SARS, MERS and COVID-19: clinical manifestations and organ-system complications: a mini review

Abstract

Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) are caused by three distinct coronaviruses belonging to the same genus. COVID-19 and its two predecessors share many important features in their clinical presentations, and in their propensity for progression to severe disease which is marked by high rates of morbidity and mortality. However, comparison of the three viral illnesses also reveals a number of specific differences in clinical manifestations and complications, which suggest variability in the disease process. This narrative review delineates the pulmonary, cardiac, renal, gastrointestinal, hepatic, neurological and hematologic complications associated with these three respiratory coronaviruses. It further describes the mechanisms of immune hyperactivation-particularly cytokine release syndrome-implicated in the multi-organ system injury seen in severe cases of MERS, SARS and COVID-19.

Keywords: Middle East respiratory syndrome coronavirus; acute hepatic injury; acute kidney injury; acute neurologic syndrome; acute respiratory distress syndrome; central neurogenic respiratory failure; coronavirus disease 2019; cytokine release syndrome; heart failure; pneumonia; severe acute respiratory syndrome coronavirus 1; severe acute respiratory syndrome coronavirus 2.

Figure 1.

Proposed model of pathophysiological mechanisms underlying cytokine release syndrome (CRS) and possible therapeutic interventions. CRS begins with binding of SARS-CoV-2 or SARS-CoV-2-immune complex (if coated with an antibody) to its receptor on immune cells and endothelial cells in the vicinity of alveoli. (a) This leads to activation of resident phagocytes, mainly macrophages which ingest the virus and initiate cytokine release; namely TNF-a and IL-1b. (b) The latter act on the endothelium to become activated, upregulate the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin), increase vascular permeability and induce leukocyte recruitment. (c) Plasmacytoid dendritic cells (pDCs), on the other hand, secrete Type I interferon, to inhibit viral replication and synthesis of viral proteins and educate naïve T cells (Th0) in the lymph nodes to differentiate into effector cells, but these pDCs also secrete IL-6 which adds to the cytokine storm. (d) T cells become engaged, differentiate into Th1 subset, which secretes IFN-g that licenses macrophages to increase their phagocytic activity and cytokine production. (e) In addition, the simultaneous presence of TGF-b and IL-6 drives the differentiation of Th0 to Th-17 subset which secretes IL-17 and GM-CSF, the latter stimulates neutrophil production by the bone marrow and its recruitment to the site of tissue injury. (f) Neutrophils discharge their granule contents and increase the production of intracellular reactive oxygen species (ROS); thereby, exacerbating inflammation. (g) Licensed macrophages, in turn, produce excessive amounts of additional cytokines: IL-6, IL-1β and TNF-a further contributing to systemic toxicity. (h) IL-6 and IL-1b act on the hypothalamus to induce fever, dizziness and fatigue. TNF-a leads to decreased cardiac output, cardiomyopathy, lung injury and coagulopathy. These processes represent potential targets for immunotherapy, some of which are still under clinical investigation. Tociluzimab (anti-IL-6 receptor antagonist) remains the current mainstay for management of CRS, although other drugs including anti-IL-1b antagonists (Anakinra), TNFR-antagonists (TNFR-Ig), or GM-CSF antagonists (Lenizulumab) act as potential therapeutics. Hydroxychloroquine (HCQ) can interfere with viral entry and replication; and can also inhibit immune cell overactivation and cytokine production. Key: IL-12, interleukin 12; IL-6, interleukin 6; IL-17, interleukin 17; IL-10, interleukin 10; IL-1b, interleukin 1beta; TNF-a, tumor necrosis factor alpha; TGF-b, transforming growth factor beta; IFN-g, interferon gamma; Type I IFN, Type I interferon; ROS, reactive oxygen species; ICAM-1, intercellular adhesion molecule; VCAM-1, vascular cellular adhesion molecules; GM-CSF, granulocyte monocyte colony stimulating factor; Th1, T helper subset 1; Th17, T helper subset 17; Th0, naïve T cells; TNFR-Ig, tumor necrosis factor alpha receptor-immunoglobulin fusion protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; HCQ, Hydroxychloroquine.