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Damian McNamara is a journalist for Medscape Medical News and MDedge. He worked full-time for MDedge as the Miami Bureau covering a dozen medical specialties during 2001-2012, then as a freelancer for Medscape and MDedge, before being hired on staff by Medscape in 2018. Now the two companies are one. He uses what he learned in school – Damian has a BS in chemistry and an MS in science, health and environmental reporting/journalism. He works out of a home office in Miami, with a 100-pound chocolate lab known to snore under his desk during work hours.
‘Profound human toll’ in excess deaths from COVID-19 calculated in two studies
However, additional deaths could be indirectly related because people avoided emergency care during the pandemic, new research shows.
Deaths linked to COVID-19 varied by state and phase of the pandemic, as reported in a study from researchers at Virginia Commonwealth University and Yale University that was published online October 12 in JAMA.
Another study published online simultaneously in JAMA took more of an international perspective. Investigators from the University of Pennsylvania and Harvard University found that in America there were more excess deaths and there was higher all-cause mortality during the pandemic than in 18 other countries.
Although the ongoing number of deaths attributable to COVID-19 continues to garner attention, there can be a lag of weeks or months in how long it takes some public health agencies to update their figures.
“For the public at large, the take-home message is twofold: that the number of deaths caused by the pandemic exceeds publicly reported COVID-19 death counts by 20% and that states that reopened or lifted restrictions early suffered a protracted surge in excess deaths that extended into the summer,” lead author of the US-focused study, Steven H. Woolf, MD, MPH, told Medscape Medical News.
The take-away for physicians is in the bigger picture – it is likely that the COVID-19 pandemic is responsible for deaths from other conditions as well. “Surges in COVID-19 were accompanied by an increase in deaths attributed to other causes, such as heart disease and Alzheimer’s disease and dementia,” said Woolf, director emeritus and senior adviser at the Center on Society and Health and professor in the Department of Family Medicine and Population Health at the Virginia Commonwealth University School of Medicine in Richmond, Virginia.
The investigators identified 225,530 excess US deaths in the 5 months from March to July. They report that 67% were directly attributable to COVID-19.
Deaths linked to COVID-19 included those in which the disease was listed as an underlying or contributing cause. US total death rates are “remarkably consistent” year after year, and the investigators calculated a 20% overall jump in mortality.
The study included data from the National Center for Health Statistics and the US Census Bureau for 48 states and the District of Columbia. Connecticut and North Carolina were excluded because of missing data.
Woolf and colleagues also found statistically higher rates of deaths from two other causes, heart disease and Alzheimer’s disease/dementia.
Altered states
New York, New Jersey, Massachusetts, Louisiana, Arizona, Mississippi, Maryland, Delaware, Rhode Island, and Michigan had the highest per capita excess death rates. Three states experienced the shortest epidemics during the study period: New York, New Jersey, and Massachusetts.
Some lessons could be learned by looking at how individual states managed large numbers of people with COVID-19. “Although we suspected that states that reopened early might have put themselves at risk of a pandemic surge, the consistency with which that occurred and the devastating numbers of deaths they suffered was a surprise,” Woolf said.
“The goal of our study is not to look in the rearview mirror and lament what happened months ago but to learn the lesson going forward: Our country will be unable to take control of this pandemic without more robust efforts to control community spread,” Woolf said. “Our study found that states that did this well, such as New York and New Jersey, experienced large surges but bent the curve and were back to baseline in less than 10 weeks.
“If we could do this as a country, countless lives could be saved.”
A global perspective
The United States experienced high mortality linked to COVID-19, as well as high all-cause mortality, compared with 18 other countries, as reported in the study by University of Pennsylvania and Harvard University researchers.
The United States ranked third, with 72 deaths per 100,000 people, among countries with moderate or high mortality. Although perhaps not surprising given the state of SARS-CoV-2 infection across the United States, a question remains as to what extent the relatively high mortality rate is linked to early outbreaks vs “poor long-term response,” the researchers note.
Alyssa Bilinski, MSc, and lead author Ezekiel J. Emanuel, MD, PhD, chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, calculated the difference in COVID-19 deaths among countries through Sept. 19, 2020. On this date, the United States reported a total 198,589 COVID-19 deaths.
They calculated that, if the US death rates were similar to those in Australia, the United States would have experienced 187,661 fewer COVID-19 deaths. If similar to those of Canada, there would have been 117,622 fewer deaths in the United States.
The US death rate was lower than six other countries with high COVID-19 mortality in the early spring, including Belgium, Spain, and the United Kingdom. However, after May 10, the per capita mortality rate in the United States exceeded the others.
Between May 10 and Sept. 19, the death rate in Italy was 9.1 per 100,000, vs 36.9 per 100,000.
“After the first peak in early spring, US death rates from COVID-19 and from all causes remained higher than even countries with high COVID-19 mortality,” the researchers note. “This may have been a result of several factors, including weak public health infrastructure and a decentralized, inconsistent US response to the pandemic.”
“Mortifying and motivating”
Woolf and colleagues estimate that more than 225,000 excess deaths occurred in recent months; this represents a 20% increase over expected deaths, note Harvey V. Fineberg, MD, PhD, of the Gordon and Betty Moore Foundation, in an accompanying editorial in JAMA.
“Importantly, a condition such as COVID-19 can contribute both directly and indirectly to excess mortality,” he writes.
Although the direct contribution to the mortality rates by those infected is straightforward, “the indirect contribution may relate to circumstances or choices due to the COVID-19 pandemic: for example, a patient who develops symptoms of a stroke is too concerned about COVID-19 to go to the emergency department, and a potentially reversible condition becomes fatal.”
Fineberg notes that “a general indication of the death toll from COVID-19 and the excess deaths related to the pandemic, as presented by Woolf et al, are sufficiently mortifying and motivating.”
“Profound human toll”
“The importance of the estimate by Woolf et al – which suggests that for the entirety of 2020, more than 400,000 excess deaths will occur – cannot be overstated, because it accounts for what could be declines in some causes of death, like motor vehicle crashes, but increases in others, like myocardial infarction,” write Howard Bauchner, MD, editor in chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive editor of JAMA, in another accompanying editorial.
“These deaths reflect a true measure of the human cost of the Great Pandemic of 2020,” they add.
The study from Emanuel and Bilinski was notable for calculating the excess COVID-19 and all-cause mortality to Sept. 2020, they note. “After the initial peak in early spring, US death rates from COVID-19 and from all causes remained higher than rates in countries with high COVID-19 mortality.”
“Few people will forget the Great Pandemic of 2020, where and how they lived, how it substantially changed their lives, and for many, the profound human toll it has taken,” Bauchner and Fontanarosa write.
The study by Woolf and colleagues was supported by National Center for Advancing Translational Sciences, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. The study by Bilinski and Emanuel was partially funded by the Colton Foundation. Woolf, Emanuel, Fineberg, Bauchner, and Fontanarosa have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
However, additional deaths could be indirectly related because people avoided emergency care during the pandemic, new research shows.
Deaths linked to COVID-19 varied by state and phase of the pandemic, as reported in a study from researchers at Virginia Commonwealth University and Yale University that was published online October 12 in JAMA.
Another study published online simultaneously in JAMA took more of an international perspective. Investigators from the University of Pennsylvania and Harvard University found that in America there were more excess deaths and there was higher all-cause mortality during the pandemic than in 18 other countries.
Although the ongoing number of deaths attributable to COVID-19 continues to garner attention, there can be a lag of weeks or months in how long it takes some public health agencies to update their figures.
“For the public at large, the take-home message is twofold: that the number of deaths caused by the pandemic exceeds publicly reported COVID-19 death counts by 20% and that states that reopened or lifted restrictions early suffered a protracted surge in excess deaths that extended into the summer,” lead author of the US-focused study, Steven H. Woolf, MD, MPH, told Medscape Medical News.
The take-away for physicians is in the bigger picture – it is likely that the COVID-19 pandemic is responsible for deaths from other conditions as well. “Surges in COVID-19 were accompanied by an increase in deaths attributed to other causes, such as heart disease and Alzheimer’s disease and dementia,” said Woolf, director emeritus and senior adviser at the Center on Society and Health and professor in the Department of Family Medicine and Population Health at the Virginia Commonwealth University School of Medicine in Richmond, Virginia.
The investigators identified 225,530 excess US deaths in the 5 months from March to July. They report that 67% were directly attributable to COVID-19.
Deaths linked to COVID-19 included those in which the disease was listed as an underlying or contributing cause. US total death rates are “remarkably consistent” year after year, and the investigators calculated a 20% overall jump in mortality.
The study included data from the National Center for Health Statistics and the US Census Bureau for 48 states and the District of Columbia. Connecticut and North Carolina were excluded because of missing data.
Woolf and colleagues also found statistically higher rates of deaths from two other causes, heart disease and Alzheimer’s disease/dementia.
Altered states
New York, New Jersey, Massachusetts, Louisiana, Arizona, Mississippi, Maryland, Delaware, Rhode Island, and Michigan had the highest per capita excess death rates. Three states experienced the shortest epidemics during the study period: New York, New Jersey, and Massachusetts.
Some lessons could be learned by looking at how individual states managed large numbers of people with COVID-19. “Although we suspected that states that reopened early might have put themselves at risk of a pandemic surge, the consistency with which that occurred and the devastating numbers of deaths they suffered was a surprise,” Woolf said.
“The goal of our study is not to look in the rearview mirror and lament what happened months ago but to learn the lesson going forward: Our country will be unable to take control of this pandemic without more robust efforts to control community spread,” Woolf said. “Our study found that states that did this well, such as New York and New Jersey, experienced large surges but bent the curve and were back to baseline in less than 10 weeks.
“If we could do this as a country, countless lives could be saved.”
A global perspective
The United States experienced high mortality linked to COVID-19, as well as high all-cause mortality, compared with 18 other countries, as reported in the study by University of Pennsylvania and Harvard University researchers.
The United States ranked third, with 72 deaths per 100,000 people, among countries with moderate or high mortality. Although perhaps not surprising given the state of SARS-CoV-2 infection across the United States, a question remains as to what extent the relatively high mortality rate is linked to early outbreaks vs “poor long-term response,” the researchers note.
Alyssa Bilinski, MSc, and lead author Ezekiel J. Emanuel, MD, PhD, chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, calculated the difference in COVID-19 deaths among countries through Sept. 19, 2020. On this date, the United States reported a total 198,589 COVID-19 deaths.
They calculated that, if the US death rates were similar to those in Australia, the United States would have experienced 187,661 fewer COVID-19 deaths. If similar to those of Canada, there would have been 117,622 fewer deaths in the United States.
The US death rate was lower than six other countries with high COVID-19 mortality in the early spring, including Belgium, Spain, and the United Kingdom. However, after May 10, the per capita mortality rate in the United States exceeded the others.
Between May 10 and Sept. 19, the death rate in Italy was 9.1 per 100,000, vs 36.9 per 100,000.
“After the first peak in early spring, US death rates from COVID-19 and from all causes remained higher than even countries with high COVID-19 mortality,” the researchers note. “This may have been a result of several factors, including weak public health infrastructure and a decentralized, inconsistent US response to the pandemic.”
“Mortifying and motivating”
Woolf and colleagues estimate that more than 225,000 excess deaths occurred in recent months; this represents a 20% increase over expected deaths, note Harvey V. Fineberg, MD, PhD, of the Gordon and Betty Moore Foundation, in an accompanying editorial in JAMA.
“Importantly, a condition such as COVID-19 can contribute both directly and indirectly to excess mortality,” he writes.
Although the direct contribution to the mortality rates by those infected is straightforward, “the indirect contribution may relate to circumstances or choices due to the COVID-19 pandemic: for example, a patient who develops symptoms of a stroke is too concerned about COVID-19 to go to the emergency department, and a potentially reversible condition becomes fatal.”
Fineberg notes that “a general indication of the death toll from COVID-19 and the excess deaths related to the pandemic, as presented by Woolf et al, are sufficiently mortifying and motivating.”
“Profound human toll”
“The importance of the estimate by Woolf et al – which suggests that for the entirety of 2020, more than 400,000 excess deaths will occur – cannot be overstated, because it accounts for what could be declines in some causes of death, like motor vehicle crashes, but increases in others, like myocardial infarction,” write Howard Bauchner, MD, editor in chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive editor of JAMA, in another accompanying editorial.
“These deaths reflect a true measure of the human cost of the Great Pandemic of 2020,” they add.
The study from Emanuel and Bilinski was notable for calculating the excess COVID-19 and all-cause mortality to Sept. 2020, they note. “After the initial peak in early spring, US death rates from COVID-19 and from all causes remained higher than rates in countries with high COVID-19 mortality.”
“Few people will forget the Great Pandemic of 2020, where and how they lived, how it substantially changed their lives, and for many, the profound human toll it has taken,” Bauchner and Fontanarosa write.
The study by Woolf and colleagues was supported by National Center for Advancing Translational Sciences, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. The study by Bilinski and Emanuel was partially funded by the Colton Foundation. Woolf, Emanuel, Fineberg, Bauchner, and Fontanarosa have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
However, additional deaths could be indirectly related because people avoided emergency care during the pandemic, new research shows.
Deaths linked to COVID-19 varied by state and phase of the pandemic, as reported in a study from researchers at Virginia Commonwealth University and Yale University that was published online October 12 in JAMA.
Another study published online simultaneously in JAMA took more of an international perspective. Investigators from the University of Pennsylvania and Harvard University found that in America there were more excess deaths and there was higher all-cause mortality during the pandemic than in 18 other countries.
Although the ongoing number of deaths attributable to COVID-19 continues to garner attention, there can be a lag of weeks or months in how long it takes some public health agencies to update their figures.
“For the public at large, the take-home message is twofold: that the number of deaths caused by the pandemic exceeds publicly reported COVID-19 death counts by 20% and that states that reopened or lifted restrictions early suffered a protracted surge in excess deaths that extended into the summer,” lead author of the US-focused study, Steven H. Woolf, MD, MPH, told Medscape Medical News.
The take-away for physicians is in the bigger picture – it is likely that the COVID-19 pandemic is responsible for deaths from other conditions as well. “Surges in COVID-19 were accompanied by an increase in deaths attributed to other causes, such as heart disease and Alzheimer’s disease and dementia,” said Woolf, director emeritus and senior adviser at the Center on Society and Health and professor in the Department of Family Medicine and Population Health at the Virginia Commonwealth University School of Medicine in Richmond, Virginia.
The investigators identified 225,530 excess US deaths in the 5 months from March to July. They report that 67% were directly attributable to COVID-19.
Deaths linked to COVID-19 included those in which the disease was listed as an underlying or contributing cause. US total death rates are “remarkably consistent” year after year, and the investigators calculated a 20% overall jump in mortality.
The study included data from the National Center for Health Statistics and the US Census Bureau for 48 states and the District of Columbia. Connecticut and North Carolina were excluded because of missing data.
Woolf and colleagues also found statistically higher rates of deaths from two other causes, heart disease and Alzheimer’s disease/dementia.
Altered states
New York, New Jersey, Massachusetts, Louisiana, Arizona, Mississippi, Maryland, Delaware, Rhode Island, and Michigan had the highest per capita excess death rates. Three states experienced the shortest epidemics during the study period: New York, New Jersey, and Massachusetts.
Some lessons could be learned by looking at how individual states managed large numbers of people with COVID-19. “Although we suspected that states that reopened early might have put themselves at risk of a pandemic surge, the consistency with which that occurred and the devastating numbers of deaths they suffered was a surprise,” Woolf said.
“The goal of our study is not to look in the rearview mirror and lament what happened months ago but to learn the lesson going forward: Our country will be unable to take control of this pandemic without more robust efforts to control community spread,” Woolf said. “Our study found that states that did this well, such as New York and New Jersey, experienced large surges but bent the curve and were back to baseline in less than 10 weeks.
“If we could do this as a country, countless lives could be saved.”
A global perspective
The United States experienced high mortality linked to COVID-19, as well as high all-cause mortality, compared with 18 other countries, as reported in the study by University of Pennsylvania and Harvard University researchers.
The United States ranked third, with 72 deaths per 100,000 people, among countries with moderate or high mortality. Although perhaps not surprising given the state of SARS-CoV-2 infection across the United States, a question remains as to what extent the relatively high mortality rate is linked to early outbreaks vs “poor long-term response,” the researchers note.
Alyssa Bilinski, MSc, and lead author Ezekiel J. Emanuel, MD, PhD, chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, calculated the difference in COVID-19 deaths among countries through Sept. 19, 2020. On this date, the United States reported a total 198,589 COVID-19 deaths.
They calculated that, if the US death rates were similar to those in Australia, the United States would have experienced 187,661 fewer COVID-19 deaths. If similar to those of Canada, there would have been 117,622 fewer deaths in the United States.
The US death rate was lower than six other countries with high COVID-19 mortality in the early spring, including Belgium, Spain, and the United Kingdom. However, after May 10, the per capita mortality rate in the United States exceeded the others.
Between May 10 and Sept. 19, the death rate in Italy was 9.1 per 100,000, vs 36.9 per 100,000.
“After the first peak in early spring, US death rates from COVID-19 and from all causes remained higher than even countries with high COVID-19 mortality,” the researchers note. “This may have been a result of several factors, including weak public health infrastructure and a decentralized, inconsistent US response to the pandemic.”
“Mortifying and motivating”
Woolf and colleagues estimate that more than 225,000 excess deaths occurred in recent months; this represents a 20% increase over expected deaths, note Harvey V. Fineberg, MD, PhD, of the Gordon and Betty Moore Foundation, in an accompanying editorial in JAMA.
“Importantly, a condition such as COVID-19 can contribute both directly and indirectly to excess mortality,” he writes.
Although the direct contribution to the mortality rates by those infected is straightforward, “the indirect contribution may relate to circumstances or choices due to the COVID-19 pandemic: for example, a patient who develops symptoms of a stroke is too concerned about COVID-19 to go to the emergency department, and a potentially reversible condition becomes fatal.”
Fineberg notes that “a general indication of the death toll from COVID-19 and the excess deaths related to the pandemic, as presented by Woolf et al, are sufficiently mortifying and motivating.”
“Profound human toll”
“The importance of the estimate by Woolf et al – which suggests that for the entirety of 2020, more than 400,000 excess deaths will occur – cannot be overstated, because it accounts for what could be declines in some causes of death, like motor vehicle crashes, but increases in others, like myocardial infarction,” write Howard Bauchner, MD, editor in chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive editor of JAMA, in another accompanying editorial.
“These deaths reflect a true measure of the human cost of the Great Pandemic of 2020,” they add.
The study from Emanuel and Bilinski was notable for calculating the excess COVID-19 and all-cause mortality to Sept. 2020, they note. “After the initial peak in early spring, US death rates from COVID-19 and from all causes remained higher than rates in countries with high COVID-19 mortality.”
“Few people will forget the Great Pandemic of 2020, where and how they lived, how it substantially changed their lives, and for many, the profound human toll it has taken,” Bauchner and Fontanarosa write.
The study by Woolf and colleagues was supported by National Center for Advancing Translational Sciences, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. The study by Bilinski and Emanuel was partially funded by the Colton Foundation. Woolf, Emanuel, Fineberg, Bauchner, and Fontanarosa have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Three major COVID vaccine developers release detailed trial protocols
Typically, manufacturers guard the specifics of preclinical vaccine trials. This rare move follows calls for greater transparency. For example, the American Medical Association wrote a letter in late August asking the Food and Drug Administration to keep physicians informed of their COVID-19 vaccine review process.
On September 17, ModernaTx released the phase 3 trial protocol for its mRNA-1273 SARS-CoV-2 vaccine. In short order, on September 19, Pfizer/BioNTech shared their phase 1/2/3 trial vaccine protocol. AstraZeneca, which is developing a vaccine along with Oxford University, also released its protocol.
The AstraZeneca vaccine trial made headlines recently for having to be temporarily halted because of unexpected illnesses that arose in two participants, according to the New York Times and other sources.
“I applaud the release of the clinical trial protocols by the companies. The public trust in any COVID-19 vaccine is paramount, especially given the fast timeline and perceived political pressures of these candidates,” Robert Kruse, MD, PhD, told Medscape Medical News when asked to comment.
AstraZeneca takes a shot at transparency
The three primary objectives of the AstraZeneca AZD1222 trial outlined in the 110-page protocol include estimating the efficacy, safety, tolerability, and reactogenicity associated with two intramuscular doses of the vaccine in comparison with placebo in adults.
The projected enrollment is 30,000 participants, and the estimated primary completion date is Dec. 2, 2020, according to information on clinicaltrials.gov.
“Given the unprecedented global impact of the coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial,” the company said in a statement. “As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials.
“AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company added.
Moderna methodology
The ModernaTX 135-page protocol outlines the primary trial objectives of evaluating efficacy, safety, and reactogenicity of two injections of the vaccine administered 28 days apart. Researchers also plan to randomly assign 30,000 adults to receive either vaccine or placebo. The estimated primary completion date is Oct. 27, 2022.
A statement that was requested from ModernaTX was not received by press time.
Pfizer protocol
In the Pfizer/BioNTech vaccine trial, researchers plan to evaluate different doses in different age groups in a multistep protocol. The trial features 20 primary safety objectives, which include reporting adverse events and serious adverse events, including any local or systemic events.
Efficacy endpoints are secondary objectives. The estimated enrollment is 29,481 adults; the estimated primary completion date is April 19, 2021.
“Pfizer and BioNTech recognize that the COVID-19 pandemic is a unique circumstance, and the need for transparency is clear,” Pfizer spokesperson Sharon Castillo told Medscape Medical News. By making the full protocol available, “we believe this will reinforce our long-standing commitment to scientific and regulatory rigor that benefits patients,” she said.
“Based on current infection rates, Pfizer and BioNTech continue to expect that a conclusive read-out on efficacy is likely by the end of October. Neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial,” Castillo said.
If clinical work and regulatory approval or authorization proceed as planned, Pfizer and BioNTech expect to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses worldwide by the end of 2021.
Pfizer is not willing to sacrifice safety and efficacy in the name of expediency, Castillo said. “We will not cut corners in this pursuit. Patient safety is our highest priority, and Pfizer will not bring a vaccine to market without adequate evidence of safety and efficacy.”
A positive move
“COVID-19 vaccines will only be useful if many people are willing to receive them,” said Kruse, a postgraduate year 3 resident in the Department of Pathology at Johns Hopkins Medicine in Baltimore, Maryland.
“By giving the general public along with other scientists and physicians the opportunity to critique the protocols, everyone can understand what the metrics would be for an early look at efficacy,” Kruse said. He noted that information could help inform a potential FDA emergency use authorization.
Kruse has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Typically, manufacturers guard the specifics of preclinical vaccine trials. This rare move follows calls for greater transparency. For example, the American Medical Association wrote a letter in late August asking the Food and Drug Administration to keep physicians informed of their COVID-19 vaccine review process.
On September 17, ModernaTx released the phase 3 trial protocol for its mRNA-1273 SARS-CoV-2 vaccine. In short order, on September 19, Pfizer/BioNTech shared their phase 1/2/3 trial vaccine protocol. AstraZeneca, which is developing a vaccine along with Oxford University, also released its protocol.
The AstraZeneca vaccine trial made headlines recently for having to be temporarily halted because of unexpected illnesses that arose in two participants, according to the New York Times and other sources.
“I applaud the release of the clinical trial protocols by the companies. The public trust in any COVID-19 vaccine is paramount, especially given the fast timeline and perceived political pressures of these candidates,” Robert Kruse, MD, PhD, told Medscape Medical News when asked to comment.
AstraZeneca takes a shot at transparency
The three primary objectives of the AstraZeneca AZD1222 trial outlined in the 110-page protocol include estimating the efficacy, safety, tolerability, and reactogenicity associated with two intramuscular doses of the vaccine in comparison with placebo in adults.
The projected enrollment is 30,000 participants, and the estimated primary completion date is Dec. 2, 2020, according to information on clinicaltrials.gov.
“Given the unprecedented global impact of the coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial,” the company said in a statement. “As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials.
“AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company added.
Moderna methodology
The ModernaTX 135-page protocol outlines the primary trial objectives of evaluating efficacy, safety, and reactogenicity of two injections of the vaccine administered 28 days apart. Researchers also plan to randomly assign 30,000 adults to receive either vaccine or placebo. The estimated primary completion date is Oct. 27, 2022.
A statement that was requested from ModernaTX was not received by press time.
Pfizer protocol
In the Pfizer/BioNTech vaccine trial, researchers plan to evaluate different doses in different age groups in a multistep protocol. The trial features 20 primary safety objectives, which include reporting adverse events and serious adverse events, including any local or systemic events.
Efficacy endpoints are secondary objectives. The estimated enrollment is 29,481 adults; the estimated primary completion date is April 19, 2021.
“Pfizer and BioNTech recognize that the COVID-19 pandemic is a unique circumstance, and the need for transparency is clear,” Pfizer spokesperson Sharon Castillo told Medscape Medical News. By making the full protocol available, “we believe this will reinforce our long-standing commitment to scientific and regulatory rigor that benefits patients,” she said.
“Based on current infection rates, Pfizer and BioNTech continue to expect that a conclusive read-out on efficacy is likely by the end of October. Neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial,” Castillo said.
If clinical work and regulatory approval or authorization proceed as planned, Pfizer and BioNTech expect to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses worldwide by the end of 2021.
Pfizer is not willing to sacrifice safety and efficacy in the name of expediency, Castillo said. “We will not cut corners in this pursuit. Patient safety is our highest priority, and Pfizer will not bring a vaccine to market without adequate evidence of safety and efficacy.”
A positive move
“COVID-19 vaccines will only be useful if many people are willing to receive them,” said Kruse, a postgraduate year 3 resident in the Department of Pathology at Johns Hopkins Medicine in Baltimore, Maryland.
“By giving the general public along with other scientists and physicians the opportunity to critique the protocols, everyone can understand what the metrics would be for an early look at efficacy,” Kruse said. He noted that information could help inform a potential FDA emergency use authorization.
Kruse has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Typically, manufacturers guard the specifics of preclinical vaccine trials. This rare move follows calls for greater transparency. For example, the American Medical Association wrote a letter in late August asking the Food and Drug Administration to keep physicians informed of their COVID-19 vaccine review process.
On September 17, ModernaTx released the phase 3 trial protocol for its mRNA-1273 SARS-CoV-2 vaccine. In short order, on September 19, Pfizer/BioNTech shared their phase 1/2/3 trial vaccine protocol. AstraZeneca, which is developing a vaccine along with Oxford University, also released its protocol.
The AstraZeneca vaccine trial made headlines recently for having to be temporarily halted because of unexpected illnesses that arose in two participants, according to the New York Times and other sources.
“I applaud the release of the clinical trial protocols by the companies. The public trust in any COVID-19 vaccine is paramount, especially given the fast timeline and perceived political pressures of these candidates,” Robert Kruse, MD, PhD, told Medscape Medical News when asked to comment.
AstraZeneca takes a shot at transparency
The three primary objectives of the AstraZeneca AZD1222 trial outlined in the 110-page protocol include estimating the efficacy, safety, tolerability, and reactogenicity associated with two intramuscular doses of the vaccine in comparison with placebo in adults.
The projected enrollment is 30,000 participants, and the estimated primary completion date is Dec. 2, 2020, according to information on clinicaltrials.gov.
“Given the unprecedented global impact of the coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial,” the company said in a statement. “As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials.
“AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company added.
Moderna methodology
The ModernaTX 135-page protocol outlines the primary trial objectives of evaluating efficacy, safety, and reactogenicity of two injections of the vaccine administered 28 days apart. Researchers also plan to randomly assign 30,000 adults to receive either vaccine or placebo. The estimated primary completion date is Oct. 27, 2022.
A statement that was requested from ModernaTX was not received by press time.
Pfizer protocol
In the Pfizer/BioNTech vaccine trial, researchers plan to evaluate different doses in different age groups in a multistep protocol. The trial features 20 primary safety objectives, which include reporting adverse events and serious adverse events, including any local or systemic events.
Efficacy endpoints are secondary objectives. The estimated enrollment is 29,481 adults; the estimated primary completion date is April 19, 2021.
“Pfizer and BioNTech recognize that the COVID-19 pandemic is a unique circumstance, and the need for transparency is clear,” Pfizer spokesperson Sharon Castillo told Medscape Medical News. By making the full protocol available, “we believe this will reinforce our long-standing commitment to scientific and regulatory rigor that benefits patients,” she said.
“Based on current infection rates, Pfizer and BioNTech continue to expect that a conclusive read-out on efficacy is likely by the end of October. Neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial,” Castillo said.
If clinical work and regulatory approval or authorization proceed as planned, Pfizer and BioNTech expect to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses worldwide by the end of 2021.
Pfizer is not willing to sacrifice safety and efficacy in the name of expediency, Castillo said. “We will not cut corners in this pursuit. Patient safety is our highest priority, and Pfizer will not bring a vaccine to market without adequate evidence of safety and efficacy.”
A positive move
“COVID-19 vaccines will only be useful if many people are willing to receive them,” said Kruse, a postgraduate year 3 resident in the Department of Pathology at Johns Hopkins Medicine in Baltimore, Maryland.
“By giving the general public along with other scientists and physicians the opportunity to critique the protocols, everyone can understand what the metrics would be for an early look at efficacy,” Kruse said. He noted that information could help inform a potential FDA emergency use authorization.
Kruse has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Infectious COVID-19 can persist in gut for weeks
Stool tests were positive among people with no GI symptoms, and in some cases up to 6 days after nasopharyngeal swabs yielded negative results.
The small pilot study suggests a quiescent but active infection in the gut. Stool testing revealed genomic evidence of active infection in 7 of the 15 participants tested in one of two hospitals in Hong Kong.
“We found active and prolonged SARS-CoV-2 infection in the stool of patients with COVID-19, even after recovery, suggesting that coronavirus could remain in the gut of asymptomatic carriers,” senior author Siew C. Ng, MBBS, PhD, told Medscape Medical News.
“Due to the potential threat of fecal-oral transmission, it is important to maintain long-term coronavirus and health surveillance,” said Ng, Associate Director of the Centre for Gut Microbiota Research at the Chinese University of Hong Kong (CUHK).
“Discharged patients and their caretakers should remain vigilant and observe strict personal and toileting hygiene,” she added.
The prospective, observational study was published online July 20 in Gut.
Ramping up COVID-19 testing
As a follow-up to these and other findings – including the testing of more than 2,000 stool samples in children and the needy arriving at Hong Kong airports starting March 29 – the same investigators are establishing a CUHK Coronavirus Testing Center.
As of Aug. 31, the detection rate in tested children was 0.28%. The Center plans to offer as many as 2,000 COVID-19 tests daily going forward to help identify asymptomatic carriers, the investigators announced in a Sept. 7 news release.
In contrast to nasopharyngeal sampling, stool specimens are “more convenient, safe and non-invasive to collect in the pediatric population,” professor Paul Chan, chairman of the Department of Microbiology, CU Medicine, said in the release. “This makes the stool test a better option for COVID-19 screening in babies, young children and those whose respiratory samples are difficult to collect.”
Even though previous researchers identified SARS-CoV-2 in the stool, the activity and infectivity of the virus in the gastrointestinal tract during and after COVID-19 respiratory positivity remained largely unknown.
Active infection detected in stool
This prospective study involved 15 people hospitalized with COVID-19 in March and April. Participants were a median 55 years old (range, 22-71 years) and all presented with respiratory symptoms. Only one patient had concurrent GI symptoms at admission. Median length of stay was 21 days.
Investigators collected fecal samples serially until discharge. They extracted viral DNA to test for transcriptional genetic evidence of active infection, which they detected in 7 of 15 patients. The patient with GI symptoms was not in this positive group.
The findings suggest a “quiescent but active GI infection,” the researchers note.
Three of the seven patients continued to test positive for active infection in their stool up to 6 days after respiratory clearance of SARS-CoV-2.
Microbiome matters
The investigators also extracted, amplified, and sequenced DNA from the stool samples. Their “metagenomic” profile revealed the type and amounts of bacterial strains in each patient’s gut microbiome.
Interestingly, bacterial strains differed between people with high SARS-CoV-2 infectivity versus participants with low to no evidence of active infection.
“Stool with high viral activity had higher abundance of pathogenic bacteria,” Ng said. In contrast, people with low or no infectivity had more beneficial bacterial strains, including bacteria that play critical roles in boosting host immunity.
Each patient’s microbiome composition changed during the course of the study. Whether the microbiome alters the course of COVID-19 or COVID-19 alters the composition of the microbiome requires further study, the authors note.
The U.S. Food and Drug Administration and officials in other countries have contacted the Hong Kong investigators for more details on their stool testing strategy, professor Francis K.L. Chan, dean of the faculty of medicine and director of the Centre for Gut Microbiota Research at CUHK, stated in the news release.
Further research into revealing the infectivity and pathogenesis of SARS-CoV-2 in the GI tract is warranted. The value of modulating the human gut microbiome in this patient population could be worthwhile to investigate as well, the researchers said.
Novel finding
“Some of it is not-so-new news and some is new,” David A. Johnson, MD, told Medscape Medical News when asked to comment on the study.
For example, previous researchers have detected SARS-CoV-2 virus in the stool. However, this study takes it a step further and shows that the virus present in stool can remain infectious on the basis of metagenomic signatures.
Furthermore, the virus can remain infectious in the gut even after a patient tests negative for COVID-19 through nasopharyngeal sampling – in this report up to 6 days later, said Johnson, professor of medicine, chief of gastroenterology, Eastern Virginia Medical School in Norfolk, Va.
The study carries important implications for people who currently test negative following active COVID-19 infection, he added. Centers for Disease Control and Prevention criteria clear a person as negative after two nasopharyngeal swabs at least 24 hours apart.
People in this category could believe they are no longer infectious and might return to a setting where they could infect others, Johnson said.
One potential means for spreading SARS-CoV-2 from the gut is from a toilet plume, as Johnson previously highlighted in a video report for Medscape Medical News.
The study authors disclosed no relevant financial relationships. Johnson serves as an adviser to WebMD/Medscape.
This article first appeared on Medscape.com.
Stool tests were positive among people with no GI symptoms, and in some cases up to 6 days after nasopharyngeal swabs yielded negative results.
The small pilot study suggests a quiescent but active infection in the gut. Stool testing revealed genomic evidence of active infection in 7 of the 15 participants tested in one of two hospitals in Hong Kong.
“We found active and prolonged SARS-CoV-2 infection in the stool of patients with COVID-19, even after recovery, suggesting that coronavirus could remain in the gut of asymptomatic carriers,” senior author Siew C. Ng, MBBS, PhD, told Medscape Medical News.
“Due to the potential threat of fecal-oral transmission, it is important to maintain long-term coronavirus and health surveillance,” said Ng, Associate Director of the Centre for Gut Microbiota Research at the Chinese University of Hong Kong (CUHK).
“Discharged patients and their caretakers should remain vigilant and observe strict personal and toileting hygiene,” she added.
The prospective, observational study was published online July 20 in Gut.
Ramping up COVID-19 testing
As a follow-up to these and other findings – including the testing of more than 2,000 stool samples in children and the needy arriving at Hong Kong airports starting March 29 – the same investigators are establishing a CUHK Coronavirus Testing Center.
As of Aug. 31, the detection rate in tested children was 0.28%. The Center plans to offer as many as 2,000 COVID-19 tests daily going forward to help identify asymptomatic carriers, the investigators announced in a Sept. 7 news release.
In contrast to nasopharyngeal sampling, stool specimens are “more convenient, safe and non-invasive to collect in the pediatric population,” professor Paul Chan, chairman of the Department of Microbiology, CU Medicine, said in the release. “This makes the stool test a better option for COVID-19 screening in babies, young children and those whose respiratory samples are difficult to collect.”
Even though previous researchers identified SARS-CoV-2 in the stool, the activity and infectivity of the virus in the gastrointestinal tract during and after COVID-19 respiratory positivity remained largely unknown.
Active infection detected in stool
This prospective study involved 15 people hospitalized with COVID-19 in March and April. Participants were a median 55 years old (range, 22-71 years) and all presented with respiratory symptoms. Only one patient had concurrent GI symptoms at admission. Median length of stay was 21 days.
Investigators collected fecal samples serially until discharge. They extracted viral DNA to test for transcriptional genetic evidence of active infection, which they detected in 7 of 15 patients. The patient with GI symptoms was not in this positive group.
The findings suggest a “quiescent but active GI infection,” the researchers note.
Three of the seven patients continued to test positive for active infection in their stool up to 6 days after respiratory clearance of SARS-CoV-2.
Microbiome matters
The investigators also extracted, amplified, and sequenced DNA from the stool samples. Their “metagenomic” profile revealed the type and amounts of bacterial strains in each patient’s gut microbiome.
Interestingly, bacterial strains differed between people with high SARS-CoV-2 infectivity versus participants with low to no evidence of active infection.
“Stool with high viral activity had higher abundance of pathogenic bacteria,” Ng said. In contrast, people with low or no infectivity had more beneficial bacterial strains, including bacteria that play critical roles in boosting host immunity.
Each patient’s microbiome composition changed during the course of the study. Whether the microbiome alters the course of COVID-19 or COVID-19 alters the composition of the microbiome requires further study, the authors note.
The U.S. Food and Drug Administration and officials in other countries have contacted the Hong Kong investigators for more details on their stool testing strategy, professor Francis K.L. Chan, dean of the faculty of medicine and director of the Centre for Gut Microbiota Research at CUHK, stated in the news release.
Further research into revealing the infectivity and pathogenesis of SARS-CoV-2 in the GI tract is warranted. The value of modulating the human gut microbiome in this patient population could be worthwhile to investigate as well, the researchers said.
Novel finding
“Some of it is not-so-new news and some is new,” David A. Johnson, MD, told Medscape Medical News when asked to comment on the study.
For example, previous researchers have detected SARS-CoV-2 virus in the stool. However, this study takes it a step further and shows that the virus present in stool can remain infectious on the basis of metagenomic signatures.
Furthermore, the virus can remain infectious in the gut even after a patient tests negative for COVID-19 through nasopharyngeal sampling – in this report up to 6 days later, said Johnson, professor of medicine, chief of gastroenterology, Eastern Virginia Medical School in Norfolk, Va.
The study carries important implications for people who currently test negative following active COVID-19 infection, he added. Centers for Disease Control and Prevention criteria clear a person as negative after two nasopharyngeal swabs at least 24 hours apart.
People in this category could believe they are no longer infectious and might return to a setting where they could infect others, Johnson said.
One potential means for spreading SARS-CoV-2 from the gut is from a toilet plume, as Johnson previously highlighted in a video report for Medscape Medical News.
The study authors disclosed no relevant financial relationships. Johnson serves as an adviser to WebMD/Medscape.
This article first appeared on Medscape.com.
Stool tests were positive among people with no GI symptoms, and in some cases up to 6 days after nasopharyngeal swabs yielded negative results.
The small pilot study suggests a quiescent but active infection in the gut. Stool testing revealed genomic evidence of active infection in 7 of the 15 participants tested in one of two hospitals in Hong Kong.
“We found active and prolonged SARS-CoV-2 infection in the stool of patients with COVID-19, even after recovery, suggesting that coronavirus could remain in the gut of asymptomatic carriers,” senior author Siew C. Ng, MBBS, PhD, told Medscape Medical News.
“Due to the potential threat of fecal-oral transmission, it is important to maintain long-term coronavirus and health surveillance,” said Ng, Associate Director of the Centre for Gut Microbiota Research at the Chinese University of Hong Kong (CUHK).
“Discharged patients and their caretakers should remain vigilant and observe strict personal and toileting hygiene,” she added.
The prospective, observational study was published online July 20 in Gut.
Ramping up COVID-19 testing
As a follow-up to these and other findings – including the testing of more than 2,000 stool samples in children and the needy arriving at Hong Kong airports starting March 29 – the same investigators are establishing a CUHK Coronavirus Testing Center.
As of Aug. 31, the detection rate in tested children was 0.28%. The Center plans to offer as many as 2,000 COVID-19 tests daily going forward to help identify asymptomatic carriers, the investigators announced in a Sept. 7 news release.
In contrast to nasopharyngeal sampling, stool specimens are “more convenient, safe and non-invasive to collect in the pediatric population,” professor Paul Chan, chairman of the Department of Microbiology, CU Medicine, said in the release. “This makes the stool test a better option for COVID-19 screening in babies, young children and those whose respiratory samples are difficult to collect.”
Even though previous researchers identified SARS-CoV-2 in the stool, the activity and infectivity of the virus in the gastrointestinal tract during and after COVID-19 respiratory positivity remained largely unknown.
Active infection detected in stool
This prospective study involved 15 people hospitalized with COVID-19 in March and April. Participants were a median 55 years old (range, 22-71 years) and all presented with respiratory symptoms. Only one patient had concurrent GI symptoms at admission. Median length of stay was 21 days.
Investigators collected fecal samples serially until discharge. They extracted viral DNA to test for transcriptional genetic evidence of active infection, which they detected in 7 of 15 patients. The patient with GI symptoms was not in this positive group.
The findings suggest a “quiescent but active GI infection,” the researchers note.
Three of the seven patients continued to test positive for active infection in their stool up to 6 days after respiratory clearance of SARS-CoV-2.
Microbiome matters
The investigators also extracted, amplified, and sequenced DNA from the stool samples. Their “metagenomic” profile revealed the type and amounts of bacterial strains in each patient’s gut microbiome.
Interestingly, bacterial strains differed between people with high SARS-CoV-2 infectivity versus participants with low to no evidence of active infection.
“Stool with high viral activity had higher abundance of pathogenic bacteria,” Ng said. In contrast, people with low or no infectivity had more beneficial bacterial strains, including bacteria that play critical roles in boosting host immunity.
Each patient’s microbiome composition changed during the course of the study. Whether the microbiome alters the course of COVID-19 or COVID-19 alters the composition of the microbiome requires further study, the authors note.
The U.S. Food and Drug Administration and officials in other countries have contacted the Hong Kong investigators for more details on their stool testing strategy, professor Francis K.L. Chan, dean of the faculty of medicine and director of the Centre for Gut Microbiota Research at CUHK, stated in the news release.
Further research into revealing the infectivity and pathogenesis of SARS-CoV-2 in the GI tract is warranted. The value of modulating the human gut microbiome in this patient population could be worthwhile to investigate as well, the researchers said.
Novel finding
“Some of it is not-so-new news and some is new,” David A. Johnson, MD, told Medscape Medical News when asked to comment on the study.
For example, previous researchers have detected SARS-CoV-2 virus in the stool. However, this study takes it a step further and shows that the virus present in stool can remain infectious on the basis of metagenomic signatures.
Furthermore, the virus can remain infectious in the gut even after a patient tests negative for COVID-19 through nasopharyngeal sampling – in this report up to 6 days later, said Johnson, professor of medicine, chief of gastroenterology, Eastern Virginia Medical School in Norfolk, Va.
The study carries important implications for people who currently test negative following active COVID-19 infection, he added. Centers for Disease Control and Prevention criteria clear a person as negative after two nasopharyngeal swabs at least 24 hours apart.
People in this category could believe they are no longer infectious and might return to a setting where they could infect others, Johnson said.
One potential means for spreading SARS-CoV-2 from the gut is from a toilet plume, as Johnson previously highlighted in a video report for Medscape Medical News.
The study authors disclosed no relevant financial relationships. Johnson serves as an adviser to WebMD/Medscape.
This article first appeared on Medscape.com.
Unexpected results in new COVID-19 ‘cytokine storm’ data
The immune system overactivation known as a “cytokine storm” does not play a major role in more severe COVID-19 outcomes, according to unexpected findings in new research. The findings stand in direct contrast to many previous reports.
“We were indeed surprised by the results of our study,” senior study author Peter Pickkers, MD, PhD, said in an interview.
In a unique approach, Dr. Pickkers and colleagues compared cytokine levels in critically ill people with COVID-19 with those in patients with bacterial sepsis, trauma, and after cardiac arrest.
“For the first time, we measured the cytokines in different diseases using the same methods. Our results convincingly show that the circulating cytokine concentrations are not higher, but lower, compared to other diseases,” said Dr. Pickkers, who is affiliated with the department of intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
The team’s research was published online on Sept. 3 in a letter in JAMA.
Cytokines lower than expected
Normally, cytokines trigger inflammation and promote healing after trauma, infection, or other conditions.
Although a cytokine storm remains ill defined, the authors noted, many researchers have implicated a hyperinflammatory response involving these small proteins in the pathophysiology of COVID-19.
The question remains, however, whether all cytokine storms strike people with different conditions the same way.
Dr. Pickkers, lead author Matthijs Kox, PhD, and colleagues studied 46 people with COVID-19 and acute respiratory distress syndrome (ARDS) who were admitted to the ICU at Radboud University Medical Center. All participants underwent mechanical ventilation and were treated between March 11 and April 27, 2020.
The investigators measured plasma levels of cytokines, including tumor necrosis factor (TNF), interleukin-6, and IL-8. They compared results in this group with those in 51 patients who experienced septic shock and ARDS, 15 patients with septic shock without ARDS, 30 people with out-of-hospital cardiac arrest, and 62 people who experienced multiple traumas. They used historical data for the non–COVID-19 cohorts.
Conditional findings
Compared with patients with septic shock and ARDS, the COVID-19 cohort had lower levels of TNF, IL-6, and IL-8. The differences were statistically significant for TNF (P < .01), as well as for IL-6 and IL-8 concentrations (for both, P < .001).
In addition, the COVID-19 group had significantly lower IL-6 and IL-8 concentrations compared with the patients who had septic shock without ARDS.
The researchers likewise found lower concentrations of IL-8 in patients with COVID-19, compared with the out-of-hospital cardiac arrest patients. IL-8 levels did not differ between the COVID-19 and trauma groups.
Furthermore, the researchers found no differences in IL-6 concentrations between patients with COVID-19 and those who experienced out-of-hospital cardiac arrest or trauma.
However, levels of TNF in people with COVID-19 were higher than in trauma patients.
The small sample sizes and single-center study design are limitations.
“The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm,” the researchers noted. However, they added, “whether anticytokine therapies will benefit patients with COVID-19 remains to be determined.”
Going forward, Dr. Pickkers and colleagues are investigating the effectiveness of different treatments to lower cytokine levels. They are treating people with COVID-19, for example, with the IL-1 cytokine inhibitor anakinra and steroids.
They also plan to assess the long-term effects of COVID-19 on the immune system. “Following an infection, it is known that the immune system may be suppressed for a longer period of time, and we are determining to what extent this is also present in COVID-19 patients,” Dr. Pickkers said.
Enough to cause a storm?
The study “is quite interesting, and data in this paper are consistent with our data,” Tadamitsu Kishimoto, MD, PhD, of the department of immune regulation at the Immunology Frontier Research Center at Osaka (Japan) University, said in an interview.
His study, published online August 21 in PNAS, also revealed lower serum IL-6 levels among people with COVID-19, compared with patients with bacterial ARDS or sepsis.
Dr. Kishimoto drew a distinction, however: COVID-19 patients can develop severe respiratory failure, suggesting a distinct immune reaction, compared with patients with bacterial sepsis. SARS-CoV-2 directly infects and activates endothelial cells rather than macrophages, as occurs in sepsis.
For this reason, Dr. Kishimoto said, “SARS-CoV-2 infection causes critical illness and severe dysfunction in respiratory organs and induces a cytokine storm,” even in the setting of lower but still elevated serum IL-6 levels.
Dr. Pickkers and Dr. Kishimoto reported no relevant financial relationships.
This story first appeared on Medscape.com.
The immune system overactivation known as a “cytokine storm” does not play a major role in more severe COVID-19 outcomes, according to unexpected findings in new research. The findings stand in direct contrast to many previous reports.
“We were indeed surprised by the results of our study,” senior study author Peter Pickkers, MD, PhD, said in an interview.
In a unique approach, Dr. Pickkers and colleagues compared cytokine levels in critically ill people with COVID-19 with those in patients with bacterial sepsis, trauma, and after cardiac arrest.
“For the first time, we measured the cytokines in different diseases using the same methods. Our results convincingly show that the circulating cytokine concentrations are not higher, but lower, compared to other diseases,” said Dr. Pickkers, who is affiliated with the department of intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
The team’s research was published online on Sept. 3 in a letter in JAMA.
Cytokines lower than expected
Normally, cytokines trigger inflammation and promote healing after trauma, infection, or other conditions.
Although a cytokine storm remains ill defined, the authors noted, many researchers have implicated a hyperinflammatory response involving these small proteins in the pathophysiology of COVID-19.
The question remains, however, whether all cytokine storms strike people with different conditions the same way.
Dr. Pickkers, lead author Matthijs Kox, PhD, and colleagues studied 46 people with COVID-19 and acute respiratory distress syndrome (ARDS) who were admitted to the ICU at Radboud University Medical Center. All participants underwent mechanical ventilation and were treated between March 11 and April 27, 2020.
The investigators measured plasma levels of cytokines, including tumor necrosis factor (TNF), interleukin-6, and IL-8. They compared results in this group with those in 51 patients who experienced septic shock and ARDS, 15 patients with septic shock without ARDS, 30 people with out-of-hospital cardiac arrest, and 62 people who experienced multiple traumas. They used historical data for the non–COVID-19 cohorts.
Conditional findings
Compared with patients with septic shock and ARDS, the COVID-19 cohort had lower levels of TNF, IL-6, and IL-8. The differences were statistically significant for TNF (P < .01), as well as for IL-6 and IL-8 concentrations (for both, P < .001).
In addition, the COVID-19 group had significantly lower IL-6 and IL-8 concentrations compared with the patients who had septic shock without ARDS.
The researchers likewise found lower concentrations of IL-8 in patients with COVID-19, compared with the out-of-hospital cardiac arrest patients. IL-8 levels did not differ between the COVID-19 and trauma groups.
Furthermore, the researchers found no differences in IL-6 concentrations between patients with COVID-19 and those who experienced out-of-hospital cardiac arrest or trauma.
However, levels of TNF in people with COVID-19 were higher than in trauma patients.
The small sample sizes and single-center study design are limitations.
“The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm,” the researchers noted. However, they added, “whether anticytokine therapies will benefit patients with COVID-19 remains to be determined.”
Going forward, Dr. Pickkers and colleagues are investigating the effectiveness of different treatments to lower cytokine levels. They are treating people with COVID-19, for example, with the IL-1 cytokine inhibitor anakinra and steroids.
They also plan to assess the long-term effects of COVID-19 on the immune system. “Following an infection, it is known that the immune system may be suppressed for a longer period of time, and we are determining to what extent this is also present in COVID-19 patients,” Dr. Pickkers said.
Enough to cause a storm?
The study “is quite interesting, and data in this paper are consistent with our data,” Tadamitsu Kishimoto, MD, PhD, of the department of immune regulation at the Immunology Frontier Research Center at Osaka (Japan) University, said in an interview.
His study, published online August 21 in PNAS, also revealed lower serum IL-6 levels among people with COVID-19, compared with patients with bacterial ARDS or sepsis.
Dr. Kishimoto drew a distinction, however: COVID-19 patients can develop severe respiratory failure, suggesting a distinct immune reaction, compared with patients with bacterial sepsis. SARS-CoV-2 directly infects and activates endothelial cells rather than macrophages, as occurs in sepsis.
For this reason, Dr. Kishimoto said, “SARS-CoV-2 infection causes critical illness and severe dysfunction in respiratory organs and induces a cytokine storm,” even in the setting of lower but still elevated serum IL-6 levels.
Dr. Pickkers and Dr. Kishimoto reported no relevant financial relationships.
This story first appeared on Medscape.com.
The immune system overactivation known as a “cytokine storm” does not play a major role in more severe COVID-19 outcomes, according to unexpected findings in new research. The findings stand in direct contrast to many previous reports.
“We were indeed surprised by the results of our study,” senior study author Peter Pickkers, MD, PhD, said in an interview.
In a unique approach, Dr. Pickkers and colleagues compared cytokine levels in critically ill people with COVID-19 with those in patients with bacterial sepsis, trauma, and after cardiac arrest.
“For the first time, we measured the cytokines in different diseases using the same methods. Our results convincingly show that the circulating cytokine concentrations are not higher, but lower, compared to other diseases,” said Dr. Pickkers, who is affiliated with the department of intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
The team’s research was published online on Sept. 3 in a letter in JAMA.
Cytokines lower than expected
Normally, cytokines trigger inflammation and promote healing after trauma, infection, or other conditions.
Although a cytokine storm remains ill defined, the authors noted, many researchers have implicated a hyperinflammatory response involving these small proteins in the pathophysiology of COVID-19.
The question remains, however, whether all cytokine storms strike people with different conditions the same way.
Dr. Pickkers, lead author Matthijs Kox, PhD, and colleagues studied 46 people with COVID-19 and acute respiratory distress syndrome (ARDS) who were admitted to the ICU at Radboud University Medical Center. All participants underwent mechanical ventilation and were treated between March 11 and April 27, 2020.
The investigators measured plasma levels of cytokines, including tumor necrosis factor (TNF), interleukin-6, and IL-8. They compared results in this group with those in 51 patients who experienced septic shock and ARDS, 15 patients with septic shock without ARDS, 30 people with out-of-hospital cardiac arrest, and 62 people who experienced multiple traumas. They used historical data for the non–COVID-19 cohorts.
Conditional findings
Compared with patients with septic shock and ARDS, the COVID-19 cohort had lower levels of TNF, IL-6, and IL-8. The differences were statistically significant for TNF (P < .01), as well as for IL-6 and IL-8 concentrations (for both, P < .001).
In addition, the COVID-19 group had significantly lower IL-6 and IL-8 concentrations compared with the patients who had septic shock without ARDS.
The researchers likewise found lower concentrations of IL-8 in patients with COVID-19, compared with the out-of-hospital cardiac arrest patients. IL-8 levels did not differ between the COVID-19 and trauma groups.
Furthermore, the researchers found no differences in IL-6 concentrations between patients with COVID-19 and those who experienced out-of-hospital cardiac arrest or trauma.
However, levels of TNF in people with COVID-19 were higher than in trauma patients.
The small sample sizes and single-center study design are limitations.
“The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm,” the researchers noted. However, they added, “whether anticytokine therapies will benefit patients with COVID-19 remains to be determined.”
Going forward, Dr. Pickkers and colleagues are investigating the effectiveness of different treatments to lower cytokine levels. They are treating people with COVID-19, for example, with the IL-1 cytokine inhibitor anakinra and steroids.
They also plan to assess the long-term effects of COVID-19 on the immune system. “Following an infection, it is known that the immune system may be suppressed for a longer period of time, and we are determining to what extent this is also present in COVID-19 patients,” Dr. Pickkers said.
Enough to cause a storm?
The study “is quite interesting, and data in this paper are consistent with our data,” Tadamitsu Kishimoto, MD, PhD, of the department of immune regulation at the Immunology Frontier Research Center at Osaka (Japan) University, said in an interview.
His study, published online August 21 in PNAS, also revealed lower serum IL-6 levels among people with COVID-19, compared with patients with bacterial ARDS or sepsis.
Dr. Kishimoto drew a distinction, however: COVID-19 patients can develop severe respiratory failure, suggesting a distinct immune reaction, compared with patients with bacterial sepsis. SARS-CoV-2 directly infects and activates endothelial cells rather than macrophages, as occurs in sepsis.
For this reason, Dr. Kishimoto said, “SARS-CoV-2 infection causes critical illness and severe dysfunction in respiratory organs and induces a cytokine storm,” even in the setting of lower but still elevated serum IL-6 levels.
Dr. Pickkers and Dr. Kishimoto reported no relevant financial relationships.
This story first appeared on Medscape.com.
High mortality rates reported in large COVID-19 study
Factors including older age and certain comorbidities have been linked to more serious COVID-19 outcomes in previous research, and now a large dataset collected from hundreds of hospitals nationwide provides more detailed data regarding risk for mechanical ventilation and death.
History of pulmonary disease or smoking, interestingly, were not.
One expert urges caution when interpreting the results, however. Although the study found a number of risk factors for ventilation and mortality, she says the dataset lacks information on race and disease severity, and the sample may not be nationally representative.
The investigators hope their level of granularity will further assist researchers searching for effective treatments and clinicians seeking to triage patients during the COVID-19 pandemic.
The study was published online August 28 in Clinical Infectious Diseases.
COVID-19 and comorbidities
“What I found most illuminating was this whole concept of comorbid conditions. This provides suggestive data about who we need to worry about most and who we may need to worry about less,” study author Robert S. Brown Jr, MD, MPH, told Medscape Medical News.
Comorbid conditions included hypertension in 47% of patients, diabetes in 28%, and cardiovascular disease in 19%. Another 16% were obese and 12% had chronic kidney disease. People with comorbid obesity, chronic kidney disease, and cardiovascular disease were more likely to receive mechanical ventilation compared to those without a history of these conditions in an adjusted, multivariable logistic analysis.
With the exception of obesity, the same factors were associated with risk for death during hospitalization.
In contrast, hypertension, history of smoking, and history of pulmonary disease were associated with a lower risk of needing mechanical ventilation and/or lower risk for mortality.
Furthermore, people with liver disease, gastrointestinal diseases, and even autoimmune diseases – which are likely associated with immunosuppression – “are not at that much of an increased risk that we noticed it in our data,” Brown said.
“As I tell many of my patients who have mild liver disease, for example, I would rather have mild liver disease and be on immunosuppressant therapy than be an older, obese male,” he added.
Assessing data for people in 38 U.S. states, and not limiting outcomes to patients in a particular COVID-19 hot spot, was a unique aspect of the research, said Brown, clinical chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medicine in New York City.
Brown, lead author Michael W. Fried, MD, from TARGET PharmaSolutions in Durham, North Carolina, and colleagues studied adults from a commercially available Target Real-World Evidence (RWE) dataset of nearly 70,000 patients. They examined hospital chargemaster data and ICD-10 codes for COVID-19 inpatients between February 15 and April 20.
This population tended to be older, with 60% older than 60 years. A little more than half of participants, 53%, were men.
Key findings
A total of 21% of patients died after a median hospital length of stay of 8 days.
Older patients were significantly more likely to die, particularly those older than 60 years (P < .0001).
“This confirms some of the things we know about age and its impact on outcome,” Brown said.
The risk for mortality among patients older than 60 years was 7.2 times that of patients between 18 and 40 years in an adjusted multivariate analysis. The risk for death for those between 41 and 60 years of age was lower (odds ratio [OR], 2.6), compared with the youngest cohort.
Men were more likely to die than women (OR, 1.5).
When asked if he was surprised by the high mortality rates, Brown said, “Having worked here in New York? No, I was not.”
Mechanical ventilation and mortality
Male sex, age older than 40 years, obesity, and presence of cardiovascular or chronic kidney disease were risk factors for mechanical ventilation.
Among the nearly 2,000 hospitalized adults requiring mechanical ventilation in the current report, only 27% were discharged alive. “The outcomes of people who are mechanically ventilated are really quite sobering,” Brown said.
People who ever required mechanical ventilation were 32 times more likely to die compared with others whose highest level of oxygenation was low-flow, high-flow, or no-oxygen therapy in an analysis that controlled for demographics and comorbidities.
Furthermore, patients placed on mechanical ventilation earlier – within 24 hours of admission – tended to experience better outcomes.
COVID-19 therapies?
Brown and colleagues also evaluated outcomes in patients who were taking either remdesivir or hydroxychloroquine. A total of 48 people were treated with remdesivir.
The four individuals receiving remdesivir who died were among 11 who were taking remdesivir and also on mechanical ventilation.
“The data for remdesivir is very encouraging,” Brown said.
Many more participants were treated with hydroxychloroquine, more than 4,200 or 36% of the total study population.
A higher proportion of people treated with hydroxychloroquine received mechanical ventilation, at 25%, versus 12% not treated with hydroxychloroquine.
The unadjusted mortality rate was also higher among those treated with the agent, at 25%, compared to 20% not receiving hydroxychloroquine.
The data with hydroxychloroquine can lead to two conclusions, Brown said: “One, it doesn’t work. Or two, it doesn’t work in the way that we use it.”
The researchers cautioned that their hydroxychloroquine findings must be interpreted carefully because those treated with the agent were also more likely to have comorbidities and greater COVID-19 disease severity.
“This study greatly contributes to understanding the natural course of COVID-19 infection by describing characteristics and outcomes of patients with COVID-19 hospitalized throughout the US,” the investigators note. “It identified categories of patients at greatest risk for poor outcomes, which should be used to prioritize prevention and treatment strategies in the future.”
Some limitations
“The findings that patients with hypertension and who were smokers had lower ventilation rates, and patients with hypertension, pulmonary disease, who were smokers had lower mortality risks was very surprising,” Ninez A. Ponce, PhD, MPP, told Medscape Medical News when asked to comment on the study.
Although the study identified multiple risk factors for ventilation and mortality, “unfortunately the dataset did not have race available or disease severity,” said Ponce, director of the UCLA Center for Health Policy Research and professor in the Department of Health Policy and Management at the UCLA Fielding School of Public Health.
“These omitted variables could have a considerable effect on the significance, magnitude, and direction of point estimates provided, so I would be cautious in interpreting the results as a picture of a nationally representative sample,” she said.
On a positive note, the study and dataset could illuminate the utility of medications used to treat COVID-19, Ponce said. In addition, as the authors note, “the data will expand over time.”
Brown has reported receiving grants and consulting for Gilead. Ponce has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Factors including older age and certain comorbidities have been linked to more serious COVID-19 outcomes in previous research, and now a large dataset collected from hundreds of hospitals nationwide provides more detailed data regarding risk for mechanical ventilation and death.
History of pulmonary disease or smoking, interestingly, were not.
One expert urges caution when interpreting the results, however. Although the study found a number of risk factors for ventilation and mortality, she says the dataset lacks information on race and disease severity, and the sample may not be nationally representative.
The investigators hope their level of granularity will further assist researchers searching for effective treatments and clinicians seeking to triage patients during the COVID-19 pandemic.
The study was published online August 28 in Clinical Infectious Diseases.
COVID-19 and comorbidities
“What I found most illuminating was this whole concept of comorbid conditions. This provides suggestive data about who we need to worry about most and who we may need to worry about less,” study author Robert S. Brown Jr, MD, MPH, told Medscape Medical News.
Comorbid conditions included hypertension in 47% of patients, diabetes in 28%, and cardiovascular disease in 19%. Another 16% were obese and 12% had chronic kidney disease. People with comorbid obesity, chronic kidney disease, and cardiovascular disease were more likely to receive mechanical ventilation compared to those without a history of these conditions in an adjusted, multivariable logistic analysis.
With the exception of obesity, the same factors were associated with risk for death during hospitalization.
In contrast, hypertension, history of smoking, and history of pulmonary disease were associated with a lower risk of needing mechanical ventilation and/or lower risk for mortality.
Furthermore, people with liver disease, gastrointestinal diseases, and even autoimmune diseases – which are likely associated with immunosuppression – “are not at that much of an increased risk that we noticed it in our data,” Brown said.
“As I tell many of my patients who have mild liver disease, for example, I would rather have mild liver disease and be on immunosuppressant therapy than be an older, obese male,” he added.
Assessing data for people in 38 U.S. states, and not limiting outcomes to patients in a particular COVID-19 hot spot, was a unique aspect of the research, said Brown, clinical chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medicine in New York City.
Brown, lead author Michael W. Fried, MD, from TARGET PharmaSolutions in Durham, North Carolina, and colleagues studied adults from a commercially available Target Real-World Evidence (RWE) dataset of nearly 70,000 patients. They examined hospital chargemaster data and ICD-10 codes for COVID-19 inpatients between February 15 and April 20.
This population tended to be older, with 60% older than 60 years. A little more than half of participants, 53%, were men.
Key findings
A total of 21% of patients died after a median hospital length of stay of 8 days.
Older patients were significantly more likely to die, particularly those older than 60 years (P < .0001).
“This confirms some of the things we know about age and its impact on outcome,” Brown said.
The risk for mortality among patients older than 60 years was 7.2 times that of patients between 18 and 40 years in an adjusted multivariate analysis. The risk for death for those between 41 and 60 years of age was lower (odds ratio [OR], 2.6), compared with the youngest cohort.
Men were more likely to die than women (OR, 1.5).
When asked if he was surprised by the high mortality rates, Brown said, “Having worked here in New York? No, I was not.”
Mechanical ventilation and mortality
Male sex, age older than 40 years, obesity, and presence of cardiovascular or chronic kidney disease were risk factors for mechanical ventilation.
Among the nearly 2,000 hospitalized adults requiring mechanical ventilation in the current report, only 27% were discharged alive. “The outcomes of people who are mechanically ventilated are really quite sobering,” Brown said.
People who ever required mechanical ventilation were 32 times more likely to die compared with others whose highest level of oxygenation was low-flow, high-flow, or no-oxygen therapy in an analysis that controlled for demographics and comorbidities.
Furthermore, patients placed on mechanical ventilation earlier – within 24 hours of admission – tended to experience better outcomes.
COVID-19 therapies?
Brown and colleagues also evaluated outcomes in patients who were taking either remdesivir or hydroxychloroquine. A total of 48 people were treated with remdesivir.
The four individuals receiving remdesivir who died were among 11 who were taking remdesivir and also on mechanical ventilation.
“The data for remdesivir is very encouraging,” Brown said.
Many more participants were treated with hydroxychloroquine, more than 4,200 or 36% of the total study population.
A higher proportion of people treated with hydroxychloroquine received mechanical ventilation, at 25%, versus 12% not treated with hydroxychloroquine.
The unadjusted mortality rate was also higher among those treated with the agent, at 25%, compared to 20% not receiving hydroxychloroquine.
The data with hydroxychloroquine can lead to two conclusions, Brown said: “One, it doesn’t work. Or two, it doesn’t work in the way that we use it.”
The researchers cautioned that their hydroxychloroquine findings must be interpreted carefully because those treated with the agent were also more likely to have comorbidities and greater COVID-19 disease severity.
“This study greatly contributes to understanding the natural course of COVID-19 infection by describing characteristics and outcomes of patients with COVID-19 hospitalized throughout the US,” the investigators note. “It identified categories of patients at greatest risk for poor outcomes, which should be used to prioritize prevention and treatment strategies in the future.”
Some limitations
“The findings that patients with hypertension and who were smokers had lower ventilation rates, and patients with hypertension, pulmonary disease, who were smokers had lower mortality risks was very surprising,” Ninez A. Ponce, PhD, MPP, told Medscape Medical News when asked to comment on the study.
Although the study identified multiple risk factors for ventilation and mortality, “unfortunately the dataset did not have race available or disease severity,” said Ponce, director of the UCLA Center for Health Policy Research and professor in the Department of Health Policy and Management at the UCLA Fielding School of Public Health.
“These omitted variables could have a considerable effect on the significance, magnitude, and direction of point estimates provided, so I would be cautious in interpreting the results as a picture of a nationally representative sample,” she said.
On a positive note, the study and dataset could illuminate the utility of medications used to treat COVID-19, Ponce said. In addition, as the authors note, “the data will expand over time.”
Brown has reported receiving grants and consulting for Gilead. Ponce has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Factors including older age and certain comorbidities have been linked to more serious COVID-19 outcomes in previous research, and now a large dataset collected from hundreds of hospitals nationwide provides more detailed data regarding risk for mechanical ventilation and death.
History of pulmonary disease or smoking, interestingly, were not.
One expert urges caution when interpreting the results, however. Although the study found a number of risk factors for ventilation and mortality, she says the dataset lacks information on race and disease severity, and the sample may not be nationally representative.
The investigators hope their level of granularity will further assist researchers searching for effective treatments and clinicians seeking to triage patients during the COVID-19 pandemic.
The study was published online August 28 in Clinical Infectious Diseases.
COVID-19 and comorbidities
“What I found most illuminating was this whole concept of comorbid conditions. This provides suggestive data about who we need to worry about most and who we may need to worry about less,” study author Robert S. Brown Jr, MD, MPH, told Medscape Medical News.
Comorbid conditions included hypertension in 47% of patients, diabetes in 28%, and cardiovascular disease in 19%. Another 16% were obese and 12% had chronic kidney disease. People with comorbid obesity, chronic kidney disease, and cardiovascular disease were more likely to receive mechanical ventilation compared to those without a history of these conditions in an adjusted, multivariable logistic analysis.
With the exception of obesity, the same factors were associated with risk for death during hospitalization.
In contrast, hypertension, history of smoking, and history of pulmonary disease were associated with a lower risk of needing mechanical ventilation and/or lower risk for mortality.
Furthermore, people with liver disease, gastrointestinal diseases, and even autoimmune diseases – which are likely associated with immunosuppression – “are not at that much of an increased risk that we noticed it in our data,” Brown said.
“As I tell many of my patients who have mild liver disease, for example, I would rather have mild liver disease and be on immunosuppressant therapy than be an older, obese male,” he added.
Assessing data for people in 38 U.S. states, and not limiting outcomes to patients in a particular COVID-19 hot spot, was a unique aspect of the research, said Brown, clinical chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medicine in New York City.
Brown, lead author Michael W. Fried, MD, from TARGET PharmaSolutions in Durham, North Carolina, and colleagues studied adults from a commercially available Target Real-World Evidence (RWE) dataset of nearly 70,000 patients. They examined hospital chargemaster data and ICD-10 codes for COVID-19 inpatients between February 15 and April 20.
This population tended to be older, with 60% older than 60 years. A little more than half of participants, 53%, were men.
Key findings
A total of 21% of patients died after a median hospital length of stay of 8 days.
Older patients were significantly more likely to die, particularly those older than 60 years (P < .0001).
“This confirms some of the things we know about age and its impact on outcome,” Brown said.
The risk for mortality among patients older than 60 years was 7.2 times that of patients between 18 and 40 years in an adjusted multivariate analysis. The risk for death for those between 41 and 60 years of age was lower (odds ratio [OR], 2.6), compared with the youngest cohort.
Men were more likely to die than women (OR, 1.5).
When asked if he was surprised by the high mortality rates, Brown said, “Having worked here in New York? No, I was not.”
Mechanical ventilation and mortality
Male sex, age older than 40 years, obesity, and presence of cardiovascular or chronic kidney disease were risk factors for mechanical ventilation.
Among the nearly 2,000 hospitalized adults requiring mechanical ventilation in the current report, only 27% were discharged alive. “The outcomes of people who are mechanically ventilated are really quite sobering,” Brown said.
People who ever required mechanical ventilation were 32 times more likely to die compared with others whose highest level of oxygenation was low-flow, high-flow, or no-oxygen therapy in an analysis that controlled for demographics and comorbidities.
Furthermore, patients placed on mechanical ventilation earlier – within 24 hours of admission – tended to experience better outcomes.
COVID-19 therapies?
Brown and colleagues also evaluated outcomes in patients who were taking either remdesivir or hydroxychloroquine. A total of 48 people were treated with remdesivir.
The four individuals receiving remdesivir who died were among 11 who were taking remdesivir and also on mechanical ventilation.
“The data for remdesivir is very encouraging,” Brown said.
Many more participants were treated with hydroxychloroquine, more than 4,200 or 36% of the total study population.
A higher proportion of people treated with hydroxychloroquine received mechanical ventilation, at 25%, versus 12% not treated with hydroxychloroquine.
The unadjusted mortality rate was also higher among those treated with the agent, at 25%, compared to 20% not receiving hydroxychloroquine.
The data with hydroxychloroquine can lead to two conclusions, Brown said: “One, it doesn’t work. Or two, it doesn’t work in the way that we use it.”
The researchers cautioned that their hydroxychloroquine findings must be interpreted carefully because those treated with the agent were also more likely to have comorbidities and greater COVID-19 disease severity.
“This study greatly contributes to understanding the natural course of COVID-19 infection by describing characteristics and outcomes of patients with COVID-19 hospitalized throughout the US,” the investigators note. “It identified categories of patients at greatest risk for poor outcomes, which should be used to prioritize prevention and treatment strategies in the future.”
Some limitations
“The findings that patients with hypertension and who were smokers had lower ventilation rates, and patients with hypertension, pulmonary disease, who were smokers had lower mortality risks was very surprising,” Ninez A. Ponce, PhD, MPP, told Medscape Medical News when asked to comment on the study.
Although the study identified multiple risk factors for ventilation and mortality, “unfortunately the dataset did not have race available or disease severity,” said Ponce, director of the UCLA Center for Health Policy Research and professor in the Department of Health Policy and Management at the UCLA Fielding School of Public Health.
“These omitted variables could have a considerable effect on the significance, magnitude, and direction of point estimates provided, so I would be cautious in interpreting the results as a picture of a nationally representative sample,” she said.
On a positive note, the study and dataset could illuminate the utility of medications used to treat COVID-19, Ponce said. In addition, as the authors note, “the data will expand over time.”
Brown has reported receiving grants and consulting for Gilead. Ponce has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Two PR employees at FDA fired after plasma therapy controversy
The US Food and Drug Administration has removed two senior public relations employees, one of whom advised the agency against unbridled promotion of convalescent blood plasma as a treatment for people with COVID-19, multiple media outlets reported Aug. 28.
Officials claim the dismissals are coincidental and are not related to a controversy about whether claims regarding convalescent plasma therapy that were put forth by President Donald Trump and FDA Commissioner Stephen M. Hahn, MD, were exaggerated, according to reports from The New York Times , CNN, and elsewhere.
One of the PR employees, Emily Miller, was on the job less than 2 weeks. The White House named her FDA chief spokeswoman 11 days ago, but Hahn removed her from that post Aug. 28.
On Aug. 27, the US Department of Health and Human Services terminated the contract for Wayne L. Pines, a PR consultant to the FDA. Pines reportedly advised Hahn to apologize for making misleading claims about the therapeutic benefits of convalescent plasma therapy for COVID-19.
The FDA did not respond to multiple requests for comment.
The controversy stems from comments Hahn made about the announcement of the emergency use authorization for convalescent plasma for patients with COVID-19. He said that plasma had been found to save the lives of 35 out of every 100 people who were treated. That statement was later found to be erroneous because he presented a relative risk reduction as an absolute decrease in risk. He later apologized via Twitter.
Researchers running clinical trials to evaluate the efficacy of convalescent plasma for COVID-19 are concerned that the emergency use authorization could thwart efforts to recruit participants for their studies.
This article first appeared on Medscape.com.
The US Food and Drug Administration has removed two senior public relations employees, one of whom advised the agency against unbridled promotion of convalescent blood plasma as a treatment for people with COVID-19, multiple media outlets reported Aug. 28.
Officials claim the dismissals are coincidental and are not related to a controversy about whether claims regarding convalescent plasma therapy that were put forth by President Donald Trump and FDA Commissioner Stephen M. Hahn, MD, were exaggerated, according to reports from The New York Times , CNN, and elsewhere.
One of the PR employees, Emily Miller, was on the job less than 2 weeks. The White House named her FDA chief spokeswoman 11 days ago, but Hahn removed her from that post Aug. 28.
On Aug. 27, the US Department of Health and Human Services terminated the contract for Wayne L. Pines, a PR consultant to the FDA. Pines reportedly advised Hahn to apologize for making misleading claims about the therapeutic benefits of convalescent plasma therapy for COVID-19.
The FDA did not respond to multiple requests for comment.
The controversy stems from comments Hahn made about the announcement of the emergency use authorization for convalescent plasma for patients with COVID-19. He said that plasma had been found to save the lives of 35 out of every 100 people who were treated. That statement was later found to be erroneous because he presented a relative risk reduction as an absolute decrease in risk. He later apologized via Twitter.
Researchers running clinical trials to evaluate the efficacy of convalescent plasma for COVID-19 are concerned that the emergency use authorization could thwart efforts to recruit participants for their studies.
This article first appeared on Medscape.com.
The US Food and Drug Administration has removed two senior public relations employees, one of whom advised the agency against unbridled promotion of convalescent blood plasma as a treatment for people with COVID-19, multiple media outlets reported Aug. 28.
Officials claim the dismissals are coincidental and are not related to a controversy about whether claims regarding convalescent plasma therapy that were put forth by President Donald Trump and FDA Commissioner Stephen M. Hahn, MD, were exaggerated, according to reports from The New York Times , CNN, and elsewhere.
One of the PR employees, Emily Miller, was on the job less than 2 weeks. The White House named her FDA chief spokeswoman 11 days ago, but Hahn removed her from that post Aug. 28.
On Aug. 27, the US Department of Health and Human Services terminated the contract for Wayne L. Pines, a PR consultant to the FDA. Pines reportedly advised Hahn to apologize for making misleading claims about the therapeutic benefits of convalescent plasma therapy for COVID-19.
The FDA did not respond to multiple requests for comment.
The controversy stems from comments Hahn made about the announcement of the emergency use authorization for convalescent plasma for patients with COVID-19. He said that plasma had been found to save the lives of 35 out of every 100 people who were treated. That statement was later found to be erroneous because he presented a relative risk reduction as an absolute decrease in risk. He later apologized via Twitter.
Researchers running clinical trials to evaluate the efficacy of convalescent plasma for COVID-19 are concerned that the emergency use authorization could thwart efforts to recruit participants for their studies.
This article first appeared on Medscape.com.
FDA approves point-of-care COVID-19 antigen test
The BinaxNOW COVID-19 Ag Card (Abbott) is similar in some ways to a home pregnancy test. Clinicians read results on a card – one line for a negative result, two lines for positive.
A health care provider swabs a symptomatic patient’s nose, twirls the sample on a test card with a reagent, and waits approximately 15 minutes for results. No additional equipment is required.
Abbott expects the test to cost about $5.00, the company announced.
Office-based physicians, ED physicians, and school nurses could potentially use the product as a point-of-care test. The FDA granted the test emergency use authorization. It is approved for people suspected of having COVID-19 who are within 7 days of symptom onset.
“This new COVID-19 antigen test is an important addition to available tests because the results can be read in minutes, right off the testing card,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, wrote in a news release. “This means people will know if they have the virus in almost real time.”
“This fits into the testing landscape as a simple, inexpensive test that does not require additional equipment,” Marcus Lynch, PhD, assistant manager of the Health Care Horizon Scanning program at ECRI, told Medscape Medical News when asked to comment. ECRI is an independent, nonprofit organization that reviews and analyses COVID-19 therapeutics and diagnostics.
The test could help with early triage of patients who test positive, perhaps alerting physicians to the need to start COVID-19 therapy, added Lynch, who specializes in immunology and vaccine development. The test also could be useful in low-resource settings.
The FDA included a caveat: antigen tests are generally less sensitive than molecular assays. “Due to the potential for decreased sensitivity compared to molecular assays, negative results from an antigen test may need to be confirmed with a molecular test prior to making treatment decisions,” the agency noted.
Lynch agreed and said that when a patient tests negative, physicians still need to use their clinical judgment on the basis of symptoms and other factors. The test is not designed for population-based screening of asymptomatic people, he added.
Abbott announced plans to make up to 50 million tests available per month in the United States starting in October. The product comes with a free smartphone app that people can use to share results with an employer or with others as needed.
This article first appeared on Medscape.com.
The BinaxNOW COVID-19 Ag Card (Abbott) is similar in some ways to a home pregnancy test. Clinicians read results on a card – one line for a negative result, two lines for positive.
A health care provider swabs a symptomatic patient’s nose, twirls the sample on a test card with a reagent, and waits approximately 15 minutes for results. No additional equipment is required.
Abbott expects the test to cost about $5.00, the company announced.
Office-based physicians, ED physicians, and school nurses could potentially use the product as a point-of-care test. The FDA granted the test emergency use authorization. It is approved for people suspected of having COVID-19 who are within 7 days of symptom onset.
“This new COVID-19 antigen test is an important addition to available tests because the results can be read in minutes, right off the testing card,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, wrote in a news release. “This means people will know if they have the virus in almost real time.”
“This fits into the testing landscape as a simple, inexpensive test that does not require additional equipment,” Marcus Lynch, PhD, assistant manager of the Health Care Horizon Scanning program at ECRI, told Medscape Medical News when asked to comment. ECRI is an independent, nonprofit organization that reviews and analyses COVID-19 therapeutics and diagnostics.
The test could help with early triage of patients who test positive, perhaps alerting physicians to the need to start COVID-19 therapy, added Lynch, who specializes in immunology and vaccine development. The test also could be useful in low-resource settings.
The FDA included a caveat: antigen tests are generally less sensitive than molecular assays. “Due to the potential for decreased sensitivity compared to molecular assays, negative results from an antigen test may need to be confirmed with a molecular test prior to making treatment decisions,” the agency noted.
Lynch agreed and said that when a patient tests negative, physicians still need to use their clinical judgment on the basis of symptoms and other factors. The test is not designed for population-based screening of asymptomatic people, he added.
Abbott announced plans to make up to 50 million tests available per month in the United States starting in October. The product comes with a free smartphone app that people can use to share results with an employer or with others as needed.
This article first appeared on Medscape.com.
The BinaxNOW COVID-19 Ag Card (Abbott) is similar in some ways to a home pregnancy test. Clinicians read results on a card – one line for a negative result, two lines for positive.
A health care provider swabs a symptomatic patient’s nose, twirls the sample on a test card with a reagent, and waits approximately 15 minutes for results. No additional equipment is required.
Abbott expects the test to cost about $5.00, the company announced.
Office-based physicians, ED physicians, and school nurses could potentially use the product as a point-of-care test. The FDA granted the test emergency use authorization. It is approved for people suspected of having COVID-19 who are within 7 days of symptom onset.
“This new COVID-19 antigen test is an important addition to available tests because the results can be read in minutes, right off the testing card,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, wrote in a news release. “This means people will know if they have the virus in almost real time.”
“This fits into the testing landscape as a simple, inexpensive test that does not require additional equipment,” Marcus Lynch, PhD, assistant manager of the Health Care Horizon Scanning program at ECRI, told Medscape Medical News when asked to comment. ECRI is an independent, nonprofit organization that reviews and analyses COVID-19 therapeutics and diagnostics.
The test could help with early triage of patients who test positive, perhaps alerting physicians to the need to start COVID-19 therapy, added Lynch, who specializes in immunology and vaccine development. The test also could be useful in low-resource settings.
The FDA included a caveat: antigen tests are generally less sensitive than molecular assays. “Due to the potential for decreased sensitivity compared to molecular assays, negative results from an antigen test may need to be confirmed with a molecular test prior to making treatment decisions,” the agency noted.
Lynch agreed and said that when a patient tests negative, physicians still need to use their clinical judgment on the basis of symptoms and other factors. The test is not designed for population-based screening of asymptomatic people, he added.
Abbott announced plans to make up to 50 million tests available per month in the United States starting in October. The product comes with a free smartphone app that people can use to share results with an employer or with others as needed.
This article first appeared on Medscape.com.
Cutaneous clues linked to COVID-19 coagulation risk
, new evidence suggests.
Researchers at Weill Cornell Medicine NewYork–Presbyterian Medical Center in New York linked livedoid and purpuric skin eruptions to a greater likelihood for occlusive vascular disease associated with SARS-CoV-2 infection in a small case series.
These skin signs could augment coagulation assays in this patient population. “Physicians should consider a hematology consult for potential anticoagulation in patients with these skin presentations and severe COVID-19,” senior author Joanna Harp, MD, said in an interview.
“Physicians should also consider D-dimer, fibrinogen, coagulation studies, and a skin biopsy given that there are other diagnoses on the differential as well.”
The research letter was published online on Aug. 5 in JAMA Dermatology.
The findings build on multiple previous reports of skin manifestations associated with COVID-19, including a study of 375 patients in Spain. Among people with suspected or confirmed SARS-CoV-2 infection, senior author of the Spanish research, Ignacio Garcia-Doval, MD, PhD, also observed livedoid and necrotic skin eruptions more commonly in severe disease.
“I think that this case series [from Harp and colleagues] confirms the findings of our previous paper – that patients with livedoid or necrotic lesions have a worse prognosis, as these are markers of vascular occlusion,” he said in an interview.
Dr. Harp and colleagues reported their observations with four patients aged 40-80 years. Each had severe COVID-19 with acute respiratory distress syndrome and required intubation. Treating clinicians requested a dermatology consult to assess acral fixed livedo racemosa and retiform purpura presentations.
D-dimer levels exceeded 3 mcg/mL in each case. All four patients had a suspected pulmonary embolism within 1-5 days of the dermatologic findings. Prophylactic anticoagulation at admission was changed to therapeutic anticoagulation because of increasing D-dimer levels and the suspected thrombotic events.
“I think that the paper is interesting because it shows the associated histopathological findings and has important clinical implications due to the association with pulmonary embolism,” said Dr. Garcia-Doval, a researcher at the Spanish Academy of Dermatology in Madrid. “These patients should probably be anticoagulated.”
Skin biopsy results
Punch biopsies revealed pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, arterioles, or small arteries.
Livedo racemosa skin findings point to partial occlusion of cutaneous blood vessels, whereas retiform purpura indicate full occlusion of cutaneous blood vessels.
An inability to confirm the exact timing of the onset of the skin rash was a limitation of the study.
“The findings suggest that clinicians caring for patients with COVID-19 should be aware of livedoid and purpuric rashes as potential manifestations of an underlying hypercoagulable state,” the authors noted. “If these skin findings are identified, a skin biopsy should be considered because the result may guide anticoagulation management.”
Observations during an outbreak
The researchers observed these cases between March 13 and April 3, during the peak of the COVID-19 outbreak in New York.
“We did see additional cases since our study period. However, it has decreased significantly with the falling number of COVID-19 cases in the city,” said Dr. Harp, a dermatologist at NewYork–Presbyterian.
Another contributing factor in the drop in cases was “implementation of earlier, more aggressive anticoagulation in many of these patients at our institution,” she added.
The investigators plan to continue the research. “We are working on a more formalized study,” lead author Caren Droesch, MD, said in an interview.
“But given very low patient numbers in our area we have not started recruiting patients,” said Dr. Droesch, a resident at Weill Cornell Medicine and NewYork–Presbyterian at the time of the study. She is now a dermatologist at Mass General Brigham in Wellesley, Mass.
Consider a dermatology consult
“This is a small case series of four patients, but mirrors what we have seen at our institution and what others have reported about individual patients around the world,” Anthony Fernandez, MD, PhD, a dermatologist at Cleveland Clinic, said in an interview. “The skin, like many other organ systems, can be affected by thrombotic events within the setting of COVID-19 disease.”
As in the current study, Dr. Fernandez observed skin manifestations in people with severe COVID-19 with elevated D-dimer levels. These patients typically require mechanical ventilation in the intensive care unit, he added.
“As these authors point out, it is important for all clinicians caring for COVID-19 patients to look for these rashes,” said Dr. Fernandez, who coauthored a report on skin manifestations in this patient population. “We also agree that clinicians should have a low threshold for consulting dermatology. A skin biopsy is minimally invasive and can be important in confirming or refuting that such rashes are truly reflective of thrombotic vasculopathy.”
Dr. Harp, Dr. Droesch and Dr. Garcia-Doval have disclosed no relevant financial relationships. Dr. Fernandez received funding from the Clinical and Translational Science Collaborative at Case Western Reserve University to study skin manifestations of COVID-19.
A version of this article originally appeared on Medscape.com.
, new evidence suggests.
Researchers at Weill Cornell Medicine NewYork–Presbyterian Medical Center in New York linked livedoid and purpuric skin eruptions to a greater likelihood for occlusive vascular disease associated with SARS-CoV-2 infection in a small case series.
These skin signs could augment coagulation assays in this patient population. “Physicians should consider a hematology consult for potential anticoagulation in patients with these skin presentations and severe COVID-19,” senior author Joanna Harp, MD, said in an interview.
“Physicians should also consider D-dimer, fibrinogen, coagulation studies, and a skin biopsy given that there are other diagnoses on the differential as well.”
The research letter was published online on Aug. 5 in JAMA Dermatology.
The findings build on multiple previous reports of skin manifestations associated with COVID-19, including a study of 375 patients in Spain. Among people with suspected or confirmed SARS-CoV-2 infection, senior author of the Spanish research, Ignacio Garcia-Doval, MD, PhD, also observed livedoid and necrotic skin eruptions more commonly in severe disease.
“I think that this case series [from Harp and colleagues] confirms the findings of our previous paper – that patients with livedoid or necrotic lesions have a worse prognosis, as these are markers of vascular occlusion,” he said in an interview.
Dr. Harp and colleagues reported their observations with four patients aged 40-80 years. Each had severe COVID-19 with acute respiratory distress syndrome and required intubation. Treating clinicians requested a dermatology consult to assess acral fixed livedo racemosa and retiform purpura presentations.
D-dimer levels exceeded 3 mcg/mL in each case. All four patients had a suspected pulmonary embolism within 1-5 days of the dermatologic findings. Prophylactic anticoagulation at admission was changed to therapeutic anticoagulation because of increasing D-dimer levels and the suspected thrombotic events.
“I think that the paper is interesting because it shows the associated histopathological findings and has important clinical implications due to the association with pulmonary embolism,” said Dr. Garcia-Doval, a researcher at the Spanish Academy of Dermatology in Madrid. “These patients should probably be anticoagulated.”
Skin biopsy results
Punch biopsies revealed pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, arterioles, or small arteries.
Livedo racemosa skin findings point to partial occlusion of cutaneous blood vessels, whereas retiform purpura indicate full occlusion of cutaneous blood vessels.
An inability to confirm the exact timing of the onset of the skin rash was a limitation of the study.
“The findings suggest that clinicians caring for patients with COVID-19 should be aware of livedoid and purpuric rashes as potential manifestations of an underlying hypercoagulable state,” the authors noted. “If these skin findings are identified, a skin biopsy should be considered because the result may guide anticoagulation management.”
Observations during an outbreak
The researchers observed these cases between March 13 and April 3, during the peak of the COVID-19 outbreak in New York.
“We did see additional cases since our study period. However, it has decreased significantly with the falling number of COVID-19 cases in the city,” said Dr. Harp, a dermatologist at NewYork–Presbyterian.
Another contributing factor in the drop in cases was “implementation of earlier, more aggressive anticoagulation in many of these patients at our institution,” she added.
The investigators plan to continue the research. “We are working on a more formalized study,” lead author Caren Droesch, MD, said in an interview.
“But given very low patient numbers in our area we have not started recruiting patients,” said Dr. Droesch, a resident at Weill Cornell Medicine and NewYork–Presbyterian at the time of the study. She is now a dermatologist at Mass General Brigham in Wellesley, Mass.
Consider a dermatology consult
“This is a small case series of four patients, but mirrors what we have seen at our institution and what others have reported about individual patients around the world,” Anthony Fernandez, MD, PhD, a dermatologist at Cleveland Clinic, said in an interview. “The skin, like many other organ systems, can be affected by thrombotic events within the setting of COVID-19 disease.”
As in the current study, Dr. Fernandez observed skin manifestations in people with severe COVID-19 with elevated D-dimer levels. These patients typically require mechanical ventilation in the intensive care unit, he added.
“As these authors point out, it is important for all clinicians caring for COVID-19 patients to look for these rashes,” said Dr. Fernandez, who coauthored a report on skin manifestations in this patient population. “We also agree that clinicians should have a low threshold for consulting dermatology. A skin biopsy is minimally invasive and can be important in confirming or refuting that such rashes are truly reflective of thrombotic vasculopathy.”
Dr. Harp, Dr. Droesch and Dr. Garcia-Doval have disclosed no relevant financial relationships. Dr. Fernandez received funding from the Clinical and Translational Science Collaborative at Case Western Reserve University to study skin manifestations of COVID-19.
A version of this article originally appeared on Medscape.com.
, new evidence suggests.
Researchers at Weill Cornell Medicine NewYork–Presbyterian Medical Center in New York linked livedoid and purpuric skin eruptions to a greater likelihood for occlusive vascular disease associated with SARS-CoV-2 infection in a small case series.
These skin signs could augment coagulation assays in this patient population. “Physicians should consider a hematology consult for potential anticoagulation in patients with these skin presentations and severe COVID-19,” senior author Joanna Harp, MD, said in an interview.
“Physicians should also consider D-dimer, fibrinogen, coagulation studies, and a skin biopsy given that there are other diagnoses on the differential as well.”
The research letter was published online on Aug. 5 in JAMA Dermatology.
The findings build on multiple previous reports of skin manifestations associated with COVID-19, including a study of 375 patients in Spain. Among people with suspected or confirmed SARS-CoV-2 infection, senior author of the Spanish research, Ignacio Garcia-Doval, MD, PhD, also observed livedoid and necrotic skin eruptions more commonly in severe disease.
“I think that this case series [from Harp and colleagues] confirms the findings of our previous paper – that patients with livedoid or necrotic lesions have a worse prognosis, as these are markers of vascular occlusion,” he said in an interview.
Dr. Harp and colleagues reported their observations with four patients aged 40-80 years. Each had severe COVID-19 with acute respiratory distress syndrome and required intubation. Treating clinicians requested a dermatology consult to assess acral fixed livedo racemosa and retiform purpura presentations.
D-dimer levels exceeded 3 mcg/mL in each case. All four patients had a suspected pulmonary embolism within 1-5 days of the dermatologic findings. Prophylactic anticoagulation at admission was changed to therapeutic anticoagulation because of increasing D-dimer levels and the suspected thrombotic events.
“I think that the paper is interesting because it shows the associated histopathological findings and has important clinical implications due to the association with pulmonary embolism,” said Dr. Garcia-Doval, a researcher at the Spanish Academy of Dermatology in Madrid. “These patients should probably be anticoagulated.”
Skin biopsy results
Punch biopsies revealed pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, arterioles, or small arteries.
Livedo racemosa skin findings point to partial occlusion of cutaneous blood vessels, whereas retiform purpura indicate full occlusion of cutaneous blood vessels.
An inability to confirm the exact timing of the onset of the skin rash was a limitation of the study.
“The findings suggest that clinicians caring for patients with COVID-19 should be aware of livedoid and purpuric rashes as potential manifestations of an underlying hypercoagulable state,” the authors noted. “If these skin findings are identified, a skin biopsy should be considered because the result may guide anticoagulation management.”
Observations during an outbreak
The researchers observed these cases between March 13 and April 3, during the peak of the COVID-19 outbreak in New York.
“We did see additional cases since our study period. However, it has decreased significantly with the falling number of COVID-19 cases in the city,” said Dr. Harp, a dermatologist at NewYork–Presbyterian.
Another contributing factor in the drop in cases was “implementation of earlier, more aggressive anticoagulation in many of these patients at our institution,” she added.
The investigators plan to continue the research. “We are working on a more formalized study,” lead author Caren Droesch, MD, said in an interview.
“But given very low patient numbers in our area we have not started recruiting patients,” said Dr. Droesch, a resident at Weill Cornell Medicine and NewYork–Presbyterian at the time of the study. She is now a dermatologist at Mass General Brigham in Wellesley, Mass.
Consider a dermatology consult
“This is a small case series of four patients, but mirrors what we have seen at our institution and what others have reported about individual patients around the world,” Anthony Fernandez, MD, PhD, a dermatologist at Cleveland Clinic, said in an interview. “The skin, like many other organ systems, can be affected by thrombotic events within the setting of COVID-19 disease.”
As in the current study, Dr. Fernandez observed skin manifestations in people with severe COVID-19 with elevated D-dimer levels. These patients typically require mechanical ventilation in the intensive care unit, he added.
“As these authors point out, it is important for all clinicians caring for COVID-19 patients to look for these rashes,” said Dr. Fernandez, who coauthored a report on skin manifestations in this patient population. “We also agree that clinicians should have a low threshold for consulting dermatology. A skin biopsy is minimally invasive and can be important in confirming or refuting that such rashes are truly reflective of thrombotic vasculopathy.”
Dr. Harp, Dr. Droesch and Dr. Garcia-Doval have disclosed no relevant financial relationships. Dr. Fernandez received funding from the Clinical and Translational Science Collaborative at Case Western Reserve University to study skin manifestations of COVID-19.
A version of this article originally appeared on Medscape.com.
FROM JAMA DERMATOLOGY
Low vitamin D linked to increased COVID-19 risk
Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.
Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.
The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.
The study was published online July 23 in The FEBS Journal.
Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.
Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.
Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.
Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.
Key findings
A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).
The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.
“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.
“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.
In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.
The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).
After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).
Implications and future plans
The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.
Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.
“A compelling case”
“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.
Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.
However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”
“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
More confounders likely?
“I think the study is of interest,” Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.
“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.
For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.
“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”
Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.
Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.
The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.
The study was published online July 23 in The FEBS Journal.
Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.
Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.
Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.
Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.
Key findings
A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).
The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.
“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.
“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.
In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.
The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).
After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).
Implications and future plans
The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.
Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.
“A compelling case”
“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.
Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.
However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”
“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
More confounders likely?
“I think the study is of interest,” Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.
“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.
For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.
“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”
Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.
Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.
The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.
The study was published online July 23 in The FEBS Journal.
Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.
Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.
Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.
Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.
Key findings
A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).
The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.
“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.
“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.
In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.
The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).
After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).
Implications and future plans
The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.
Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.
“A compelling case”
“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.
Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.
However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”
“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
More confounders likely?
“I think the study is of interest,” Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.
“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.
For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.
“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”
Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Combination therapy quells COVID-19 cytokine storm
Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.
Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.
“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.
Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.
Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
Contrary to guidance?
The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.
Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”
Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.
Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.
Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.
The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.
Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.
They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.
The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.
Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.
In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.
Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
Mechanical ventilation and mortality
The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.
Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).
The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.
The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
Glucocorticoid sufficient for many
In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.
This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.
“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”
Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.
In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
Strengths and limitations
“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”
A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.
The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.
“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.
Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
‘Quite interesting’ results
“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.
“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.
“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.
“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.
Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.
Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.
Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.
“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.
Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.
Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
Contrary to guidance?
The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.
Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”
Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.
Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.
Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.
The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.
Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.
They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.
The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.
Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.
In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.
Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
Mechanical ventilation and mortality
The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.
Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).
The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.
The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
Glucocorticoid sufficient for many
In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.
This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.
“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”
Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.
In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
Strengths and limitations
“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”
A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.
The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.
“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.
Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
‘Quite interesting’ results
“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.
“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.
“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.
“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.
Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.
Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.
Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.
“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.
Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.
Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
Contrary to guidance?
The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.
Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”
Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.
Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.
Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.
The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.
Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.
They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.
The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.
Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.
In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.
Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
Mechanical ventilation and mortality
The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.
Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).
The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.
The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
Glucocorticoid sufficient for many
In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.
This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.
“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”
Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.
In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
Strengths and limitations
“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”
A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.
The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.
“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.
Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
‘Quite interesting’ results
“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.
“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.
“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.
“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.
Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.
Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.