LOX-1-Expressing Immature Neutrophils Identify Critically-Ill COVID-19 Patients at Risk of Thrombotic Complications

Front Immunol. 2021 Sep 20:12:752612. doi: 10.3389/fimmu.2021.752612. eCollection 2021.

Abstract

Background: Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity.

Objective: We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics.

Methods: We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients.

Results: The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10-CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1β, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions.

Conclusion: LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

Keywords: COVID-19; infectious diseases; innate immunity; neutrophils; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Bronchoalveolar Lavage Fluid / immunology
  • COVID-19 / complications*
  • COVID-19 / genetics
  • COVID-19 / immunology
  • COVID-19 / virology
  • Critical Illness
  • Female
  • Humans
  • Interleukin-3 Receptor alpha Subunit / genetics
  • Interleukin-3 Receptor alpha Subunit / immunology
  • Interleukin-8 / genetics
  • Interleukin-8 / immunology
  • Male
  • Middle Aged
  • Neutrophils / immunology*
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / genetics
  • Respiratory Distress Syndrome / immunology
  • SARS-CoV-2 / physiology
  • Scavenger Receptors, Class E / genetics*
  • Scavenger Receptors, Class E / immunology
  • Thrombosis / etiology*
  • Thrombosis / genetics
  • Thrombosis / immunology

Substances

  • B7-H1 Antigen
  • IL3RA protein, human
  • Interleukin-3 Receptor alpha Subunit
  • Interleukin-8
  • OLR1 protein, human
  • Scavenger Receptors, Class E