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The more transmissible variants of SARS-CoV-2 were responsible for the four major waves of infections that spread across the globe starting in early 2020, with omicron (B.1.1.529) becoming the dominant variant after the summer of 2021, followed by the emergence of other omicron sublineages in 2022 (BA.2, BA.3, BA.4, and BA.5).
In a global effort that is unparalleled in modern history, there has been a race to find drugs and biological treatments to save the lives of patients who are hospitalised or severely ill and to develop vaccines.
Indeed, COVID-19 vaccines have contributed to the reduced risk of SARS-CoV-2 infection, and provide protection against severe disease caused by the SARS-CoV-2 variants, including omicron.
Nonetheless, to reduce severe COVID-19-related illness, overcrowding of hospitals, and treatment costs,
there has also been a focus on how primary care physicians can treat initial mild to moderate symptoms in outpatients with COVID-19. This approach would provide an opportunity to intervene before infected individuals develop severe illness. Since mild to moderate symptoms of COVID-19 might reflect an underlying excessive inflammatory response to the viral infection, the use of anti-inflammatory drugs in the community during the early stage of COVID-19 appears to be a valuable therapeutic option. However, anti-inflammatory therapy for managing people with COVID-19 at home continues to be a matter of debate, in terms of effectiveness and possible important side-effects.
Maladaptive hyperinflammatory response to SARS-CoV-2 infection
To enter target cells, the spike subunit of SARS-CoV-2 engages the host protease ACE2 as an entry receptor, after being primed by the cellular serine protease TMPRSS2.
Lysis of infected cells and SARS-CoV-2 replication in the host cells are associated with the release of inflammatory cytokines (such as TNF-α, IL-6, and IL-8) and free radicals, the induction of IFN-γ, and the recruitment and activation of leukocyte subsets, which in turn further release cytokines, chemokines, and other inflammatory mediators that determine the early inflammatory response.
It has been hypothesised that the inflammatory environment of SARS-CoV-2 infection could also be sustained by the enhanced availability of angiotensin-II as the result of the net downregulation of ACE2, due to continuous recycling of this receptor upon viral cell entry.
Since ACE2 degrades angiotensin-II, ACE2 deficiency causes angiotensin-II accumulation, which in turn (by binding to the angiotensin-I receptor) triggers inflammatory processes by stimulating proliferation of mononuclear cells and promoting the recruitment of proinflammatory cells.
Moreover, the uptake of an antibody-opsonised virus by the Fcγ receptors of monocytes and macrophages results in inflammatory cell death, which halts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.
Proinflammatory cytokines further recruit leukocytes within the lung, contributing to the propagation of the inflammatory response, as shown in patients with COVID-19 progression to severe disease.
Furthermore, evidence indicates that proinflammatory CD68 macrophages bearing ACE2 on their surface can be directly infected by SARS-CoV-2,
and their virus-induced activation appears to be relevant to the initiation and spread of the hyperinflammatory response.
Notably, CD163 monocyte-derived macrophages also accumulate in the lungs.
As shown in patients with COVID-19-related acute respiratory distress syndrome, although these cells further contribute to inflammation in the lung, they are also reprogrammed by the virus towards a profibrotic transcriptional and proteomic phenotype, resulting in pulmonary fibrosis.
Créditos: Comité científico Covid