key: cord-0904723-vrfosd3d authors: Zhao, Yan; Patel, Jenil; Huang, Ying; Yin, Lijuan; Tang, Lei title: Cardiac markers of multisystem inflammatory syndrome in children (MIS-C) in COVID-19 patients: A meta-analysis date: 2021-05-18 journal: Am J Emerg Med DOI: 10.1016/j.ajem.2021.05.044 sha: fa45d4abd45cad35c0c695c7977e2dd50884b4f0 doc_id: 904723 cord_uid: vrfosd3d OBJECTIVE: A meta-analysis of laboratory cardiac markers for multisystem inflammatory syndrome in children (MIS-C) was performed in patients with coronavirus disease 2019 (COVID-19). METHODS: Eight databases were searched until April 10, 2021, for studies on cardiac markers, including B-type natriuretic peptide (BNP)/N-terminal pro-BNP (NT-proBNP), troponin, aspartate aminotransferase (AST), in MIS-C patients. RESULTS: Of the 2583 participants enrolled in 24 studies, 1613 patients were diagnosed with MIS-C. MIS-C patients exhibited higher BNP levels than patients with non-severe COVID-19 [SMD (95% CI): 1.13 (0.48, 1.77), p < 0.05]. No significant differences in BNP levels were observed between patients with MIS-C and severe COVID-19 [SMD (95% CI): 0.29 (−0.07, 0.65), p = 0.117]. Comparisons of MIS-C patients to all COVID-19 patients revealed no significant differences in levels of troponin [SMD (95% CI): 0.13 (−0.07, 0.32), p = 0.212] or AST [SMD (95% CI): 0.10 (−0.11, 0.31), p = 0.336]. Compared to patients with non-severe MIS-C, those with severe MIS-C exhibited higher levels of BNP [SMD (95% CI): 0.26 (0.04, 0.48), p < 0.05], but no differences in troponin [SMD (95% CI): 0.05 (−0.06, 0.16) p = 0.387] or AST [SMD (95% CI): 0.19 (−0.34, 0.71), p = 0.483] were observed. Moreover, there was no significant difference in BNP [SMD (95% CI): −0.21 (−1.07, 0.64), p = 0.624] or troponin [SMD (95% CI): −0.07 (−0.45, 0.31), p = 0.710] between MIS-C with and without coronary artery abnormality. Sensitivity analyses were performed to assess stability. No publication bias was detected based on Begg's test. CONCLUSIONS: The key cardiac marker that showed differences between patients with MIS-C/non-severe COVID-19 and between patients with severe/non-severe MIS-C was BNP. Other markers, such as troponin and AST, did not exhibit notable differences in indicating cardiac injury between patients with MIS-C and COVID-19. Coronavirus disease 2019 (COVID- 19) , which is caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally to become a significant burden worldwide [1] . The presentation of COVID-19 in children ranges from mild to severe, and a variety of complications develop during disease progression. Increasing numbers of pediatric patients with severe systemic hyperinflammation, shock or Kawasaki-like syndrome associated with COVID-19 have been widely reported worldwide [2, 3] . This condition was identified as multisystem inflammatory syndrome in children (MIS-C), also termed pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PMIS/PIMS-TS) [4] . The term MIS-C is used throughout this meta-analysis. The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are highly expressed in the lungs, myocytes and vascular endothelial cells [5] . Cardiac involvement is frequent in MIS-C and presents as a wide range of conditions, such as systemic hyperinflammatory conditions, including acute myocardial dysfunction or extracorporeal membrane oxygenation (ECMO) therapy, and diligent long-term follow-up due to the risk of cardiac progression [6] . Cardiac markers [7] , including brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-pro BNP), troponin, and aspartate aminotransferase (AST), are frequently used clinical parameters to predict the progression of deterioration in earlier phases. Natriuretic peptides are primarily synthesized in the heart and upregulated by myocardial stress. BNP and its precursor hormone NT-pro BNP are suitable laboratory cardiac markers for the diagnosis and risk stratification of heart failure [7] . NT-pro BNP is also a potential biomarker for predicting coronary artery lesions in patients with Kawasaki disease [8] . Troponin is a muscle-associated protein that is released into the blood circulation during cell injury, and it is used as a cardiac marker for screening and detecting cardiac injury [9] . Because of its cardiac specificity, the laboratory cardiac marker troponin may be the criterion for the diagnosis of myocardial injury [10] . AST, also named glutamate oxaloacetate transaminase (GOT), is released from necrotic cardiac myocytes and may be detected in serum [7] . Several studies reported elevated BNP or NT pro-BNP and troponin levels in patients with severe COVID-19 who were admitted to intensive care units, required ventilation or died [11, 12] . Laboratory parameters of inflammatory or cardiac markers are frequently used to optimize management guidelines in clinical practice. An increasing number of studies reported the characteristics of cardiac markers in MIS-C patients, but no relative meta-analysis on these studies was performed. The present study performed a meta-analysis to provide evidence-based data on the characteristics of cardiac laboratory markers in MIS-C patients to assist clinicians in the management of MIS-C patients. The early identification of the characteristics of cardiac involvement in MIS-C patients is vital in designing prompt treatment modalities and preventing cardiovascular complications. Journal Pre-proof The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and it is registered in the International Prospective Register of Systematic Reviews database (PROSPERO) (CRD42020220509). heading (MESH) terms used were "coronavirus disease 2019", "COVID-19", "severe acute respiratory syndrome coronavirus 2", "SARS-CoV-2", "multisystem inflammatory syndrome", "MIS-C", "pediatric inflammatory multisystem syndrome", "pediatric multisystem inflammatory syndrome", "PIMS-TS", "PMIS", "Kawasaki-like disease", and "hyperinflammatory syndrome". A manual search of the article references was also performed. The following inclusion criteria for the studies in the meta-analysis were used: 1) cohort studies or case-control studies; 2) the patients had MIS-C, PIMS-TS or PMIS; and 3) the primary cardiac biomarker outcomes included at least BNP/NT-pro BNP or troponin, and the secondary outcome included AST. We excluded studies with no relevant outcomes or no original data and reviews, case series, editorials or opinions. Two investigators (YZ and LY) independently screened the titles, abstracts and full texts of eligible studies and subsequently assessed the studies for inclusion. All discrepancies were resolved via discussion with a third investigator (YH). The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies [13] . According to the criteria, each item was scored as 0 or 1, with 4 points in selection, 2 points in comparability and 3 points in outcome/exposure. The overall score ranged from 0 to 9, and the studies were classified as low (1-3), moderate (4-6) or high J o u r n a l P r e -p r o o f Journal Pre-proof (7) (8) (9) quality based on the total point score. Any dispute was resolved via discussion among the reviewers. Two investigators (YZ and LY) extracted the data using Microsoft Excel. The data included study details (author, publication year, country, study design, participant age, study period, number of patients, and number of cases/controls) and cardiac marker outcomes (BNP/NT-pro BNP, troponin, and AST). Among the study groups, patients with severe COVID-19 were defined as COVID-19 patients with acute respiratory distress syndrome (ARDS) who required mechanical ventilation or invasive respiratory support or patients with an increase in positive pressure support above baseline and who did not meet the diagnostic criteria for MIS-C. Severe MIS-C patients were defined as patients who met the diagnostic criteria for MIS-C and required admission to the ICU, invasive respiratory support or mechanical ventilation and patients who suffered complications, such as shock, needed inotropic support or fluid resuscitation, or had a fatal outcome. Heterogeneity was estimated using the chi-squared test and the I 2 statistic. An I 2 value less than 50% indicated no presence of statistical heterogeneity, and a fixed effects model (FEM) was used in these cases. When the I 2 value was greater than 50%, statistical heterogeneity was present, and a random effects model (REM) was used. I 2 values of 50% and 75% indicated moderate and high heterogeneity, respectively. Sensitivity analysis was performed to explore the source of heterogeneity. After excluding potential clinical heterogeneity, REMs were generated using the DerSimonian and Laird methods to evaluate the effect sizes. Due to different units for serum levels of cardiac markers, continuous variables are presented as standard mean differences (SMDs) and corresponding 95% confidence intervals (95% CIs) using forest plots. Begg's test and funnel plots were used to evaluate publication bias. A P value <0.05 was considered statistically significant. The analyses were performed using STATA v12 (Stata Corp, College Station, TX, USA). Journal Pre-proof A total of 3,944 studies were identified from the database search. Of these, 2,055 duplicate studies were removed; 1,663 studies were excluded after title and abstract screening, and 202 were excluded following full text screening based on the set inclusion criteria. Twenty-four studies were ultimately included in the meta-analysis (Figure 1 ). Table 1 . No statistically significant heterogeneity was found for the cardiac markers BNP (p=0.196, Except for the comparison of BNP between severe and non-severe MIS-C patients, the results of sensitivity analyses were not affected by the exclusion of any study, which indicated that the meta-analysis had high reliability and stability. The results of Begg's test indicated no evidence of publication bias in the analysis. Journal Pre-proof The rapid worldwide spread of COVID-19 affects all age groups, including pediatric patients [1] . Despite the lower incidence of COVID-19 in children, MIS-C is now a common condition in pediatric COVID-19 patients [6] . New reports [2, 3, 6] showed COVID-19 may present with involvement of major organs, including the cardiovascular system [6] . Myocardial cells infected with SARS-CoV-2 may directly cause myocardial injury and lead to myocarditis, impairment of cardiac function or malignant arrhythmias, and eventual cardiac failure [41, 42] . Up to 28% of COVID-19 patients have myocardial J o u r n a l P r e -p r o o f injury [43] . Some fatal cases of COVID-19 were also associated with cardiac injury caused by fulminant myocarditis [44] . Autopsies have shown inflammatory infiltrate in myocardial tissue with a high viral load [45] [46] [47] , and a high proportion of MIS-C patients exhibit elevated levels of cardiac markers, including troponin and BNP/pro-BNP [2, 48] . Our meta-analysis showed that MIS-C patients showed higher BNP levels than patients with non-severe COVID-19, but no significant difference was found in BNP levels between patients with MIS-C and severe COVID-19. We demonstrated that MIS-C patients may share an equal elevation in BNP levels with patients with severe COVID-19. This finding may assist clinicians in designing optimal management guidelines based on the diagnosis of MIS-C and COVID-19 in children. It is imperative to note a higher tendency to develop a severe condition in the clinical management of MIS-C. The meta-analysis showed that BNP levels were higher in patients with severe MIS-C than patients with non-severe MIS-C, but troponin and AST levels were not significantly different between patients with severe and non-severe MIS-C. The observed difference in BNP levels between patients with severe and non-severe MIS-C may indicate a difference in prognosis. Researchers also suggested the routine measurement of cardiac markers. [5] Dynamic measurements may be useful for clinicians to monitor and predict the disease course and help triage patients to a different level of care. MIS-C has some overlapping features with Kawasaki disease and CAA, including coronary artery dilation or aneurysms, and these features have been reported in 6-24% of patients [6] . Some studies reported large or giant coronary artery aneurysms [3, 17] . Close and prompt follow-up is indicated for patients with CAA development. Therefore, questions remained in clinical practice about which index to rely on for early detection and the triage of MIS-C patients into high-and low-risk groups for CAA [9] . However, the results of our meta-analysis There were no significant differences observed. BNP: B-type natriuretic peptide; CAA: coronary artery abnormality; MIS-C, multisystem inflammatory syndrome in children. Table 2 The results of the meta-analysis standard mean difference; BNP, brain natriuretic peptide; AST, aspartate aminotransferase. * REM was used because of moderate heterogeneity (I 2 50-75%). 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