Insights into the Role of Neutrophils and Neutrophil Extracellular Traps in Causing Cardiovascular Complications in Patients with COVID-19: A Systematic Review

Abstract

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has resulted in significant mortality and burdening of healthcare resources. While initially noted as a pulmonary pathology, subsequent studies later identified cardiovascular involvement with high mortalities reported in specific cohorts of patients. While cardiovascular comorbidities were identified early on, the exact manifestation and etiopathology of the infection remained elusive. This systematic review aims to investigate the role of inflammatory pathways, highlighting several culprits including neutrophil extracellular traps (NETs) which have since been extensively investigated.

Method: A search was conducted using three databases (MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations and EMBASE). Data from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were considered for the processing of the algorithm and treatment of inflammatory response during SARS-CoV-2 infection. Studies without the SARS-CoV-2 Infection period and case reports were excluded.

Results: A total of 47 studies were included in this study. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining outcomes. Some of the mechanisms of activation of these pathways have been highlighted in previous studies and are highlighted.

Conclusion: NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, COVID-19 remains an entity that has not been fully understood with long-term effects remaining uncertain and requiring ongoing monitoring and research.

Keywords: COVID-19; SARS-CoV-2 infection; coronary artery thrombosis; neutrophil extracellular traps (NETs).

Figure 1

Autopsies substantially contributed to unveiling many unsolved aspects relating to the pathogenesis revealing the role of mononuclear cell infiltration leading to increased cytokine expression in patients who died with single or multi-failure organ pathologies. Abbreviations; DAD, diffuse alveolar damage; IL: interleukine; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RNA, ribonucleic acid; TNF, tumor necrosis factor.

Figure 2

Prisma FloW Chart 2020 allowed to reach 47 determinant publications for the systematic review. * Search database; ** excluded for no meet criteria.

Figure 3

Pathogenic Th1 cells and inflammatory monocytes in severe COVID-19. Pathogenic CD4⁺ Th1 (GM-CSF⁺IFN-γ⁺) cells were rapidly activated to produce GM-CSF and other inflammatory cytokines to form a cascade signature of inflammatory monocytes (CD14⁺CD16⁺ with high expression of IL-6) and their progeny. These activated immune cells may enter the pulmonary circulation in large numbers and played an immune-damaging role in severe-pulmonary-syndrome patients. The monoclonal antibodies that target the GM-CSF or interleukin-6 receptor may potentially prevent or curb immunopathology caused by COVID-19. Abbreviations; GM-CSF, granulocyte-macrophage colony stimulating factor; IL, interleukine; IFN-γ, interféron gamma; SARS-CoV-2: severe acute respiratory syndrome-coronavirus-2.

Figure 4

The acute clinical manifestations of COVID-19 are well characterized in the first and second phase, revealing an inflammatory response, endothelial dysfunction and overlapping infection that can evolve into thromboembolic and pulmonary complications, myocardial infarction and DIC. The third stage determines the COVID-19 heart condition after SARS-CoV-2 infection in which patients may reveal a range of increased cardiovascular risks. Abbreviations; CRP, C-reactive protein; DIC; disseminated intravascular coagulation. Other abbreviations in the previous figures. ↑, increase.

Figure 5

The mechanism leading to cardiac injury from NETs formation in patients with severe COVID-19 is determined by vascular inflammation, thrombogenesis and NETOSIS through the instability of the atherosclerotic plaque. Abbreviations: HMGB1, mobility group box; ISG-15; interferon-stimulated gene; LDG, low-density granulocytes; NDG, normal density granulocytes; NAD, nicotin adenin dinucleotide; ROS, reactive oxygen species; SIRT3, Sirtuin 3. Other abbreviations in previous figure. ↑, increase; ↓, decrease.

Figure 6

SARS-CoV-2 determines the activation of neutrophils mediated by IL-8, G-CSF, resistin, lipocalin-2, hepatocyte growth factor and NET release. The immune response of NK and T lymphocytes contributes to the formation of NETs with the increased level of a completement system (C5 and C3). The generated microvascular thrombosis leads to organ damage. Abbreviations: C, complement; GF, grow factor; IL, interleukine; NK; natural killer. Bottom left depict the biochemical reaction for the formation of NETs Other abbreviations in previous figure. ↑, increase; ↓, decrease.

Figure 7

SARS-CoV-2 infection determines dysregulations in coagulation system. The coagulopathy is supported by the DIC, cytokine storm process, and direct action of the virus, inducing damage and activation of macrophages. RAAS overactivation associated with platelet and complement overactivation (direct and indirect) leads to fibrinolysis inhibition. Abbreviations are as shown in previous figures. Arrows explain the increase or decrease of relative component. ↑, increase; ↓, decrease.

Figure 8

The infection from SARS-CoV-2 caused a variability in the manifestation of the disease. This explains the different population rates of infection and the distinct mortality rates of manifest cases in various regions and countries. Inflammatory response, increased age, and bed rest, which are most frequently seen in severe coronavirus disease 2019 (COVID-19), may contribute to thrombosis and adverse events resulting from multiorgan involvement. FDA timeline of antivirals approval and EUAs. Veklury^® EUA was formalized in January 2020. Its definitive approval occurred in October, 2020. Molnupiravir and Paxlovid^® EUAs followed in December 2021. Abbreviations: ATE, arterial thromboembolism.; COVID-19, coronavirus disease 2019; DIC, disseminated intravascular coagulation; EUA: Emergency Use Authorization; FDA: Food and Drug Administration; NSAIDs, non-steroid anti-inflammatory drugs; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; VTE, venous thromboembolism.