Extrapulmonary manifestations and complications of severe acute respiratory syndrome coronavirus-2 infection: a systematic review

Abstract

Introduction: We 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. Methods: We 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. Results: 169 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. Conclusion: Although 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.