• Jiacai Cho, Joanne Lee, Ching-Hui Sia, Chieh Sian Koo, Benjamin Y Q Tan, Weizhen Hong, Ellie Choi, Xueying Goh, Louis Chai, Nisha Suyien Chandran, Horng Ruey Chua, L ChanBernard PBPDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore., Mark Muthiah, Ting Ting Low, Eng Soo Yap, and Manjari Lahiri.
• Division of Rheumatology, Department of Medicine, National University Hospital; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
• Singapore Med J. 2023 Jun 1; 64 (6): 349365349-365.

IntroductionWe aimed to describe the extrapulmonary manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including their frequency, onset with respect to respiratory symptoms, pathogenesis and association with disease severity.MethodsWe searched the MEDLINE and Embase databases for SARS-CoV-2-related studies. Meta-analysis, observational studies, case series and case reports published in English or Chinese between 1 January 2020 and 1 May 2020 were included. Reports with only paediatric or obstetric cases were excluded.Results169 articles were included. Early manifestations (preceding respiratory symptoms until Day 6 of onset) included olfactory and gustatory disturbance (self-reported in up to 68% and 85% of cases, respectively), gastrointestinal symptoms (up to 65.9%) and rash (up to 20.4%). From Day 7 onwards, hypercytokinaemia, paralleled multi-organ complications including acute cardiac injury (pooled incidence of 17.7% in 1,412 patients, mostly with severe disease and 17.4% mortality), kidney and liver injury (up to 17% and 33%, respectively) and thrombocytopenia (up to 30%). Hypercoagulability resulted in venous thromboembolic events in up to 31% of all patients. Uncommon disease presentation and complications comprised Guillain-Barré syndrome, rhabdomyolysis, otitis media, meningoencephalitis and spontaneous pneumomediastinum.ConclusionAlthough the systemic manifestations of SARS-CoV-2 infection are variegated, they are deeply interwoven by shared mechanisms. Two phases of extrapulmonary disease were identified: (a) an early phase with possible gastrointestinal, ocular and cutaneous involvement; and (b) a late phase characterised by multiorgan dysfunction and clinical deterioration. A clear, multidisciplinary consensus to define and approach thromboinflammation and cytokine release syndrome in SARS-CoV-2 is needed.

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