unit stay and had a higher mortality rate than patients in HIC.
Conclusion MIS-C is a severe multisystem disease with better mortality outcomes in HIC as compared with MIC. The findings emphasise the need for standardised protocols and further research to optimise patient care and address disparities between HIC and MIC.
PROSPERO registration number CRD42020195823.
- COVID-19
- mortality
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. As this is a meta-analysis, all data are available in individual studies and in the online supplemental file. Data analysis code and raw Excel data sheets can be made available on reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Multisystem inflammatory syndrome in children (MIS-C) can present acutely with multi-organ involvement and shock requiring intensive care admission, and can prove to be fatal.
WHAT THIS STUDY ADDS
Our systematic review is based on data from 120 observational studies and over 20 000 patients, providing a comprehensive global picture of the clinical and diagnostic features, management strategies and outcomes of MIS-C.
Variances in disease parameters between high-income countries (HIC) and middle-income countries (MIC) were explored in this review, specifically highlighting the higher mortality rate in MIC as compared with HIC.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The identification of a high mortality rate in MIC necessitates the requirement of large-scale studies to determine the true burden of disease and to develop standardised diagnostic criteria for MIS-C.
Pooled data from our review can help create management guidelines and policies, and conduct randomised controlled trials on currently available drugs and new treatments, exploring the resulting short-term and long-term outcomes in patients with MIS-C.
Introduction
SARS-CoV-2 emerged in late 2019 as a novel coronavirus that swiftly reached pandemic proportions, leading to >750 million cases and approximately 7 million deaths, globally.1 Initially, COVID-19 was thought to present as a mild respiratory infection in the paediatric population.2 3 However, it soon became apparent that some children can present with severe illness with features of hyperinflammatory shock and multi-organ involvement, after several reports from different countries (including the UK, the USA and Italy).4–6 This condition was termed multisystem inflammatory syndrome in children (MIS-C) or paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Since then, MIS-C has been reported from different parts of the world with a varied presentation and has been likened to other diseases, including Kawasaki disease (KD), toxic shock syndrome (TSS), macrophage activation syndrome (MAS), haemophagocytic lymphocytic histiocytosis, and even appendicitis, due to overlapping clinical manifestations which complicated the diagnosis.7–11
Due to a varied disease presentation, multiple case definitions have been suggested by entities like WHO, Centers for Disease Control and Prevention (CDC) and Royal College of Paediatrics and Child Health (RCPCH), to help guide clinicians towards the diagnosis.12–14 The Council of State and Territorial Epidemiologists and CDC have recently provided an updated case definition that is more specific and aligned with the evolving knowledge of this syndrome.15 MIS-C primarily affects children and young adults up to 21 years of age, and presents as persistent fever, elevated inflammatory markers, evidence of SARS-CoV-2 infection (or history of close contact with infected individuals) and multisystem organ involvement (at least two systems) with no alternative plausible diagnosis, requiring hospital admission. Management largely focuses on supportive care, including fluid resuscitation, inotropic and respiratory support as needed and immunomodulation, which includes steroids and intravenous immunoglobulins (IVIG).16–18
Multiple descriptive and analytic studies, predominantly from high-income countries (HIC), have summarised the clinical and diagnostic features associated with MIS-C on a small or national scale.19–23 Management has largely been guided by expert opinion, with the Delphi process being used by the UK and the USA.17 18 This systematic review aims to provide a comprehensive review of the currently available literature on MIS-C and examine the clinical and diagnostic features, management and outcomes associated with the disease. Furthermore, we want to highlight the key differences in the disease profile and outcomes of patients with MIS-C between HIC and middle-income countries (MIC).
Methods
Eligibility criteria
The review included case series, prospective and retrospective cohort, case-control and cross-sectional studies that recorded the clinical presentation, diagnostic features, management and outcomes of patients with MIS-C, with a sample size of 10 or more patients. We included studies that used clinical definitions to diagnose MIS-C, provided by WHO, CDC or RCPCH, and their own institutional/regional criteria (see online supplemental table 1 for details on various diagnostic criteria for MIS-C). The population defined for this review consisted of individuals between the ages of 0 and 21 years with a history of SARS-CoV-2 contact, a PCR test result positive for SARS-CoV-2 through nasopharyngeal, throat, blood or stool samples and/or a positive SARS-CoV-2 serology (antigen or antibody) test at any point during their clinical evaluation. We excluded studies lacking details of the hospital course of the patient, or mixed MIS-C patient data with another group of patients (eg, overall data for COVID-19-affected children not diagnosed with MIS-C, or paediatric and adult population with multisystem inflammatory syndrome).
Supplemental material
Search strategy
We conducted a systematic search in four databases including PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library and LitCovid. Additionally, we screened medRxiv and bioRxiv for pre-print papers. The search strategy had both free text and Medical Subject Headings terms related to MIS-C (eg, multisystem inflammatory syndrome, PIMS-TS), COVID-19 (eg, SARS-CoV-2) and paediatric populations (eg, child* and adolescent*) (see full search strategy in online supplemental table 2). We limited the search to English-language articles and included all eligible studies published since December 2019 up to March 2023. The bibliographies of all included studies and existing systematic reviews were hand-searched. The methods used in this study followed the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)24 and the study was registered with PROSPERO (CRD42020195823), however, no protocol was prepared or published.
Study selection
We imported all retrieved articles into Covidence,25 where two reviewers independently screened each title and abstract, and a third reviewer resolved all conflicts. Two reviewers assessed full-text reports of screened articles for eligibility, with a third resolving disagreements. To evaluate studies for patient data overlap, we cross-checked studies for their data collection centres and data collection period, and included the studies that had more variables, a bigger sample size and better quality of assessment. When it was unclear, efforts were made to contact the authors to ensure they reported results from different centres or during different periods (details of overlapping studies can be found in online supplemental table 3).
Data extraction
Two investigators independently extracted the data into a prepiloted extraction form (the study team conducted pilot testing on five studies for flow and clarity, after which we modified five, removed three and added five fields) and this was cross-checked by a senior investigator. The extracted variables included the study design, country of study, study period, sample size, demographic information, comorbidities, clinical presentation, diagnostic criteria, COVID-19 diagnosis, diagnostic evaluations, management strategies, hospital and paediatric intensive care unit (PICU) length of stay (LOS) and mortality. The income status of the country of study was recorded according to the new World Bank country classifications.26 Upper-income and lower-middle-income countries were grouped into one category named MIC. This was done to simplify the analysis, making it easier to compare findings without needing to stratify data into multiple income categories. Our study only included race and ethnicity data from studies exhibiting diversity (>1 race/ethnic group was mentioned).
We adopted the normal laboratory reference ranges reported in each individual study as the standard for that respective study. Values were not standardised across studies due to the absence of individual patient data in most cases. Many studies provided only mean laboratory values for the overall patient sample and/or the number of patients categorised as having normal, high or low laboratory values according to their respective reference ranges. In our analysis, we considered ‘normal’, ‘high’ and ‘low’ values exactly as defined by each study to preserve the original data as reported, maintaining context-specific interpretation of results based on the reference ranges provided by the respective laboratories. Wherever possible, we converted various SI units used in different studies to one selected SI unit for each laboratory parameter. This conversion was carried out to facilitate a more uniform comparison across studies and to enhance the interpretability of our findings, ensuring consistency in the reporting of laboratory measurements.
Quality assessment
We appraised the risk of bias through the National Institutes of Health Quality Assessment Tool, using the 14-point Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, the 12-point Quality Assessment for Case-Control Studies and the 9-point Quality Assessment Tool for Case Series Studies.27 Two reviewers assessed each paper independently, resolving any disagreements via discussion, and scored reports according to their study designs, obtaining a mean quality rating for each study type.
Outcomes
The primary outcome of this study is pooled mortality among patients diagnosed with MIS-C.
The secondary outcomes include:
Characteristics of patients with MIS-C: this includes pooled estimates of demographic factors (age, gender, race), comorbidities (such as obesity, asthma, systemic disease) and COVID-19 status among patients with MIS-C.
Clinical presentation: this encompasses pooled estimates of clinical manifestations observed in patients with MIS-C, such as fever, gastrointestinal symptoms, cardiovascular complications and respiratory distress.
Diagnostic features: this includes pooled estimates of abnormal laboratory findings, imaging studies and other diagnostic modalities employed in MIS-C.
Management strategies: this involves pooled estimates of the utilisation of various treatment approaches in MIS-C, including pharmacological interventions and supportive care measures.
Data analysis
We conducted descriptive statistics for demographics and study characteristics. Meta-analyses were conducted for each variable using a random-effects model. For categorical data, pooled effect size (prevalence) was estimated and presented as a percentage with 95% CI. For continuous data, we calculated weighted means for each study and pooled them, presented as means with 95% CI. If results in reports were presented as median with IQR or median with range, data transformation was employed to obtain mean and SD according to Wan et al.28 Data transformation in this manner, however, assumes that normal distribution is present and does not account for skewed data. As a result, transformed mean and SD values represent approximations of the true underlying distribution.
We performed subgroup analysis based on the income status of the country where the studies were conducted (according to the World Bank classification) for variables where at least three studies were available for analysis.26 Studies were categorised into HIC, MIC or multiregional studies (which contained data from both HIC and MIC). We created forest plots for each outcome variable presenting all subgroups. Pooled means and prevalences obtained from subgroup analysis were compared using the test for subgroup differences. A p value for interaction between HIC and MIC subgroups (p interaction) was obtained for each variable in subgroup analysis with significance set at p≤0.05. For our primary outcome, we performed a leave-one-out sensitivity analysis, as well as a meta-regression during subgroup analysis.
We assessed overall heterogeneity among studies using τ2, χ² and I2 statistics. Heterogeneity among effect sizes obtained from subgroup analysis was assessed using the Cochran Q test, where a p value of <0.05 was deemed statistically significant. Due to the presence of high heterogeneity (as expected and observed) among the included reports, we employed a mixed generalised linear model with logit transformation. We created forest plots for each variable that was analysed and publication bias was assessed by funnel plots via Egger test and Doi plot analysis. The Egger test quantitatively determines publication bias by examining the relationship between effect size and its precision, and we employed this method for continuous data (means with CI). Categorical data were analysed by Doi plots.29–31 The minimum number of studies for publication bias assessment via either method was kept at 10. All statistical analyses were performed using R Statistical Software (packages used were ‘meta’ and ‘ggplot2’; V.4.1.2; R Core Team 2021).32
Patient and public involvement
As a systematic review of existing literature, our research did not involve direct interaction with patients or the public. Therefore, there were no opportunities for their input or participation in the study design, conduct or analysis.
Results
Study characteristics
Our search strategy identified a total of 6589 reports, of which 120 studies meeting the inclusion criteria were finally included, representing 20 881 cases across 5 continents (PRISMA diagram in online supplemental figure 1).33–152 Details of the geographical distribution of included studies can be found in table 1. A proportional symbol map of the geographical distribution and the study characteristics are shown in online supplemental figure 2 and online supplemental table 4, respectively. A summary of all the findings of our study is presented in figure 1.
Summary of key findings. This infographic provides a summary of all the key findings of our systematic review including the demographic, clinical and diagnostic features, management strategies and outcomes in multisystem inflammatory syndrome in children. It also displays the main differences in disease profile between high-income and middle-income countries. ECMO, extracorporeal membrane oxygenation; HIC, high-income countries; IL, interleukin; IVIG, intravenous immunoglobulins; LVEF, left ventricular ejection fraction; MIC, middle-income countries; PICU, paediatric intensive care unit.
Geographical distribution of included studies
Quality assessment for the studies included in our review revealed that the included case series, case-control, cohort studies and cross-sectional studies obtained a mean score of 7.2, 8, 8.8 and 7.9, respectively. Details of quality assessment can be found in online supplemental table 5.
Demographics
The overall mean age of the patients with MIS-C was 7.8 years (95% CI 7.4 to 8.3 years; 92 studies), and a male predominance was noted, comprising 59.5% (95% CI 58.1% to 60.9%; 114 studies) of the study population. Obesity was the most commonly reported comorbidity (13.2%; 95% CI 9.7% to 17.7%; 38 studies), followed by respiratory diseases (7.8%; 95% CI 5.3% to 11.2%; 13 studies), prematurity (7.8%; 95% CI 0.9% to 44.1%; 8 studies) and asthma (7.1%; 95% CI 4.9% to 10%; 22 studies).
A total of 96 studies (12 107 cases) reported COVID-19 testing; 80.6% (95% CI 75.1% to 85.1%; 96 studies) showed positive serological tests (Rapid Testing or ELISA-based testing for IgG and IgM) and 25% (95% CI 20.9% to 29.7%; 88 studies) showed positive COVID-19 PCR tests. Details of patient demographics (including racial and ethnic distribution) are shown in table 2.
Pooled estimates of demographic and clinical features of patients with MIS-C
Clinical presentation
The most common presenting clinical feature was fever (99.9%; 95% CI 99.6% to 100%; 102 studies). The gastrointestinal system was the most commonly involved organ system (76.7%; 95% CI 73.1% to 79.9%; 108 studies), followed by the dermatological system (63.3%; 95% CI 58.7% to 67.7%; 98 studies), the cardiovascular system (58.8%; 95% CI 50.5% to 66.6%; 89 studies) and the respiratory system (38.5%; 95% CI 34.2% to 43%; 96 studies). At presentation or during the hospital stay, 46.9% (95% CI 38.4% to 55.6%; 62 studies) of patients exhibited shock, whereas 16.5% (95% CI 11.6% to 22.9%; 28 studies) of patients experienced acute kidney injury. Details of the prevalence of clinical signs and symptoms are shown in table 2.
Diagnostic features
Laboratory blood testing showed raised inflammatory markers including C reactive protein (CRP) (95.8%; 95% CI 91.4% to 98%; 32 studies), erythrocyte sedimentation rate (75.1%; 95% CI 65.2% to 83%; 21 studies) and procalcitonin (73.9%; 95% CI 53.2% to 87.6%; 17 studies), and abnormally raised coagulation markers, including D-dimer (86.2%; 95% CI 77.5% to 91.9%; 30 studies), fibrinogen (69.6%; 95% CI 58.4% to 78.8%; 11 studies) and international normalised ratio (47.9%; 95% CI 13.8% to 84.1%; 8 studies). Additionally, we noted a rise in N-terminal pro-B-type natriuretic peptide (76.4%; 95% CI 59.3% to 87.8%; 22 studies) and troponin-T (54.1%; 95% CI 36.4% to 70.7%; 9 studies). Specific haematological features revealed neutrophilia (69.5%; 95% CI 48.9% to 84.4%; 7 studies), lymphopenia (60.8%; 95% CI 53.6% to 67.6%; 32 studies) and thrombocytopenia (36%; 95% CI 31.1% to 41.2%; 35 studies).
Approximately 52.7% (95% CI 45.6% to 59.7%; 49 studies) of cases reported echocardiographic abnormalities including ventricular dysfunction (30.3%; 95% CI 26.5% to 34.4%; 62 studies), valvular dysfunction (34%; 95% CI 26.3% to 42.6%; 47 studies) and coronary aneurysm/dilation (16%; 95% CI 13.4% to 19%; 82 studies). Details of the diagnostic features of MIS-C are outlined in table 3.
Pooled estimates of diagnostic features, management strategies and outcomes of patients with MIS-C
Management strategies and outcomes
The most common specific therapies provided to patients with MIS-C included IVIG (87.5%; 95% CI 82.9% to 91%; 101 studies) and steroids (74.7%; 95% CI 68.7% to 79.9%; 100 studies). Furthermore, aspirin was administered in 74.7% (95% CI 64.3% to 82.8%; 50 studies) and anticoagulants in 53.6% (95% CI 43% to 63.9%; 53 studies) of patients with MIS-C. Around 41.6% (95% CI 37% to 46.2%; 91 studies) of cases required vasopressor-inotropic support. Anakinra and other IL inhibitors were used in 12.5% (95% CI 7.9% to 19.3%; 38 studies) of cases. Respiratory support included oxygen support via mask or nasal cannula (31.3%; 95% CI 25.7% to 37.5%; 50 studies), non-invasive ventilation (11.9%; 95% CI 8.3% to 16.8%; 36 studies), invasive mechanical ventilation (14.9%; 95% CI 12.3% to 18%; 72 studies) and extracorporeal membrane oxygenation (2.4%; 95% CI 1.7% to 3.4%; 26 studies). An estimated 53.1% (95% CI 47.3% to 58.9%; 82 studies) of patients required PICU admission.
The mean LOS in the hospital was 9 days (95% CI 8.1 to 9.9 days; 62 studies). Overall, 299 deaths (3.9%; 95% CI 2.7% to 5.6%; 47 studies) were recorded. Pooled estimates of all management strategies and outcomes have been provided in table 3. Forest plots, funnel plots and Doi plots of all variables mentioned in our results can be found in online supplemental figures 3–6.
Supplemental material
Supplemental material
HIC versus MIC subgroup analysis results
The subgroup analysis according to income classification also revealed some significant differences. The mean age of patients with MIS-C in studies from HIC was 8.6 years (95% CI 8.1 to 9.1 years; 51 studies), compared with 6.9 years (95% CI 6.1 to 7.6 years; 37 studies) in studies from MIC (p<0.01). A lower proportion of patients reported no significant comorbidities at admission in HIC (76.4%; 95% CI 72.5% to 79.9%; 39 studies) than MIC (88.9%; 95% CI 83% to 93%; 30 studies) (p<0.01). Obesity was more common in HIC (18.5%; 95% CI 13.6% to 24.6%; 21 studies) than in MIC (8.5%; 95% CI 4.5% to 15.5%; 14 studies) (p=0.01). Asthma was also reportedly higher in HIC (8.6%; 95% CI 5.8% to 12.6%; 16 studies) than in MIC (3.4%; 95% CI 1.4% to 7.9%; 5 studies) (p<0.01).
Signs of respiratory distress were less common in patients from HIC (18.2%; 95% CI 12.6% to 25.4%; 20 studies) than in MIC (32.7%; 95% CI 20.9% to 47.2%; 22 studies) (p=0.03). However, the frequency of gastrointestinal symptoms was reported to be higher in patients from HIC (82.6%; 95% CI 77.5% to 86.8%; 53 studies) than in MIC (70.1%; 95% CI, 65.2% to 74.6%; 49 studies) (p<0.01).
Subgroup analysis of mean laboratory values showed a higher mean fibrinogen of 592.2 mg/dL (95% CI 554 to 630.4 mg/dL; 19 studies) in HIC, compared with 474.5 mg/dL (95% CI 415.6 to 533.5 mg/dL; 15 studies) in MIC (p<0.01). HIC also reported a higher mean CRP of 17.7 mg/dL (95% CI 15.7 to 19.6 mg/dL; 35 studies) compared with MIC (14.4 mg/dL, 95% CI 12.3 to 16.5 mg/dL; 25 studies) (p=0.02). However, a lower frequency of raised procalcitonin was present in patients from HIC (64.4%; 95% CI 35.6% to 85.6%; seven studies) as compared with MIC (83.5%; 95% CI 82.1% to 84.9%; nine studies) (p=0.03).
On echocardiography, a higher proportion of patients presented with a left ventricular ejection fraction (LVEF) <55% in HIC (44.5%; 95% CI 32.7% to 57.1%; 13 studies) as compared with MIC (30.3%; 95% CI 21.7% to 40.5%; 16 studies) (p=0.05). Similarly, the frequency of pericardial effusion on echocardiography was also higher in patients from HIC (23.3%; 95% CI 17.3% to 30.6%; 27 studies) than MIC (12.6%; 95% CI 8.2% to 18.7%; 28 studies) (p=0.01). The mean LOS was noted to be 8.1 days (95% CI 7.1 to 9 days; 36 studies) in HIC, and 10.7 days (95% CI 8.8 to 12.5 days; 24 studies) in MIC (p=0.01). Moreover, in HIC, the mean LOS in PICU was 4 days (95% CI 3.3 to 4.7 days; 14 studies) and in MIC, 6.1 days (95% CI 3.8 to 8.4 days; 9 studies) (p=0.05). Detailed comparative pooled estimates for HIC versus MIC can be found in tables 4 and 5.
Comparison of pooled estimates of demographic and clinical features of patients with MIS-C between HIC and MIC
Comparison of pooled estimates of diagnostic features, management strategies and outcomes of patients with MIS-C between HIC and MIC
The studies reported a mortality rate of 1.3% (95% CI 0.9% to 1.9%; 16 studies) in HIC and 7.4% (95% CI 5.1% to 10.6%; 28 studies) in MIC (forest plot for pooled prevalence of mortality can be found in figure 2). The leave-one-out sensitivity analysis revealed no influential studies impacting the pooled estimate for our primary outcome (online supplemental figure 6). This shows that removing any single study would not significantly impact the overall effect size. The regression results and bubble plot revealed a significant difference in mortality rates between the two groups, with MIC having a higher estimated effect size (1.596; 95% CI 1.003 to 2.189; p<0.0001) compared with HIC (the reference category) (results of meta-regression are detailed in online supplemental table 6).
Forest plot showing pooled estimates of mortality. The pooled estimates of the prevalence of mortality in multisystem inflammatory syndrome in children, with subgroup analysis between HIC and MIC using a generalised linear mixed model. Diamond indicates total estimates for each subgroup with 95% CI. GLMM, generalised linear mixed model; HIC, high-income countries; MIC, middle-income countries.
Discussion
Our systematic review presents an in-depth analysis of the various aspects of MIS-C. Patients presented with fever, gastrointestinal symptoms, rash and cardiovascular symptoms with raised inflammatory, coagulation and cardiac markers. Patients in HIC were older (mean age of 9 years in HIC vs 7 years in MIC), more likely to have a comorbidity (eg, obesity, asthma), less likely to present with respiratory distress (prevalence of 18% in HIC vs 33% in MIC) and more likely to have an LVEF <55% (45% in HIC vs 30% in MIC). MIS-C causes a severe disease course, with likely admission to the PICU, requiring respiratory and haemodynamic support, with low overall mortality. IVIG and steroids are the mainstays of specific management. The mean LOS was shorter in HIC than in MIC, with a much lower mortality rate (1% in HIC vs 7% in MIC).
In line with previously conducted systematic reviews, our study shows an approximate 3:2 ratio between male and female patients, and among comorbidities, obesity was the most common comorbid condition.153–157 A disparity was noted among data for race/ethnicity as our findings report that the Caucasian population represented the highest proportion of MIS-C cases (30%). In previously conducted observational studies and systematic reviews, the black population has been noted to be disproportionately affected with a higher complication and mortality rate.154–163 There can be several potential reasons for this discrepancy, including geographic and regional variation (due to the inclusion of a larger number of countries in our study), differences in methodology and inclusion criteria and changes over time as MIS-C is an evolving disease and our study includes data from studies spanning across >3 years of the pandemic.36 93 132 143 150
Due to the broad spectrum of clinical presentation, MIS-C shares various features with diseases like KD, TSS and MAS among others.7 8 164 165 Hence, it was crucial for us to conduct a meticulous assessment of both clinical and diagnostic features. As previously reported in systematic reviews, the most prevalent symptom in our review was also fever (99.9%), followed by gastrointestinal symptoms (76.7%) and dermatological symptoms (63.3%).153 154 156–158 Clinical presentation was similar in HIC and MIC subgroups, however, the frequency of patients presenting with signs of respiratory distress was much lower in HIC than in MIC (18% vs 33%). This finding was supported by a systematic review conducted on Indian studies which showed a 42% prevalence of respiratory symptoms in patients with MIS-C.166 A few likely explanations for this could be environmental factors, the underlying burden of respiratory comorbidities and infections and delayed or inadequate access to healthcare.100 124 133 145 Moreover, this might also be owing to the high heterogeneity in our data due to the various diagnostic criteria used in different studies. As a result, patients with acute COVID-19 might be included in the population with MIS-C, dramatically increasing the prevalence of respiratory symptoms in the regional population.
Biomarkers for inflammation, coagulation and cardiac injury were similarly elevated in both MIC and HIC. As per the clinical criteria, neutrophilia (69%), lymphopenia (46%) and thrombocytopenia (15%) were noted in patients with MIS-C. A meta-analysis on MIS-C diagnostic features in 12 studies showed very similar results to our review, hypothesising that immune system activation against a viral infection elicits a CD8+ response that suppresses bone marrow function causing thrombocytopenia.167 168 Additionally, inflammatory cytokines interleukin-6, interleukin-8 and tumour necrosis factor-α have been routinely found to be elevated in MIS-C and severe COVID-19 cases causing an exaggerated inflammatory response.169 Consistently increased cardiac markers suggest that cardiac injury is a predominant feature of MIS-C, as confirmed by the echocardiogram findings in our study, which revealed decreased ejection fraction in 37% of patients and coronary artery changes in 16% of patients. Our study found a significant difference in LVEF <55 and evidence of pericardial effusion between HIC and MIC. Conversely, cardiovascular involvement is frequent in patients with MIS-C, with literature suggesting that >80% of patients have some degree of involvement, ranging from left ventricular dysfunction to coronary or valvular abnormalities.56 Additionally, complications such as shock, arrhythmias, coronary aneurysms and pericardial effusion are common.170 The reasons for this are not clearly understood, but may be due to antibody-dependent enhancement or antibody or T-cell-mediated injury to the heart and coronary vessels.171 Moreover, high coagulation markers are associated with increased rates of mortality in COVID-19 infections.41 55 148 172
The management of patients with MIS-C varied across different healthcare settings due to the diverse presentations of the patients. IVIG was the most commonly administered immuno-modulator drug with a pooled proportion of 87.5%, followed by steroids (74.7%), in line with existing MIS-C guidelines.16 173 Our observation revealed no significant difference in the utilisation of steroids, IVIG or fluid resuscitation between HIC and MIC, as it was the first-line management overall.174 A recently published randomised controlled trial (RCT) (Swissped RECOVERY (Randomised Evaluation of COVID-19 ThERapY) trial) has studied the effectiveness of methylprednisone against IVIG and recommended that intravenous methylprednisone can be used as a first-line agent in patients with MIS-C.175 Future RCTs can also focus on the dosing of steroids and related outcomes in patients with MIS-C. Furthermore, aspirin and anticoagulants were noted to be judiciously used in patients with MIS-C for thromboprophylaxis and to treat thromboembolic events (with no significant difference observed between HIC and MIC). Thromboembolism is a significant complication seen in MIS-C, presenting with a high risk of morbidity and mortality. Hence, standard-dose prophylactic anticoagulation and low-dose aspirin should be considered in all hospitalised patients with MIS-C, based on their thromboembolism risk.176 177 Anakinra and other IL inhibitors were noted to have a high overall prevalence, but subgroup analysis was not possible due to lack of data on this important therapeutic modality in MIC, possibly due to limited availability and access in this region. This could be an important potential factor contributing to the higher rate of respiratory symptoms and a higher mortality rate observed in MIC, and needs to be studied.177 178
This review highlighted that a significant proportion of patients with MIS-C required PICU admission (53%), vasopressor support (42%) and intubation (15%). Children with MIS-C have a propensity to develop severe disease and require more intensive therapies. This could be due to late or delayed presentation, genetic predisposition, the stigma associated with COVID-19 during the pandemic period and a lack of prehospital care.179 180 Based on recent evidence, we recommend initiating treatment with steroids or IVIG for suspected patients with MIS-C, and transferring them to a high-acuity area (PICU) for close monitoring and support.179
The overall mortality rate was 4%, but patients with MIS-C from MIC had a disproportionately higher mortality rate (7% in MIC vs 1% in HIC). This could be due to a younger age of presentation in MIC, delayed or limited access to healthcare and life-saving interventions (including limited use of drugs like IVIG and IL inhibitors), and the presence of underlying, undiagnosed, coexisting diseases and nutritional deficiencies.181 182 Multiple studies have highlighted this gap in mortality between HIC and MIC, reporting mortality rates ranging from 12% to 19% in MIC,125 179 compared with the USA, where the mortality rate ranges from 1.2% to 2%.63 183 184
Strengths and limitations
Our review is the most comprehensive systematic review conducted on MIS-C to date, containing studies up to March 2023. Our sample size consists of >20 000 patients from 45 countries around the world, which enhances the generalisability of the findings and allows for a more robust analysis. Moreover, we have also conducted a subgroup analysis based on the income class of the country of origin revealing pertinent data that highlight the differences in presentation, therapies and outcomes between different socioeconomic settings.
We limited our review to English-language literature only which might have underpresented data from certain geographies and economies. Furthermore, due to various diagnostic criteria being used over various sites and the evolution of knowledge regarding MIS-C, the data were significantly heterogeneous which might affect the comparability of the findings. Moreover, a majority of the reports were from the USA, an HIC, resulting in an over-representation of data from this region, however, subgroup analysis was employed to address this limitation. Although efforts were made to extensively check for overlapping patient data, there is still a possibility of duplication which could influence the accuracy of the reported results. A lack of RCT on MIS-C (only one has been published as of yet) and its management limited our ability to establish causality and evaluate the efficacy of specific treatment strategies. Long-term outcomes and causes of mortality in the patient population were not explored as a part of our study as comprehensive studies capturing these data have been limited.
Conclusions
This comprehensive systematic review presents all the available global data on MIS-C in the English language, delving into the clinical and diagnostic features, management strategies and patient outcomes. Additionally, we assessed these variables based on a country’s socioeconomic status, distinguishing between HIC and MIC. Our analysis revealed substantial inequalities, and some similarities, among patients with MIS-C between the two strata. MIS-C is a severe disease requiring hospitalisation and admission into the PICU, but with overall low mortality. However, MIS-C in MIC presents with a more severe disease course, with predominant respiratory involvement, and has a higher mortality rate compared with HIC. This issue needs to be further investigated and strategies need to be developed to overcome this disparity.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. As this is a meta-analysis, all data are available in individual studies and in the online supplemental file. Data analysis code and raw Excel data sheets can be made available on reasonable request.
Ethics statements
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Ethics approval
Not applicable.
References
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Footnotes
QA and HA are joint first authors.
X @hdrali93
QA and HA contributed equally.
Contributors QA, ZSL and JKD conceptualised and designed the study. HA, FAm, ZHH, MHK, ZAP, FAb, DI, ZA, SB, FS and AS performed the study screening, selection and data extraction. QA and JKD oversaw data collection and verified underlying data. ARR conducted the statistical analyses, supervised by JKD. QA, HA and JKD interpreted the data. HA, ZA and MHK wrote the first draft of the manuscript. QA, JKD and SM reviewed and provided input to the final draft. All authors revised and approved the final version of this manuscript. QA had the final responsibility for the decision to submit for publication and is the author responsible for the overall content as the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests No, there are no competing interests.
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