Introduction
In December 2019, authorities in Wuhan, China reported a cluster of pneumonia cases caused by an unknown etiologic agent. The pathogen was soon identified and sequenced as a novel coronavirus related to the agent of severe acute respiratory syndrome (SARS) and was subsequently termed SARS Coronavirus-19 (SARS-CoV-2). The infection spread in the subsequent 3 months on all continents and was declared a pandemic by the World Health Organization. As of April 2, 2020, 961,818 documented cases were reported worldwide, and 49,165 patients had died (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). This novel coronavirus has a tropism for the lung, causing community-acquired pneumonia (CAP). Some patients with pneumonia suddenly deteriorate into severe respiratory failure (SRF) and require intubation and mechanical ventilation (MV). The risk of death of these patients is high, reaching even 60% (Arabi et al., 2020).
Proper management mandates better understanding of disease pathogenesis. The majority of physicians use sepsis as a prototype of critical illness for the understanding of severe coronavirus disease 2019 (COVID-19) pathogenesis. This is mostly because severe COVID-19 is associated with hyper-cytokinemia (Guan et al., 2020, Huang et al., 2020). Lethal sepsis is commonly arising from bacterial CAP, often leading to SRF and the need for MV. The peculiar clinical course of CAP caused by SARS-CoV-2, including the sudden deterioration of the clinical condition 7–8 days after the first symptoms, generates the hypothesis that this illness is driven by a unique pattern of immune dysfunction that is likely different from sepsis. The features of lymphopenia with hepatic dysfunction and increase of D-dimers (Qin et al., 2020) in these patients with severe disease further support this hypothesis.
Immune responses of critically ill patients with sepsis can be classified into three patterns: macrophage-activation syndrome (MAS) (Kyriazopoulou et al., 2017), sepsis-induced immunoparalysis characterized by low expression of the human leukocyte antigen D related (HLA-DR) on CD14 monocytes (Lukaszewicz et al., 2009), and an intermediate functional state of the immune system lacking obvious dysregulation. We investigated whether this classification might apply to patients with SRF caused by SARS-CoV-2. Results revealed that approximately one fourth of patients with SRF have MAS and that most patients suffer from immune dysregulation dominated by low expression of HLA-DR on CD14 monocytes, which is triggered by monocyte hyperactivation, excessive release of interleukin-6 (IL-6), and profound lymphopenia. This pattern is distinct from the immunoparalysis state reported in either bacterial sepsis or SRF caused by 2009 H1N1 influenza.