A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients

Abstract

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16 Int ) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16 Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16 Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16 Int LDN subset contributes to COVID-19–associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape

“…Though the precise mechanisms are unclear, several functional links have been proposed, including an interaction between the plasminogen, complement, and platelet-activating systems in severe disease ( 2 ). Both neutrophils and LDNs have an increased tendency to spontaneously produce neutrophil extracellular traps (NETs), which has been observed in COVID-19 and suggested to contribute to coagulopathy in COVID-19 ( 92 , 93 ). We identified that both monocytes and LDNs presented transcriptional signatures associated with aggregation as well as homotypic adhesion in severe COVID-19.…”

Combined Transcriptome and Proteome Leukocyte’s Profiling Reveals Up-Regulated Module of Genes/Proteins Related to Low Density Neutrophils and Impaired Transcription and Translation Processes in Clinical Sepsis

“…Previous studies have suggested that LDNs are associated with the suppression of T cell function and proliferation, similar to the findings of the IPA analysis reported in the present study. Thus, the increase in the number of LDNs might be correlated to the severity of infectious diseases, such as sepsis and COVID-19 (38,39,42,43). Additionally, these cells are also known to be endowed with a high propensity to spontaneously produce neutrophil extracellular traps (NETs) (41,54).…”

“…Generally, neutrophils do not fractionate along with PBMCs owing to their higher density as compared to mononuclear cells. However, some low-density neutrophils (LDNs) also known as myeloidderived suppressor cells (MDSCs) have been previously shown to get fractionated along with PBMC preparations in certain pathologies, such as coronavirus disease 2019 (COVID-19) (38,39), tuberculosis (40) human Ebola virus disease (41), and also sepsis (42,43). To further support that the source of these genes/ proteins found in module 1 were derived from LDNs, we performed flow cytometry with PBMC samples obtained from the same cohort of septic patients included in the proteomic analysis.…”

Early treatment with inhaled GM-CSF improves oxygenation and anti-viral immunity in COVID-19 induced lung injury – a randomized clinical trial

“…Between randomization and day 6, virtually all patients demonstrated amelioration of these key laboratory parameters, irrespective of their treatment arm (Table 2). Systemic GM-CSF has been shown to promote the priming of neutrophils in other forms of ARDS, and low density CD24 + activated neutrophils 49 were seen in higher numbers in our COVID-19 cohort, compared with HC. Sargramostim treatment did however not promote this neutrophil activation state (Fig 3b).…”