Extrapulmonary Manifestations of Covid-19: A Review

Abstract

Coronavirus disease 2019 (covid-19) presents in a wide variety of clinical pictures ranging from completely asymptomatic or mild forms to rapidly progressive disease, including pulmonary and extrapulmonary manifestations. SARS-CoV-2 –the etiological agent of covid-19- access to their target cells via a transmembrane protein, the angiotensin-converting enzyme II (ACE2). ACE-2 is a type-I metallocarboxypeptidase with homology to ACE, an essential enzyme in the Renin-Angiotensin System [1]. This enzyme is expressed in vascular endothelial cells, renal tubular epithelium, Leydig cells in the testes, lungs, kidneys, brain, heart, vasculature, and gastrointestinal tract [2-7]. As such, the clinical manifestations of covid-19 are explained by the tissular distribution of ACE-2. Beyond the tissular affectation “per se”, another pathological feature is the “cytokine storm” phenomenon (CS).  CS is an exaggerated immune response characterized by a high level of circulating inflammatory cytokines sustained over time. It is rapidly progressive and has a high mortality.  CS has been detected in critical patients with covid-19 and it is considered a major cause of acute respiratory distress syndrome (ARDS) and multiorgan failure. Serum levels of proinflammatory cytokines are significantly increased in patients with ARDS, and their levels are positively correlated with mortality [8,9]. CS may also cause inflammation and injury of the Central Nervous System (CNS) Supporting this view, IL-6 levels positively correlate with covid-19 severity [10]. This syndrome has been described in sepsis, hemophagocytic syndrome and in other coronavirus infections like the severe acute respiratory syndrome (SARS) or the Middle East respiratory syndrome (MERS). Although lung involvement has been well described in many reports, extra-pulmonary manifestations are still poorly described. This paper will review the non-pulmonary manifestations of covid-19. Main extra-pulmonary symptoms comprise the neurologic, cardiac, ophthalmologic, muscular, hematologic, cutaneous, and gastrointestinal ones, as well as hepatic and renal involvement. Each one of these manifestations can arise during the disease evolution or constitute their initial manifestation.