COVID-19: it is all about sepsis

COVID-19, the disease caused by SARS-CoV-2, has affected almost all countries worldwide, stretching hospital and intensive care unit resources to their limits in many areas and causing more than 2 million documented deaths so far. Normal medical and surgical practice has been hugely impacted with many routine procedures canceled and emergency interventions organized according to new, COVID-19-safe protocols to protect staff and patients [1,2]. Initially considered as a community-acquired pneumonia that could worsen into the acute respiratory distress syndrome, it soon became apparent that dysfunction of other organs, in addition to the lungs, is often present in patients with COVID-19; indeed, multiple organ failure (MOF) accounts for most of the deaths from COVID19 [3]. MOF in COVID-19 can involve any organs, the six most common being the lungs, the cardiovascular system, the kidneys, the brain, the liver and the coagulation system. COVID-19 is characterized by a thrombotic endotheliopathy involving the entire body. The resulting endothelial dysfunction may be the link between COVID19 and MOF, and the process has been called the cornerstone of organ dysfunction in COVID-19 [4]. Autopsy studies of patients with COVID-19, including one by our group [5], have indicated the presence of viral RNA in all organs. This does not, however, imply that the virus itself is responsible for the alterations in organ function. Indeed, as our understanding of the pathogenesis of COVID-19 has advanced, it soon became clear that the initial phase of viral replication could be followed by an inadequate host response, leading to more generalized disease. By definition COVID-19 is, therefore, sepsis, which is best defined as an inadequate host response to an infection [6]. Importantly, as demonstrated in COVID-19, the causative microorganism in sepsis does not have to be bacterial; sepsis can also be caused by viruses, fungi and even parasites. Mortality rates from severe COVID-19 are similar to those observed in other forms of sepsis [7], and the complex immune response in COVID-19 cannot be distinguished from that of other forms of sepsis. The immune response to SARS-CoV-2 has been called a ‘cytokine storm’, a term that was initially used to describe the inflammatory cytokine response in the engraftment syndrome of graft versus host disease after allogeneic hematopoietic stem cell transplantation [8]. The term has been challenged in the present setting, because blood cytokine levels are not always very high in these patients, especially compared with levels in patients with nonCOVID acute respiratory distress syndrome [9]. Nevertheless, blood cytokine levels are still raised in patients with COVID-19 compared with healthy individuals, and can reach levels similar to those in patients with sepsis due to other causes [10,11]. One should emphasize this is not only a pro-inflammatory response, as blood levels of mediators such as IL-10 and alpha-1 antitrypsin are also elevated [11]. COVID-19 is also associated with increased neutrophil extracellular trap (NET) release and increased levels of free DNA in the blood, and serum from COVID-19 patients triggers release of NETs from control neutrophils [12]. The increased formation of NETs may be involved in the thrombotic endotheliopathy of COVID-19 [13]. Intriguingly, endotoxin levels are often increased in patients with severe COVID-19, and are directly related to the severity of the disease [14]. Obviously, endotoxin cannot originate from the virus, but it may have an endogenous source, released from Gram-negative bacteria of the gut, suggesting the possibility of inadequate blood flow to the various organs, including the gut.