COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases

Abstract

Background. Current management efforts of COVID-19 include: early diagnosis, use of antivirals and immune modulation. After the initial viral phase of the illness, identification of the patients developing cytokine storm syndrome is critical. Treatment of this hyper-inflammation in these patients using existing, approved therapies with proven safety profiles could address the immediate need to reduce the rising mortality. Methods. Using data from an A549 cell line, primary human bronchial epithelial (NBHE), as well as from COVID-19-infected lung, we compare the changes in the gene expression, pathways and mechanisms between SARS-CoV2, influenza A, and respiratory syncytial virus. Results. We identified FDA-approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. An important finding is that drugs in the same class will not achieve similar effects. For instance methylprednisolone and prednisolone were predicted to be effective in reverting many of the changes triggered by COVID-19, while other closely related steroids, such as prednisone or dexamethasone, were not. An independent clinical study evaluated 213 subjects, 81 (38%) and 132 (62%) in pre-and post-methylprednisolone groups, respectively. The composite end point was composed of escalation to intensive care units, need for mechanical ventilation, and death. The composite endpoint occurred at a significantly lower rate in post-methylprednisolone group compared to pre-methylprednisolone group (34.9% vs. 54.3%, p=0.005). Conclusion. Clinical results confirmed the efficacy of the in silico prediction that indicated methyl- prednisolone could improve outcomes in severe COVID-19. These findings are important for any future pandemic regardless of the virus.

Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

“…Additional support for the use of methylprednisolone in COVID-19 originates from transcriptomics data. After matching the expression changes induced by SARS-CoV2 in human lung tissue tissues and A549 lung cell line against the expression changes triggered by 5694 Food and Drug Administration–approved drugs, methylprednisolone was found to be the drug with the greatest potential to revert the changes induced by COVID-19 [ 22 ].…”

RETRACTED: Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19

“…6,31,32 A recent study that matched the expression changes induced by SARS-CoV2 in human lung tissue tissues and A549 lung cell line against the expression changes triggered by 5,694 FDA-approved drugs, found methylprednisolone to be the drug with the greatest potential to revert the changes induced by COVID-19, while other closely related corticosteroids, such as dexamethasone or prednisone, were not. 41…”

“…6,31,32 A recent study that matched the expression changes induced by SARS-CoV2 in human lung tissue tissues and A549 lung cell line against the expression changes triggered by 5,694 FDA-approved drugs, found methylprednisolone to be the drug with the greatest potential to revert the changes induced by COVID-19, while other closely related corticosteroids, such as dexamethasone or prednisone, were not. 41 The risk for decreased viral clearance with CST is overstated and the most frequently quoted article by Arabi et al, in patients that received greater than 7 days CST there was a strong trend toward lower 90- 42 Contrary to the widespread, unfounded fears of delayed viral clearance which unfortunately influenced the multiple national and international society recommendations against use of CST in COVID-19, the reality is that there is no evidence linking delayed viral clearance to worsened outcomes in critically ill COVID-19 patients, and further, it is unlikely that it would have a greater negative impact than the hosts own "cytokine storm." 26 Subsequent to the introduction of the MATHþ protocol, even more definitive support for CST was provided by a large randomized trial along with prospective observational studies.…”

MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale

“…Glucocorticoids effectively reverse the transcriptional activation of pro-inflammatory genes caused by SARS-CoV-2 thereby dampening the cytokine storm and associated tissue injury [10]. The unequivocal benefit of methylprednisolone in improving respiratory function, ventilator dependency, and mortality has been demonstrated in a number of observational studies [11][12][13][14].…”