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St. Jude Research: Limited Role Of Cytokine Storm In COVID-19 Patients
#15,562
Since the start of the COVID-19 pandemic a steady stream of pre-existing drugs have been touted as a potential therapeutic against the disease - with some anecdotally showing promise - only for hopes to be dashed after they have been put to the test in clinical trials.
It is possible that further clinical trials will find benefit in more targeted applications of some of these drugs or therapies - or other drugs will be found - but for now, we have no silver bullet against this pandemic.
That said, Remdesivir has recently been approved by the FDA (despite its poor showing in theWHO clinical trials), and dexamethasone has been shown to be beneficial for treating some severe COVID patients (see JAMA study) - but most hospital treatments remain mostly supportive (i.e. oxygen, blood thinners, fluids, etc.).
While promising, dexamethasone - a corticosteroid - is not without side effects, and its use with MERS-CoV, Avian flu, and influenza has been strongly discouraged in the past. The NIH's Rationale for Use of Corticosteroids warns:
Both beneficial and deleterious clinical outcomes have been reported with use of corticosteroids (mostly prednisone or methylprednisolone) in patients with other pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxia, prednisone therapy reduced the risk of death;2 however, in outbreaks of other novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance.3,4 In severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and death.5
Despite these concerns, limited clinical trials have shown that short-term dexamethasone therapy can inhibit cytokine storm severity in COVID-19 patients who develop pneumonia.
Given the potential downsides of this therapy, targeting those COVID-19 cases with (or who are at risk for) severe cytokine storm makes sense.
All of which brings us to a new study - published in Science Advances by researchers at St. Jude Children's Research Hospital - which somewhat surprisingly finds COVID-19 patients are less likely to experience cytokine storm than influenza patients, which would seem to limit the usefulness of dexamethasone.
First the abstract (follow the link to read the full study) followed by excerpts from a St. Jude press release, after which I'll have a postscript.
Cytokine storms play a limited role in moderate-to-severe COVID-19
St. Jude Children’s Research Hospital and Washington University research suggests steroids such as dexamethasone should be reserved for the sickest COVID-19 patients
Memphis, Tennessee, November 13, 2020
Rather than life-threatening hyperinflammation, most adults with moderate-to-severe COVID-19 have a suppressed viral immune response when compared to adults with another viral respiratory infection, influenza. St. Jude Children’s Research Hospital and Washington University School of Medicine in St. Louis led research that suggests most COVID-19 patients are not candidates for treatment with steroids such as dexamethasone. The research appears today in Science Advances.
Fewer than 5% of the COVID-19 patients in this study, including some of the sickest individuals, had the life-threatening, hyperinflammatory immune response known as cytokine storm syndrome. Cytokines are small proteins secreted by blood cells that help coordinate the immune response and trigger inflammation. Cytokine storms develop when excess or abnormally regulated cytokine production leads to hyperinflammation and tissue damage. While dexamethasone and other steroids are prescribed to treat cytokine storms, the drugs can backfire in patients whose immune response is already suppressed.
“We did identify a subset of COVID-19 patients with the broadly upregulated array of cytokines, which is a hallmark of cytokine storm,” said co-corresponding author Paul Thomas, Ph.D., of the St. Jude Department of Immunology. “But, overall, the average person with COVID-19—even patients with moderate-to-severe disease—had less inflammation than the average person with flu.
What’s needed, researchers said, is a fast, reliable and inexpensive test to measure cytokines and identify patients who are most likely to benefit from immunosuppressive treatment.
Eleven months into this pandemic, and COVID-19 continues to surprise.
Originally viewed as an `influenza-like-illness', SARS-CoV-2 has proven itself to be a far more systemic threat than influenza, with neurological, cardiac, gastrointestinal, renal, and thrombotic impacts often reported (see Nature Med. Review: Extrapulmonary manifestations of COVID-19).
https://twitter.com/KartikSehgal_MD/...95760879202304
One fascinating bit of news from the press release (see below) is that SARS-CoV-2 infection may actually ramp up the host's natural production of glucocorticoids, which in turn may be responsible for the limited, and rapidly diminishing immune response we've seen reported in many recovered patients (see EID Journal: Waning Antibody Response In Asymptomatic and Symptomatic SARS-CoV-2 Infection).
Researchers also found evidence that SARS-CoV-2 alters pathways controlling the immune response to promote steroid production by patients. “Our results suggest that most COVID-19 patients are perhaps already producing high levels of glucocorticoids prior to treatment, possibly leading to the blunted immunity we see in most of them,” Thomas said. “These patients may need therapy to turn up their immune response to knock the virus down.”
The bottom line (at least, based on this study); dexamethasone may be lifesaving for a small percentage of COVID-19 cases actually experiencing cytokine storm pneumonia, for the vast majority of COVID cases the the pharmacological cupboard for COVID-19 remains distressingly bare.
https://afludiary.blogspot.com/2020/...d-role-of.html
#15,562
Since the start of the COVID-19 pandemic a steady stream of pre-existing drugs have been touted as a potential therapeutic against the disease - with some anecdotally showing promise - only for hopes to be dashed after they have been put to the test in clinical trials.
- In late October we saw Eli Lilly & ViralClear Halt Their Clinical Trials For COVID-19 Treatments after early data suggested that the drugs being tested were not providing a benefit to hospitalized COVID patients.
- A week earlier, in BMJ: Clinical Trial On Convalescent Plasma Showed Little Benefit For COVID-19, convalescent plasma was dealt another blow (see last July's Dutch Convalescent Plasma Study For COVID-19 was Halted For Redesign).
- While in mid-October, in WHO Solidarity Therapeutics Trial: Remdesivir, HCQ, Lopinar/Ritonavir & Interferon Disappoint, we saw that 4 highly touted drug therapies were found to have `. . . had little or no effect on 28-day mortality or in-hospital course of illness.'
It is possible that further clinical trials will find benefit in more targeted applications of some of these drugs or therapies - or other drugs will be found - but for now, we have no silver bullet against this pandemic.
That said, Remdesivir has recently been approved by the FDA (despite its poor showing in theWHO clinical trials), and dexamethasone has been shown to be beneficial for treating some severe COVID patients (see JAMA study) - but most hospital treatments remain mostly supportive (i.e. oxygen, blood thinners, fluids, etc.).
While promising, dexamethasone - a corticosteroid - is not without side effects, and its use with MERS-CoV, Avian flu, and influenza has been strongly discouraged in the past. The NIH's Rationale for Use of Corticosteroids warns:
Both beneficial and deleterious clinical outcomes have been reported with use of corticosteroids (mostly prednisone or methylprednisolone) in patients with other pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxia, prednisone therapy reduced the risk of death;2 however, in outbreaks of other novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance.3,4 In severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and death.5
Despite these concerns, limited clinical trials have shown that short-term dexamethasone therapy can inhibit cytokine storm severity in COVID-19 patients who develop pneumonia.
Given the potential downsides of this therapy, targeting those COVID-19 cases with (or who are at risk for) severe cytokine storm makes sense.
All of which brings us to a new study - published in Science Advances by researchers at St. Jude Children's Research Hospital - which somewhat surprisingly finds COVID-19 patients are less likely to experience cytokine storm than influenza patients, which would seem to limit the usefulness of dexamethasone.
First the abstract (follow the link to read the full study) followed by excerpts from a St. Jude press release, after which I'll have a postscript.
Philip A. Mudd1,*,†, Jeremy Chase Crawford2,†, Jackson S. Turner3, Aisha Souquette2, Daniel Reynolds4, Diane Bender5, James P. Bosanquet6, Nitin J. Anand6, David A. Striker6, R. Scott Martin6, Adrianus C. M. Boon4, Stacey L. House1, Kenneth E. Remy4,7,8, Richard S. Hotchkiss4,8,9, Rachel M. Presti4, Jane A. O’Halloran4, William G. Powderly4, Paul G. Thomas2,* and Ali H. Ellebedy3,4,5,*
Science Advances 13 Nov 2020:
DOI: 10.1126/sciadv.abe3024
Abstract
We pursued a study of immune responses in COVID-19 and influenza cohorts. Compared to influenza patients, COVID-19 patients exhibited largely equivalent lymphocyte counts, fewer monocytes, and lower surface HLA-class II expression on select monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes was a significant predictor of COVID-19 disease severity.
Science Advances 13 Nov 2020:
DOI: 10.1126/sciadv.abe3024
Abstract
We pursued a study of immune responses in COVID-19 and influenza cohorts. Compared to influenza patients, COVID-19 patients exhibited largely equivalent lymphocyte counts, fewer monocytes, and lower surface HLA-class II expression on select monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes was a significant predictor of COVID-19 disease severity.
In contrast to prevailing assumptions about COVID-19 disease immunopathology, very few (7 of 168) COVID-19 patients exhibited cytokine profiles indicative of Cytokine Storm Syndrome.
After controlling for key confounding factors such as age and sample time point, COVID-19 patients exhibited lower cytokine levels than influenza patients. Up-regulation of IL-6, GCSF, IL-1RA, and MCP1 predicted death from acute respiratory failure among COVID-19 patients but were not statistically higher than influenza patients. Single-cell transcriptional profiling was concordant with profound suppression in interferon signaling among COVID-19 patients. When considered across the spectrum of peripheral immune profiles, COVID-19 patients are less inflamed than influenza patients.
After controlling for key confounding factors such as age and sample time point, COVID-19 patients exhibited lower cytokine levels than influenza patients. Up-regulation of IL-6, GCSF, IL-1RA, and MCP1 predicted death from acute respiratory failure among COVID-19 patients but were not statistically higher than influenza patients. Single-cell transcriptional profiling was concordant with profound suppression in interferon signaling among COVID-19 patients. When considered across the spectrum of peripheral immune profiles, COVID-19 patients are less inflamed than influenza patients.
Cytokine storms play a limited role in moderate-to-severe COVID-19
St. Jude Children’s Research Hospital and Washington University research suggests steroids such as dexamethasone should be reserved for the sickest COVID-19 patients
Memphis, Tennessee, November 13, 2020
Rather than life-threatening hyperinflammation, most adults with moderate-to-severe COVID-19 have a suppressed viral immune response when compared to adults with another viral respiratory infection, influenza. St. Jude Children’s Research Hospital and Washington University School of Medicine in St. Louis led research that suggests most COVID-19 patients are not candidates for treatment with steroids such as dexamethasone. The research appears today in Science Advances.
Fewer than 5% of the COVID-19 patients in this study, including some of the sickest individuals, had the life-threatening, hyperinflammatory immune response known as cytokine storm syndrome. Cytokines are small proteins secreted by blood cells that help coordinate the immune response and trigger inflammation. Cytokine storms develop when excess or abnormally regulated cytokine production leads to hyperinflammation and tissue damage. While dexamethasone and other steroids are prescribed to treat cytokine storms, the drugs can backfire in patients whose immune response is already suppressed.
Cytokine storms have been proposed as the cause of respiratory failure in COVID-19 patients.
“We did identify a subset of COVID-19 patients with the broadly upregulated array of cytokines, which is a hallmark of cytokine storm,” said co-corresponding author Paul Thomas, Ph.D., of the St. Jude Department of Immunology. “But, overall, the average person with COVID-19—even patients with moderate-to-severe disease—had less inflammation than the average person with flu.
“The findings suggest that treatment suppressing inflammation might only be effective in that minority of patients with the hyperinflammatory profile,” Thomas said. He, Ali Ellebedy, Ph.D., and Philip Mudd, M.D., Ph.D., of Washington University School of Medicine, are corresponding authors of the study.
What’s needed, researchers said, is a fast, reliable and inexpensive test to measure cytokines and identify patients who are most likely to benefit from immunosuppressive treatment.
Eleven months into this pandemic, and COVID-19 continues to surprise.
Originally viewed as an `influenza-like-illness', SARS-CoV-2 has proven itself to be a far more systemic threat than influenza, with neurological, cardiac, gastrointestinal, renal, and thrombotic impacts often reported (see Nature Med. Review: Extrapulmonary manifestations of COVID-19).
https://twitter.com/KartikSehgal_MD/...95760879202304
One fascinating bit of news from the press release (see below) is that SARS-CoV-2 infection may actually ramp up the host's natural production of glucocorticoids, which in turn may be responsible for the limited, and rapidly diminishing immune response we've seen reported in many recovered patients (see EID Journal: Waning Antibody Response In Asymptomatic and Symptomatic SARS-CoV-2 Infection).
Researchers also found evidence that SARS-CoV-2 alters pathways controlling the immune response to promote steroid production by patients. “Our results suggest that most COVID-19 patients are perhaps already producing high levels of glucocorticoids prior to treatment, possibly leading to the blunted immunity we see in most of them,” Thomas said. “These patients may need therapy to turn up their immune response to knock the virus down.”
The bottom line (at least, based on this study); dexamethasone may be lifesaving for a small percentage of COVID-19 cases actually experiencing cytokine storm pneumonia, for the vast majority of COVID cases the the pharmacological cupboard for COVID-19 remains distressingly bare.
https://afludiary.blogspot.com/2020/...d-role-of.html