Home Biomedical research Investigation of the mechanism of action of budesonide against SARS-CoV-2

Investigation of the mechanism of action of budesonide against SARS-CoV-2


Inhaled corticosteroids (ICS) are used as first-line treatment modalities in patients with asthma and chronic obstructive pulmonary disease (COPD) to reduce the risk of exacerbations often triggered by extrinsic factors, such as respiratory viruses. . It was recently reported that patients with asthma and COPD are less likely to be hospitalized for severe coronavirus disease 2019 (COVID-19). Evidence suggests that patients with severe infection who used ICS two weeks before hospitalization had better clinical outcomes.

To study: Damping of the respiratory cytokine storm is promoted by inhaled budesonide in patients with early-onset COVID-19.

The STOIC trial

The Steroids in COVID (STOIC) trial recruited 144 patients, aged 18 to 79, with early symptoms of COVID-19. Patients were randomized to a usual care (UC) arm, which included those who received antipyretics, while the second group of patients included those who received inhaled budesonide (BUD) at a dose of 800 micrograms (μg ) twice a day, with usual care.

All participants were assessed on day 0 (visit 1), day 7 (visit 2) and day 14 (visit 3). In the STOIC trial, inhaled budesonide, which is a corticosteroid, was evaluated as a treatment for early infection with COVID-19. The benefits of this treatment approach included improved recovery from self-reported symptoms, fewer adverse events, and faster resolution of symptoms.

About the study

The objective of a new study published on the medRxiv* Preprint server was to gain an understanding of the mechanism of action of budesonide in improving the prognosis of patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

The present study involved the evaluation of inflammatory mediators in the nasal mucosa of patients recruited for the STOIC trial and a cohort of individuals negative for SARS-CoV-2. This study was funded by the NIHR Biomedical Research Center in Oxford and AstraZeneca (Gothenburg, Sweden).

The results of this study described the inflammatory response of the nasal mucosa in patients with early COVID-19, as well as the course of inflammation during the natural course of the infection. The results demonstrated how budesonide can improve the exaggerated inflammatory response seen at the onset of COVID-19 and help improve clinical outcomes.

By comparing the inflammatory profile of nasal mucosa fluid in 20 healthy controls and in patients with early COVID-19, 14 mediators were found to be elevated in COVID-19 patients. In addition, an altered T cell response with significantly reduced levels of thymic stromal lymphopoietin (TSLP) and CCL17, as well as reduced levels of CCL2 were noted, implying impaired monocyte recruitment. There were also lower levels of vascular endothelial growth factor (VEGF), as previously described in severe hospitalized COVID-19 cases.

When examining the inflammation of the nasal mucosa in the BUD arm, during the 14 day course of COVID-19, CXCL9, CXCL10, CXCL11, interleukin (IL) -12, IL-10, IL -2, interferon (IFN) α2a, CCL2, CCL3, CCL4, IL-6, IL-4, CCL13 and tumor necrosis factor (TNF) -α were significantly reduced. Of the 14 mediators elevated at the onset of COVID-19, 11 mediators decreased over time, including CCL3, CCL4, TNF-α, IL-6, CCL13, IL-4, IFN-α2a, CXCL10, CXCL11, IL- 2, and IL-12. However, CCL11, IFN-β, and IFN-γ showed no significant variation between visits 1 and 3 and remained elevated after 14 days.

During this time, the levels of VEGF, TSLP and CCL17 did not change and remained below those of healthy controls; however, the levels of CCL2 and IL-10 were significantly reduced. Similarly, IL-1β, CXCL8, IL-33, CCL24, CCL26, IL-5, and granulocyte and macrophage colony stimulating factor (GM-CSF) have not shown no change over time, nor did the mediators PDGFA, CCL5 and TGFβ1. In particular, the levels of the chemokine CXCL9, decrease over time.

In addition, concentrations of 30 mediators were examined in the matched Visit 1 and Visit 3 samples in the BUD arm. The results showed that CCL5 was significantly reduced, while GM-CSF was not reduced. IL-2 and IL-4 concentrations were maintained in the BUD study arm, unlike the UC study arm.

When correlating viral load with expression of IFN type I and inflammatory markers of the nasal mucosa, differences between local and systemic inflammation were marked, which were thought to be related to the number of viral particles. While evaluating whether the inflammation associated with SARS-CoV-2 infection decreased over time, it was found that although some mediators decrease over the course of the disease, several mediators remain elevated in the nasal mucosa, even well after clinical recovery.

In COVID-19, the peak of the inflammatory response usually occurred early in the course of the disease. Inhaled budesonide suppressed kinetic inflammation, particularly the secondary increase in inflammation after 15e daytime.

However, elevated IFN-γ levels were recorded in the BUD arm on day 15 after symptom onset. When the kinetics of inflammation of the nasal mucosa were studied during the first seven days of symptom onset, a high eosinophilic phenotype correlated with severe disease.

To understand any aberrant immune response at the onset of SARS-CoV-2 infection, a comparison of mediators in individuals with COVID-19 and those who have clinically deteriorated was performed. To this end, in the early stages of the disease, a blunt response to infection occurs in patients who deteriorate.

In the BUD arm, serum inflammatory mediators remained elevated for up to 35 days after initial infection. The systemic inflammation was suppressed to a greater extent by inhaled budesonide, thus preventing the development of long COVID.

Persistence of systemic inflammation after 28 to 35 days of COVID-19 infection in the community is alleviated by inhaled budesonide. AF) Violin plots comparing certain mediator levels in the serum of healthy individuals (n = 19), those from the usual care arm (n = 60) and the budesonide arm (n = 62) of the study to 28-35 days after COVID- 19 infections (see S7 supplement for further results). The data were analyzed by Kruskal-Wallis with the post-hoc Dunn test. * p

Network analysis demonstrated that there was a 72% overlap between the inflammatory response at an early time and at a later time in COVID-19, indicating persistent inflammation of similar pathways. In the BUD arm, the nasal mucosal response varied, with an increased anti-inflammatory response (IL-10) and alarmins (IL-33 and TSLP) and a reduced T2 inflammatory response, thus suggesting suppression of the T2 hyperinflammatory response with COVID-19[FEMININE[FEMININE

These results indicated that ICS treatment of budesonide modulates inflammatory pathways in the upper respiratory tract and in the circulation in patients with COVID-19 by decreasing the transcription of inflammatory cytokines. Therefore, the results support the therapeutic mechanism of corticosteroids in the management of SARS-CoV-2 infection.

*Important Notice

medRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.

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