Systemic inflammatory syndrome in COVID-19-SISCoV study: systematic review and meta-analysis

Abstract

Background: There has been a recent upsurge in the cases of Multisystem inflammatory syndrome in children (MIS-C) associated with Coronavirus disease (COVID-19). We performed a systematic review and meta-analysis on the demographic profile, clinical characteristics, complications, management, and prognosis of this emerging novel entity.

Methods: Using a predefined search strategy incorporating MeSH terms and keywords, all known literature databases were searched up till 10th July 2020. The review was done in accordance with PRISMA guidelines and registered in PROSPERO (CRD4202019757).

Results: Of the 862 identified publications, 18 studies comprising 833 patients were included for meta-analysis. The socio-demographic profile showed male predilection (p = 0.0085) with no significant racial predisposition. A higher incidence of gastrointestinal symptoms (603/715, 84.3%), myocarditis (191/309, 61.8%), left ventricular dysfunction (190/422, 45.0%), pericardial (135/436, 31.0%) and neurological symptoms (138/602, 22.9%) was reported. Serological evidence of SARS-CoV-2 had higher sensitivity compared to rtPCR (291/800, 36.4% vs 495/752, 65.8%; p < 0.001). Coronary artery anomaly (CAA) was reported in 117/681 in 9 publications (17.2%). A total of 13 (1.6%) fatalities were reported.

Conclusion: Clinicians need to be vigilant in identifying the constellation of these symptoms in children with clinical or epidemiologic SARS-CoV-2 infection. Early diagnosis and treatment lead to a favorable outcome.

Impact: Key message This review analyses the demographic profile, clinical spectrum, management strategies, prognosis, and pathophysiology of MIS-C among children with SARS-CoV-2 infection. The stark differences of MIS-C from Kawasaki disease with respect to demographics and clinical spectrum is addressed. Over-reliance on rtPCR for diagnosis can miss the diagnosis of MIS-C. New addition to existing literature The first systematic review and meta-analysis of published literature on MIS-C associated with COVID-19.

Impact: The article will serve to spread awareness among the clinicians regarding this emerging novel entity, so that diagnosis can be made early and management can be initiated promptly.

Fig. 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.

Fig. 2. Forest plots of various clinical manifestations of the selected studies.

a Coronary artery abnormalities in MIS-C across the studies represented by Forest plot. b Myocarditis in MIS-C across the studies represented by Forest plot. c Gastrointestinal symptoms in MIS-C across the studies represented by Forest plot. d Left ventricular dysfunction in MIS-C across the studies represented by Forest plot. e pericardial disease in MIS-C across the studies represented by Forest plot. f Need for invasive ventilator support in MIS-C across the studies represented by Forest plot. g Neurological symptoms in MIS-C across the studies represented by Forest plot. h Need for vasopressor support in MIS-C across the studies represented by Forest plot.

Fig. 3. Clinico-demographic characteristics of the included studies.

a Component bar diagram depicting clinical profile, complications, and management strategies of MIS-C in the included studies. b Box and Whisker plots depicting median with interquartile range of male vs female distribution. c Box and Whisker plots depicting median with interquartile range of racial distribution (Blacks- including Afro-Caribbean, Asians, Whites and Hispanics). d Box and Whisker plots depicting median with interquartile range of the rtPCR for SARS-CoV2 infection vs serological evidence.

Fig. 4. Depicting the proposed pathogenesis of MIS-C with COVID-19 (the proposed pathogenesis is a constellation of various hypotheses referred accordingly).

a The early phase of SARS-CoV-2 infection is devoid of any immune response. As the disease progresses to the late phase, owing to its superantigenic property, the virus evades destruction by phagocytes. The mass proliferation of the virus subsequently triggers dysregulated activation of macrophages and initiates a hyperimmune response mediated by helper T cells. This subsequently leads to a tremendous efflux of IL-6, IL-1ß, IL-12, LAMP-1, IFNGR2, and CD244. The humoral response, mediated by the proliferation of B1 or B2 cells leads to the overproduction of antibodies (IgG, IgA, Anti-La, aminoacyl t-RNA synthetase). The antigen-antibody complexes, thus formed mediates a Type III hypersensitivity reaction resulting in further activation of mast cells, neutrophils, macrophages, secretion of CD54 (ICAM-1), CD64 (FcγR1), CD16⁺ monocytes, and activation of complement pathways. At the same time, there is a decrease in levels of CD56 bright and CD56 dim NK cells, pCDc, mDC1 and non-classical monocytes. The resultant inflammatory milieu causes protease-mediated endothelial, mesothelial, and epithelial inflammation with subsequent tissue damage leading to systemic symptoms. b Depicting the pathogenesis of the most commonly encountered organ systems involved in MIS-C. Gastrointestinal symptoms, attributed mostly to mucosal chemotaxis, are mediated by CCL20 and CCL28. This leads to elevation of the several inflammatory markers in blood like MUC4, MUC15, and FOLH1. Cardiac symptoms are attributed to inflammatory mediators of endothelial dysfunction such as P2RX4, ECE2, CLEC14A, and VEGFA. c Delineates the role of STING (stimulator of interferon gene) pathway. Transmembrane protein 173 (TMEM173), located in chromosome 5q31.2, a ~7-kb-long gene encodes the STING protein. STING can be activated by cytosolic DNA (damaged self-DNA) and RNA viruses leading to activation of NFκß, IRF-3, and subsequently overproduction of interferon ß and cytokines. This results in STING-associated vasculopathy with onset in infancy (SAVI) like manifestations characterized by fever, rash, pulmonitis, myositis, lymphopenia, inflammatory vasculopathy, and rarely acral necrosis. d Role of STING pathway in SARS-CoV pathogenesis in the early phase “During its early phase of SARS-CoV was shown to cause downregulation of the STING pathway through nsp3, nsp 16”. e While the role of the STING pathway in the early phase of SARS-CoV-2 infections remains unknown, COVID-19, in its late phase, leads to excessive upregulation of STING protein which results in massive stimulation of NF-κß and IRF-3, thereby causing a huge surge in the levels of interferon ß and cytokines. f The human tissues expressing STING protein include alveoli of the lung, endothelial cells, and spleen. g Depicts the various polymorphisms of TMEM173 gene.