BREAKING! COVID-19 Drugs: Study Trial Of Inhaled Corticosteroids Formoterol/Budesonide Shows Potential As Prophylactic And Treatment Drugs
: A randomized control trial of inhaled corticosteroids (ICS) on COPD patients led researchers to discover that inhaled corticosteroids could downregulate the expression of ACE2 receptors in the bronchial epithelial cells and also the epithelial cells in the airways. Furthermore the inhaled corticosteroids were found to also inhibit a human host protease gene ADAM17 that plays two critical roles; one it helps to prime the ACE2 for binding of the viral and human cell membranes and secondly in plays a crucial role in interleukin-6(IL-6) signaling. It was found that by inhibiting these ADAM17 genes, the inhaled corticosteroids were exhibiting both antiviral properties and specific anti-inflammatory control that could prevent cytokine storms. The combination of the corticosteroids formoterol/budesonide
exhibited the greatest potency to downregulate ACE2 expression and inhibit ADAM17 genes.
The results of the trial were published just hours ago on preprint server and is being peer-reviewed for a journal. https://www.medrxiv.org/content/10.1101/2020.08.19.20178368v1
The randomized control trial of inhaled corticosteroids is part of the DISRAM Study (clinicaltrials.gov identifier NCT02833480) aimed to determine the effects of ICS on the lung microbiome in COPD.
The study was led by researchers from University of British Columbia-Canada, University of Sydney-Australia, Providence Health Care-Canada and BC Cancer Research Centre Department of Integrative Oncology-Canada.
The study team performed a randomized, open-label, parallel treatment trial of 12 weeks treatment with ICS in combination with long-acting beta-agonist or LABA (formoterol/budesonide
12/400 μg twice daily or salmeterol/fluticasone propionate 25/250 μg twice daily), or treatment with LABA only (formoterol 12 μg twice daily), in volunteers with mild to very severe COPD.
The team obtained bronchial epithelial cell samples via bronchoscopy before and after treatment, and determined transcriptome-wide gene expression by RNA sequencing.
A total of 63 volunteers were randomized to receive treatment. Compared to formoterol alone, formoterol/budesonide
treatment decreased the expression of the SARS-CoV-2 receptor gene ACE2 and the host cell protease gene ADAM17. These genes were highly co-expressed with innate immune response genes, particularly those of the type I interferon and anti-viral response pathways, which also tended to decrease following ICS treatment.
Past studies have shown that ICS are associated with increased risk of bacterial pneumonia in COPD and impaired immune response to viruses in vitro but in the case of COVID-19, its effects are on the contrary. In fact it was observed that in Asthma and COPD pateints using ICS, they seem to have a lesser incidence of contracting COVID 19 than those not using these ICS.
In the study the researchers randomized 63 subjects with mild to very severe COPD to receive LABA monotherapy with formoterol (FOR), or LABA/ICS combination therapy with formoterol/budesonide
(FOR/BUD) or salmeterol/fluticasone (SAL/FLU), for 12 weeks. Bronchial brush samples were collected from 6-8th
generation airways via bronchoscopy before and at the end of treatment. The majority of participants were male and had moderate to severe airflow obstruction.
In order to quantify BEC gene expression, the team performed whole-transcriptome RNA sequencing (RNA-seq) on bronchial brush samples. After quality control filtering, a total of 15,263 genes were included in the expression dataset.
The team examined the expression levels of key SARS-CoV-2-related genes: ACE2 (encodes the putative SARS-CoV-2 entry receptor ACE2); BSG (encodes an alternative entry receptor basigin, also known as CD147); TMPRSS2 (encodes a cell surface metalloproteinase that primes the SARS-CoV-2 spike protein to facilitate viral entry); ADAM17 (encodes a metalloproteinase that cleaves the ACE2 protein and facilitates endocytosis of the ACE2-SARS-CoV-2 complex); and FURIN (encodes the subtilisin-like peptidase furin, which can prime the SARS-CoV-2 spike protein).
Sixty one participants had pre-treatment gene expression data available. There were no obvious differences in overall gene expression between the treatment groups at baseline. Each of the key SARS-CoV-2-related genes were expressed in pre-treatment BECs. Pre-treatment ACE2 and BSG expression were negatively associated with age (p=3.4x10-4 and p=0.033, respectively. Compared to ex-smokers, current smokers had significantly greater pre-treatment expression of ACE2 (p=9.3x10-5), BSG (p=4.8x10-4) and TMPRSS2 (p=0.028).
Fifty four participants had both pre- and post-treatment gene expression data available. Compared to baseline levels, LABA-only treatment with FOR significantly increased expression of ACE2 (median Δlog2CPM +0.47, p=0.002) and ADAM17(median Δlog2CPM +0.13, p=0.03). LABA/ICS combination treatment with FOR/BUD significantly decreased ADAM17 expression (median Δlog2CPM -0.19, p=0.003), while treatment with SAL/FLU did not significantly alter expression of any of the key genes.
A placebo arm was not included in the DISARM trial as this could predispose participants to a worsening of their COPD symptoms or acute exacerbation. However, the team was able to isolate the effects of ICS therapy by comparing the pre- to post-treatment changes in each of the LABA/ICS groups to the LABA-only group. Δlog2CPM ACE2 for FOR/BUD and SAL/FLU groups were significantly lower than that of the FOR group (p=0.049 and p=0.03, respectively), while Δlog2CPM ADAM17 for FOR/BUD was significantly lower than that of the FOR group (p=7.05x10-5) (Figure 3).
These results indicate that ICS have a suppressive effect on the transcription of these genes.
ICS have been shown to alter the expression of innate immune response pathways, including key anti-viral response genes and pro-inflammatory cytokines
To further explore how ICS affect these pathways, the team examined pre- to post treatment changes in expression of a panel of genes encompassing virus recognition, IFN-I/III signaling, and inflammatory cytokines/chemokines .
FOR/BUD treatment significantly reduced the expression of 8 genes in the panel (IL10RA, IRF3/8, IL1B, IL1R2, CCL3/5 and CXCL8), while SAL/FLU reduced the expression of a single gene (CCL5). The study team then examined how changes in the key SARS-CoV-2 genes were related to changes in these immune response genes using Pearson correlation. Notably, changes in ACE2 expression were correlated with changes in the expression of viral sensor genes (e.g. DDX58, TLR3), IFN-I/III signal transducers (e.g. JAK2, STAT1/2, IRF9) and interferon-stimulated genes (ISGs) (e.g. OAS2/3, CXCL10, RSAD2 and EIF2AK2) but not inflammatory cytokines/chemokines or their receptor genes.
Changes in ADAM17 expression were correlated with changes in most of the innate immune response genes that were examined, including inflammatory cytokines/chemokines. Together with the WGCNA gene co-expression analysis, these findings show that the expression levels of SARS-CoV-2-related genes are closely related to those of innate immune response genes, suggesting they may share common transcriptional regulation that is modified by ICS.
The researchers admitted several limitations to the study. First, the relatively small sample size may explain why there were many non-significant trends in pre- to post-treatment change in gene expression. However, the largely consistent directions of change between ICS treatment arms suggests these effects were not due to chance alone. Second, the team does not have longer-term follow-up gene expression data to know if the observed changes are durable. Third, the team enrolled only stable participants so cannot know if ICS alters the expression of these genes during unstable periods. Fourth, they studied gene rather than protein expression and so cannot necessarily infer changes in protein levels or function. Finally, the data were derived from BECs rather than alveolar or endothelial cells, and may not directly reflect the risk of SARS-CoV-2 infection or ALI in the lung.
Nevertheless the positive outcome from the study indicates that the ICS formoterol/budesonide
warrant additional research as potential drugs to treat COVID-19 or even to act as prophylactics.
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Read Also: https://www.thailandmedical.news/news/covid-19-drugs-queensland-university-of-technology-and-oxford-university-exploring-budesonide-inhaler-therapy-for-early-covid-19-patients-in-new-trial
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