Clinical

According to study of a cluster of patients in France and Switzerland, children may experience an acute cardiac decompensation from the severe inflammatory state following SARS-CoV-2 infection, termed multisystem inflammatory syndrome in children (MIS-C). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

“The pediatric and cardiology communities should be acutely aware of this new disease probably related to SARS-CoV-2 infection (MIS-C), that shares similarities with Kawasaki disease but has specificities in its presentation,” researchers led by Zahra Belhadjer, MD, of Necker-Enfants Malades Hospital in Paris, wrote in a cases series report published online in Circulation “Early diagnosis and management appear to lead to favorable outcome using classical therapies. Elucidating the immune mechanisms of this disease will afford further insights for treatment and potential global prevention of severe forms.”

Over a 2-month period that coincided with the SARS-CoV-2 pandemic in France and Switzerland, the researchers retrospectively collected clinical, biological, therapeutic, and early-outcomes data in 35 children who were admitted to pediatric ICUs in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. Their median age was 10 years, all presented with a fever, 80% had gastrointestinal symptoms of abdominal pain, vomiting, or diarrhea, and 28% had comorbidities that included body mass index of greater than 25 kg/m² (17%), asthma (9%), and lupus (3%), and overweight. Only 17% presented with chest pain. The researchers observed that left ventricular ejection fraction was less than 30% in 28% of patients, and 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation (ECMO). All patients presented with a severe inflammatory state evidenced by elevated C-reactive protein and d-dimer. Interleukin 6 was elevated to a median of 135 pg/mL in 13 of the patients. Elevation of troponin I was constant but mild to moderate, and NT-proBNP or BNP elevation was present in all children.

Nearly all patients 35 (88%) patients tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. Most patients (80%) received IV inotropic support, 71% received first-line IV immunoglobulin, 65% received anticoagulation with heparin, 34% received IV steroids having been considered high-risk patients with symptoms similar to an incomplete form of Kawasaki disease, and 8% received treatment with an interleukin-1 receptor antagonist because of a persistent severe inflammatory state. Left ventricular function was restored in 71% of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned after a median of 4.5 days.

“Some aspects of this emerging pediatric disease (MIS-C) are similar to those of Kawasaki disease: prolonged fever, multisystem inflammation with skin rash, lymphadenopathy, diarrhea, meningism, and high levels of inflammatory biomarkers,” the researchers wrote. “But differences are important and raise the question as to whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or represents a different syndrome (MIS-C). Kawasaki disease predominantly affects young children younger than 5 years, whereas the median age in our series is 10 years. Incomplete forms of Kawasaki disease occur in infants who may have fever as the sole clinical finding, whereas older patients are more prone to exhibit the complete form.”

They went on to note that the overlapping features between MIS-C and Kawasaki disease “may be due to similar pathophysiology. The etiologic agent of Kawasaki disease is unknown but likely to be ubiquitous, causing asymptomatic childhood infection but triggering the immunologic cascade of Kawasaki disease in genetically susceptible individuals. Please note that infection with a novel RNA virus that enters through the upper respiratory tract has been proposed to be the cause of the disease (see PLoS One. 2008 Feb 13;3:e1582 and J Infect Dis. 2011 Apr 1;203:1021-30).”

Based on the work of authors, it appears that a high index of suspicion for MIS-C is important for children who develop Kawasaki-like symptoms, David J. Goldberg, MD, said in an interview. “Although children have largely been spared from the acute respiratory presentation of the SARS-CoV-2 pandemic, the recognition and understanding of what appears to be a postviral inflammatory response is a critical first step in developing treatment algorithms for this disease process,” said Dr. Goldberg, a board-certified attending cardiologist in the cardiac center and fetal heart program at Children’s Hospital of Philadelphia. “If inflammatory markers are elevated, particularly if there are accompanying gastrointestinal symptoms, the possibility of cardiac involvement suggests the utility of screening echocardiography. Given the potential need for inotropic or mechanical circulatory support, the presence of myocardial dysfunction dictates care in an intensive care unit capable of providing advanced therapies. While the evidence from Dr. Belhadjer’s cohort suggests that full recovery is probable, there is still much to be learned about this unique inflammatory syndrome and the alarm has rightly been sounded.”

The researchers and Dr. Goldberg reported having no disclosures.

[email protected]

SOURCE: Belhadjer Z et al. Circulation 2020 May 17; doi: 10.1161/circulationaha.120.048360.

According to study of a cluster of patients in France and Switzerland, children may experience an acute cardiac decompensation from the severe inflammatory state following SARS-CoV-2 infection, termed multisystem inflammatory syndrome in children (MIS-C). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

“The pediatric and cardiology communities should be acutely aware of this new disease probably related to SARS-CoV-2 infection (MIS-C), that shares similarities with Kawasaki disease but has specificities in its presentation,” researchers led by Zahra Belhadjer, MD, of Necker-Enfants Malades Hospital in Paris, wrote in a cases series report published online in Circulation “Early diagnosis and management appear to lead to favorable outcome using classical therapies. Elucidating the immune mechanisms of this disease will afford further insights for treatment and potential global prevention of severe forms.”

Over a 2-month period that coincided with the SARS-CoV-2 pandemic in France and Switzerland, the researchers retrospectively collected clinical, biological, therapeutic, and early-outcomes data in 35 children who were admitted to pediatric ICUs in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. Their median age was 10 years, all presented with a fever, 80% had gastrointestinal symptoms of abdominal pain, vomiting, or diarrhea, and 28% had comorbidities that included body mass index of greater than 25 kg/m² (17%), asthma (9%), and lupus (3%), and overweight. Only 17% presented with chest pain. The researchers observed that left ventricular ejection fraction was less than 30% in 28% of patients, and 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation (ECMO). All patients presented with a severe inflammatory state evidenced by elevated C-reactive protein and d-dimer. Interleukin 6 was elevated to a median of 135 pg/mL in 13 of the patients. Elevation of troponin I was constant but mild to moderate, and NT-proBNP or BNP elevation was present in all children.

Nearly all patients 35 (88%) patients tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. Most patients (80%) received IV inotropic support, 71% received first-line IV immunoglobulin, 65% received anticoagulation with heparin, 34% received IV steroids having been considered high-risk patients with symptoms similar to an incomplete form of Kawasaki disease, and 8% received treatment with an interleukin-1 receptor antagonist because of a persistent severe inflammatory state. Left ventricular function was restored in 71% of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned after a median of 4.5 days.

“Some aspects of this emerging pediatric disease (MIS-C) are similar to those of Kawasaki disease: prolonged fever, multisystem inflammation with skin rash, lymphadenopathy, diarrhea, meningism, and high levels of inflammatory biomarkers,” the researchers wrote. “But differences are important and raise the question as to whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or represents a different syndrome (MIS-C). Kawasaki disease predominantly affects young children younger than 5 years, whereas the median age in our series is 10 years. Incomplete forms of Kawasaki disease occur in infants who may have fever as the sole clinical finding, whereas older patients are more prone to exhibit the complete form.”

They went on to note that the overlapping features between MIS-C and Kawasaki disease “may be due to similar pathophysiology. The etiologic agent of Kawasaki disease is unknown but likely to be ubiquitous, causing asymptomatic childhood infection but triggering the immunologic cascade of Kawasaki disease in genetically susceptible individuals. Please note that infection with a novel RNA virus that enters through the upper respiratory tract has been proposed to be the cause of the disease (see PLoS One. 2008 Feb 13;3:e1582 and J Infect Dis. 2011 Apr 1;203:1021-30).”

Based on the work of authors, it appears that a high index of suspicion for MIS-C is important for children who develop Kawasaki-like symptoms, David J. Goldberg, MD, said in an interview. “Although children have largely been spared from the acute respiratory presentation of the SARS-CoV-2 pandemic, the recognition and understanding of what appears to be a postviral inflammatory response is a critical first step in developing treatment algorithms for this disease process,” said Dr. Goldberg, a board-certified attending cardiologist in the cardiac center and fetal heart program at Children’s Hospital of Philadelphia. “If inflammatory markers are elevated, particularly if there are accompanying gastrointestinal symptoms, the possibility of cardiac involvement suggests the utility of screening echocardiography. Given the potential need for inotropic or mechanical circulatory support, the presence of myocardial dysfunction dictates care in an intensive care unit capable of providing advanced therapies. While the evidence from Dr. Belhadjer’s cohort suggests that full recovery is probable, there is still much to be learned about this unique inflammatory syndrome and the alarm has rightly been sounded.”

The researchers and Dr. Goldberg reported having no disclosures.

[email protected]

SOURCE: Belhadjer Z et al. Circulation 2020 May 17; doi: 10.1161/circulationaha.120.048360.

According to study of a cluster of patients in France and Switzerland, children may experience an acute cardiac decompensation from the severe inflammatory state following SARS-CoV-2 infection, termed multisystem inflammatory syndrome in children (MIS-C). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

“The pediatric and cardiology communities should be acutely aware of this new disease probably related to SARS-CoV-2 infection (MIS-C), that shares similarities with Kawasaki disease but has specificities in its presentation,” researchers led by Zahra Belhadjer, MD, of Necker-Enfants Malades Hospital in Paris, wrote in a cases series report published online in Circulation “Early diagnosis and management appear to lead to favorable outcome using classical therapies. Elucidating the immune mechanisms of this disease will afford further insights for treatment and potential global prevention of severe forms.”

Over a 2-month period that coincided with the SARS-CoV-2 pandemic in France and Switzerland, the researchers retrospectively collected clinical, biological, therapeutic, and early-outcomes data in 35 children who were admitted to pediatric ICUs in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. Their median age was 10 years, all presented with a fever, 80% had gastrointestinal symptoms of abdominal pain, vomiting, or diarrhea, and 28% had comorbidities that included body mass index of greater than 25 kg/m² (17%), asthma (9%), and lupus (3%), and overweight. Only 17% presented with chest pain. The researchers observed that left ventricular ejection fraction was less than 30% in 28% of patients, and 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation (ECMO). All patients presented with a severe inflammatory state evidenced by elevated C-reactive protein and d-dimer. Interleukin 6 was elevated to a median of 135 pg/mL in 13 of the patients. Elevation of troponin I was constant but mild to moderate, and NT-proBNP or BNP elevation was present in all children.

Nearly all patients 35 (88%) patients tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. Most patients (80%) received IV inotropic support, 71% received first-line IV immunoglobulin, 65% received anticoagulation with heparin, 34% received IV steroids having been considered high-risk patients with symptoms similar to an incomplete form of Kawasaki disease, and 8% received treatment with an interleukin-1 receptor antagonist because of a persistent severe inflammatory state. Left ventricular function was restored in 71% of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned after a median of 4.5 days.

“Some aspects of this emerging pediatric disease (MIS-C) are similar to those of Kawasaki disease: prolonged fever, multisystem inflammation with skin rash, lymphadenopathy, diarrhea, meningism, and high levels of inflammatory biomarkers,” the researchers wrote. “But differences are important and raise the question as to whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or represents a different syndrome (MIS-C). Kawasaki disease predominantly affects young children younger than 5 years, whereas the median age in our series is 10 years. Incomplete forms of Kawasaki disease occur in infants who may have fever as the sole clinical finding, whereas older patients are more prone to exhibit the complete form.”

They went on to note that the overlapping features between MIS-C and Kawasaki disease “may be due to similar pathophysiology. The etiologic agent of Kawasaki disease is unknown but likely to be ubiquitous, causing asymptomatic childhood infection but triggering the immunologic cascade of Kawasaki disease in genetically susceptible individuals. Please note that infection with a novel RNA virus that enters through the upper respiratory tract has been proposed to be the cause of the disease (see PLoS One. 2008 Feb 13;3:e1582 and J Infect Dis. 2011 Apr 1;203:1021-30).”

Based on the work of authors, it appears that a high index of suspicion for MIS-C is important for children who develop Kawasaki-like symptoms, David J. Goldberg, MD, said in an interview. “Although children have largely been spared from the acute respiratory presentation of the SARS-CoV-2 pandemic, the recognition and understanding of what appears to be a postviral inflammatory response is a critical first step in developing treatment algorithms for this disease process,” said Dr. Goldberg, a board-certified attending cardiologist in the cardiac center and fetal heart program at Children’s Hospital of Philadelphia. “If inflammatory markers are elevated, particularly if there are accompanying gastrointestinal symptoms, the possibility of cardiac involvement suggests the utility of screening echocardiography. Given the potential need for inotropic or mechanical circulatory support, the presence of myocardial dysfunction dictates care in an intensive care unit capable of providing advanced therapies. While the evidence from Dr. Belhadjer’s cohort suggests that full recovery is probable, there is still much to be learned about this unique inflammatory syndrome and the alarm has rightly been sounded.”

The researchers and Dr. Goldberg reported having no disclosures.

[email protected]

SOURCE: Belhadjer Z et al. Circulation 2020 May 17; doi: 10.1161/circulationaha.120.048360.

On March 31, soon after the Food and Drug Administration authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, N.J.

It may have worked; 11 days after receiving the plasma, Ms. Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the U.S. Department of Health & Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma – both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University, said in an interview.

Dr. Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, PhD, in Baltimore, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine, New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they wrote, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East respiratory syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.
 

Aiming to prevent infection

So far, the FDA has approved 12 plasma trials – including Dr. Shoham’s – and the NIH’s clinicaltrials.gov lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford (Calif.) Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Dr. Casadevall and Dr. Pirofski wrote.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in ED patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins, Baltimore, and at Hopkins-affiliated hospitals throughout Maryland, Dr. Shoham said. He hopes it will expand nationwide eventually, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small, compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a polymerase chain reaction–positive test; participants will be tracked for 90 days. Hospitals and health care workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen – a short-term boost of immunity rather than a long-term therapeutic.
 

What can we learn from expanded access?

Meanwhile, some 2,200 hospitals are participating in the expanded access program being led by the Mayo Clinic nationwide; more than 9,000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the U.S. COVID epicenter: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital – if it’s not being offered there, can you have them transferred?” she said in an interview.

When Northwell – through the New York Blood Bank – opened up donor registration, 800 people signed up in the first 24 hours, Dr. Brennan said. As of mid-May, 527 patients had received a transfusion.
 

Who’s the best donor and when should donation occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom free for 14 days, have a negative follow-up molecular test, and be virus free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Dr. Casadevall wrote. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, MD, PhD, from Pisa (Italy) University Hospital and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they wrote, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Dr. Shoham said in an interview. A reassuring point: Even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Dr. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Dr. Casadevall and Dr. Pirofski have disclosed no relevant financial relationships. Shoham has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

On March 31, soon after the Food and Drug Administration authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, N.J.

It may have worked; 11 days after receiving the plasma, Ms. Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the U.S. Department of Health & Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma – both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University, said in an interview.

Dr. Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, PhD, in Baltimore, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine, New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they wrote, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East respiratory syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.
 

Aiming to prevent infection

So far, the FDA has approved 12 plasma trials – including Dr. Shoham’s – and the NIH’s clinicaltrials.gov lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford (Calif.) Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Dr. Casadevall and Dr. Pirofski wrote.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in ED patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins, Baltimore, and at Hopkins-affiliated hospitals throughout Maryland, Dr. Shoham said. He hopes it will expand nationwide eventually, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small, compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a polymerase chain reaction–positive test; participants will be tracked for 90 days. Hospitals and health care workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen – a short-term boost of immunity rather than a long-term therapeutic.
 

What can we learn from expanded access?

Meanwhile, some 2,200 hospitals are participating in the expanded access program being led by the Mayo Clinic nationwide; more than 9,000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the U.S. COVID epicenter: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital – if it’s not being offered there, can you have them transferred?” she said in an interview.

When Northwell – through the New York Blood Bank – opened up donor registration, 800 people signed up in the first 24 hours, Dr. Brennan said. As of mid-May, 527 patients had received a transfusion.
 

Who’s the best donor and when should donation occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom free for 14 days, have a negative follow-up molecular test, and be virus free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Dr. Casadevall wrote. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, MD, PhD, from Pisa (Italy) University Hospital and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they wrote, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Dr. Shoham said in an interview. A reassuring point: Even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Dr. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Dr. Casadevall and Dr. Pirofski have disclosed no relevant financial relationships. Shoham has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

On March 31, soon after the Food and Drug Administration authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, N.J.

It may have worked; 11 days after receiving the plasma, Ms. Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the U.S. Department of Health & Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma – both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University, said in an interview.

Dr. Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, PhD, in Baltimore, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine, New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they wrote, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East respiratory syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.
 

Aiming to prevent infection

So far, the FDA has approved 12 plasma trials – including Dr. Shoham’s – and the NIH’s clinicaltrials.gov lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford (Calif.) Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Dr. Casadevall and Dr. Pirofski wrote.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in ED patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins, Baltimore, and at Hopkins-affiliated hospitals throughout Maryland, Dr. Shoham said. He hopes it will expand nationwide eventually, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small, compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a polymerase chain reaction–positive test; participants will be tracked for 90 days. Hospitals and health care workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen – a short-term boost of immunity rather than a long-term therapeutic.
 

What can we learn from expanded access?

Meanwhile, some 2,200 hospitals are participating in the expanded access program being led by the Mayo Clinic nationwide; more than 9,000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the U.S. COVID epicenter: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital – if it’s not being offered there, can you have them transferred?” she said in an interview.

When Northwell – through the New York Blood Bank – opened up donor registration, 800 people signed up in the first 24 hours, Dr. Brennan said. As of mid-May, 527 patients had received a transfusion.
 

Who’s the best donor and when should donation occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom free for 14 days, have a negative follow-up molecular test, and be virus free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Dr. Casadevall wrote. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, MD, PhD, from Pisa (Italy) University Hospital and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they wrote, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Dr. Shoham said in an interview. A reassuring point: Even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Dr. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Dr. Casadevall and Dr. Pirofski have disclosed no relevant financial relationships. Shoham has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

A version of this article originally appeared on Medscape.com.

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

A version of this article originally appeared on Medscape.com.

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

A version of this article originally appeared on Medscape.com.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

Case

The patient is a 65-year-old white female who recently was discovered to have a 2-cm spiculated lung mass in the right upper lobe. She is undergoing an evaluation at present but her main complaint today is that of profound weakness and fatigue. Her appetite and energy level are noticeably less; her family ascribes this to anxiety and depression. Her other medical problems include diabetes, hypertension, osteoporosis, and obesity. The patient believes that she’s lost about 20-25 pounds recently, though her family is skeptical, adding that “she’s been heavy all her life.” Her body mass index is 40. What additional interventions would you add to her workup?

SandraMatic/Thinkstock

Background

Sarcopenic obesity occurs as a natural consequence of aging. As a general rule, as many as half the women and a quarter of the men over age 80 years are affected. A total of about 18 million people are involved.

One thought as to etiology is that as one ages, proteolysis outdoes protein synthesis. Fat then replaces the body’s muscle, permeates the viscera, and becomes the prominent body form. Chronic lipodeposition leads to chronic inflammation which, in turn, augments protein catabolism. The elderly become less energetic and less active, and the muscle mass decreases further. A vicious cycle develops. Concurrently with obesity, patients suffer with the onset of dyslipidemia, osteoarthritis, osteoporosis (due to vitamin D deficiency), insulin resistance, and an overall increase in frailty.

Sarcopenic obesity also plays a prognostic role in the management of cancer patients where the presence of sarcopenia correlates with earlier death and decreased capacity for therapy. Patients seen as obese are less likely to receive the intensive care (particularly nutritional support) that patients seen as a higher risk receive. The cancer cachexia is less pronounced. The obesity seen externally masks the wasting within.

Diagnosis and treatment

Sarcopenic obesity suffers from an inexact definition. According to the World Health Organization, obesity is defined, officially, as a body mass index of greater than 30 kg/m². Muscle mass is an important part of this entity, too, but the inclusion of muscle function in this definition brings, seemingly, a point of conjecture. Is muscle function necessary? By what scale do you measure it? This imprecision makes comparative research in the field somewhat more difficult.

As clinical acumen remains the major diagnostic approach to this disease, confirmatory testing for sarcopenic obesity comprises MRIs/CTs and dual energy x-ray absorptiometry (DXA) scans. Presently DXA is used to assess bone density in the diagnosis of osteoporosis. It also reveals the decreased lean appendicular (extremity) muscle mass which, along with the increased BMI, forms the basic diagnosis of sarcopenic obesity. DXA scans are favored over CTs for the assessment of appendicular lean muscle mass. DXA scans provide a relatively inexpensive method of estimating fat, muscle, and additionally, bone density. CTs are less favored because of their radiation exposure as well as their high cost. Assessing muscle strength, using handgrip dynomometry, is available though not widely advocated.

Of the myriad modalities tried in sarcopenic obesity, many have shortcomings. No particular diet format can be advocated. Hypocaloric diets, with or without protein supplementation, offer little advantage to a good physical exercise program. The administration of vitamin D, with calcium, can be of benefit to those sarcopenically obese patients suffering with osteoporosis. Other medications, as exemplified by testosterone, vitamin K, myostatin inhibitors, or mesenchymal stem cells, are either anecdotal or dubious in nature. More research is definitely needed.

The key component for the treatment of sarcopenic obesity is exercise, both aerobic and resistant. Physical exercise recruits muscle satellite cells into the muscle fibers strengthening their composition. Growth factors are also released that stimulate the production of muscle satellite cells. Muscle mass becomes augmented and fortified. Aerobic exercise counteracts the negative metabolic effects of lipids. Resistance training is felt to improve strength when in combination with aerobic exercise, compared with aerobic exercise alone. Research has shown that high-speed resistance training, over a 12-week period, had shown a greater improvement in muscle power and capacity when compared to low-speed training. It was also recommended that patients exercise only until fatigued, not until “failure,” as a stopping point. Programs must be customized to fit the individual.

Sarcopenic obesity is a form of deconditioning that occurs naturally with age but is compounded by cancer. Research into this disease is confounded by a lack of accepted definitions. Radiographic workup and lifestyle changes are the mainstay of medical management. The foremost diagnostic tool remains, as always, clinical suspicion.
 

Dr. Killeen is a physician in Tampa, Fla. He practices internal medicine, hematology, and oncology, and has worked in hospice and hospital medicine.

Recommended reading

Gruber ES et al. Sarcopenia and Sarcopenic Obesity are independent adverse prognostic factors in resectable pancreatic ductal adenocarcinoma. PLoS One. 2019;14(5): e02115915.10.1371/journal.pone.0215915 [PMID 31059520].

Lombardo M et al. Sarcopenic Obesity: Etiology and lifestyle therapy. Eur Rev Med Pharmacol Sci. 2019; 23: 7152-62.

Petroni M et al. Prevention and treatment of Sarcopenic Obesity in women. Nutrients. 2019; Jun 8.10.3390/nu1161302 [PMID 31181771].

Barcos VE, Arribas L. Sarcopenic Obesity: Hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann Oncol. 2018;29(suppl. 2):ii1-ii9.

Zhang X et al. Association of Sarcopenic Obesity with the risk of all-cause mortality among adults over a broad range of different settings: An update meta-analysis. BMC Geriatr. 2018;19:183-97.
 

Key points

• • In sarcopenic obesity a patient’s muscle loss in mass can be clouded, overshadowed by the obese body habitus. The major diagnostic tool initially is clinical suspicion.
• • The diagnostic tests for sarcopenic obesity are DXA and CT scans.
• • The best treatment for sarcopenic obesity is a good exercise plan.

Quiz

1. What is the best treatment for sarcopenic obesity?

A. Testosterone

B. Vitamin K

C. Myostatin inhibitors

D. None of the above

Answer: D

There is no particular pharmaceutical treatment, to date, for sarcopenic obesity. Only an exercise program has proved to be of benefit. Those for whom fatigue might be problematic could benefit perhaps by doing “energy banking” or taking programmed naps/rest periods prior to exercise.



2. DXA scans are favored over CT scans because of which of the following?

A. Less cost

B. Capacity to diagnose osteoporosis

C. Less radiation exposure

D. All of the above

Answer: D

DXA scans offer all of the above advantages over CT scans. Also, patients with sarcopenic obesity found to be osteoporotic could be started on vitamin D and calcium supplementation.



3. Which of the following hamper the diagnosis and treatment of sarcopenic obesity?

A. The issue of muscle function

B. Difficulties in comparative research studies

C. Remembering that muscle wasting can occur without external evidence of cachexia

D. All of the above

Answer: D

Obtaining a precise definition of sarcopenic obesity and dealing with the issue of muscle strength and capacity make comparative studies difficult. The sarcopenic obese patient needs as much attention as the cachectic one as their wasting is from within.



4. In sarcopenic obesity and cancer the presence of sarcopenia is likely to lead to which of the following?

A. Earlier death

B. Decreased capacity for therapy

C. Less treatment focus compared to nonsarcopenic patients

D. All of the above

Answer: D

The presence of sarcopenia correlates to all of the above particularly as the obese patient is thought to require less intensive attention than others.

Case

The patient is a 65-year-old white female who recently was discovered to have a 2-cm spiculated lung mass in the right upper lobe. She is undergoing an evaluation at present but her main complaint today is that of profound weakness and fatigue. Her appetite and energy level are noticeably less; her family ascribes this to anxiety and depression. Her other medical problems include diabetes, hypertension, osteoporosis, and obesity. The patient believes that she’s lost about 20-25 pounds recently, though her family is skeptical, adding that “she’s been heavy all her life.” Her body mass index is 40. What additional interventions would you add to her workup?

SandraMatic/Thinkstock

Background

Sarcopenic obesity occurs as a natural consequence of aging. As a general rule, as many as half the women and a quarter of the men over age 80 years are affected. A total of about 18 million people are involved.

One thought as to etiology is that as one ages, proteolysis outdoes protein synthesis. Fat then replaces the body’s muscle, permeates the viscera, and becomes the prominent body form. Chronic lipodeposition leads to chronic inflammation which, in turn, augments protein catabolism. The elderly become less energetic and less active, and the muscle mass decreases further. A vicious cycle develops. Concurrently with obesity, patients suffer with the onset of dyslipidemia, osteoarthritis, osteoporosis (due to vitamin D deficiency), insulin resistance, and an overall increase in frailty.

Sarcopenic obesity also plays a prognostic role in the management of cancer patients where the presence of sarcopenia correlates with earlier death and decreased capacity for therapy. Patients seen as obese are less likely to receive the intensive care (particularly nutritional support) that patients seen as a higher risk receive. The cancer cachexia is less pronounced. The obesity seen externally masks the wasting within.

Diagnosis and treatment

Sarcopenic obesity suffers from an inexact definition. According to the World Health Organization, obesity is defined, officially, as a body mass index of greater than 30 kg/m². Muscle mass is an important part of this entity, too, but the inclusion of muscle function in this definition brings, seemingly, a point of conjecture. Is muscle function necessary? By what scale do you measure it? This imprecision makes comparative research in the field somewhat more difficult.

As clinical acumen remains the major diagnostic approach to this disease, confirmatory testing for sarcopenic obesity comprises MRIs/CTs and dual energy x-ray absorptiometry (DXA) scans. Presently DXA is used to assess bone density in the diagnosis of osteoporosis. It also reveals the decreased lean appendicular (extremity) muscle mass which, along with the increased BMI, forms the basic diagnosis of sarcopenic obesity. DXA scans are favored over CTs for the assessment of appendicular lean muscle mass. DXA scans provide a relatively inexpensive method of estimating fat, muscle, and additionally, bone density. CTs are less favored because of their radiation exposure as well as their high cost. Assessing muscle strength, using handgrip dynomometry, is available though not widely advocated.

Of the myriad modalities tried in sarcopenic obesity, many have shortcomings. No particular diet format can be advocated. Hypocaloric diets, with or without protein supplementation, offer little advantage to a good physical exercise program. The administration of vitamin D, with calcium, can be of benefit to those sarcopenically obese patients suffering with osteoporosis. Other medications, as exemplified by testosterone, vitamin K, myostatin inhibitors, or mesenchymal stem cells, are either anecdotal or dubious in nature. More research is definitely needed.

The key component for the treatment of sarcopenic obesity is exercise, both aerobic and resistant. Physical exercise recruits muscle satellite cells into the muscle fibers strengthening their composition. Growth factors are also released that stimulate the production of muscle satellite cells. Muscle mass becomes augmented and fortified. Aerobic exercise counteracts the negative metabolic effects of lipids. Resistance training is felt to improve strength when in combination with aerobic exercise, compared with aerobic exercise alone. Research has shown that high-speed resistance training, over a 12-week period, had shown a greater improvement in muscle power and capacity when compared to low-speed training. It was also recommended that patients exercise only until fatigued, not until “failure,” as a stopping point. Programs must be customized to fit the individual.

Sarcopenic obesity is a form of deconditioning that occurs naturally with age but is compounded by cancer. Research into this disease is confounded by a lack of accepted definitions. Radiographic workup and lifestyle changes are the mainstay of medical management. The foremost diagnostic tool remains, as always, clinical suspicion.
 

Dr. Killeen is a physician in Tampa, Fla. He practices internal medicine, hematology, and oncology, and has worked in hospice and hospital medicine.

Recommended reading

Gruber ES et al. Sarcopenia and Sarcopenic Obesity are independent adverse prognostic factors in resectable pancreatic ductal adenocarcinoma. PLoS One. 2019;14(5): e02115915.10.1371/journal.pone.0215915 [PMID 31059520].

Lombardo M et al. Sarcopenic Obesity: Etiology and lifestyle therapy. Eur Rev Med Pharmacol Sci. 2019; 23: 7152-62.

Petroni M et al. Prevention and treatment of Sarcopenic Obesity in women. Nutrients. 2019; Jun 8.10.3390/nu1161302 [PMID 31181771].

Barcos VE, Arribas L. Sarcopenic Obesity: Hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann Oncol. 2018;29(suppl. 2):ii1-ii9.

Zhang X et al. Association of Sarcopenic Obesity with the risk of all-cause mortality among adults over a broad range of different settings: An update meta-analysis. BMC Geriatr. 2018;19:183-97.
 

Key points

• • In sarcopenic obesity a patient’s muscle loss in mass can be clouded, overshadowed by the obese body habitus. The major diagnostic tool initially is clinical suspicion.
• • The diagnostic tests for sarcopenic obesity are DXA and CT scans.
• • The best treatment for sarcopenic obesity is a good exercise plan.

Quiz

1. What is the best treatment for sarcopenic obesity?

A. Testosterone

B. Vitamin K

C. Myostatin inhibitors

D. None of the above

Answer: D

There is no particular pharmaceutical treatment, to date, for sarcopenic obesity. Only an exercise program has proved to be of benefit. Those for whom fatigue might be problematic could benefit perhaps by doing “energy banking” or taking programmed naps/rest periods prior to exercise.



2. DXA scans are favored over CT scans because of which of the following?

A. Less cost

B. Capacity to diagnose osteoporosis

C. Less radiation exposure

D. All of the above

Answer: D

DXA scans offer all of the above advantages over CT scans. Also, patients with sarcopenic obesity found to be osteoporotic could be started on vitamin D and calcium supplementation.



3. Which of the following hamper the diagnosis and treatment of sarcopenic obesity?

A. The issue of muscle function

B. Difficulties in comparative research studies

C. Remembering that muscle wasting can occur without external evidence of cachexia

D. All of the above

Answer: D

Obtaining a precise definition of sarcopenic obesity and dealing with the issue of muscle strength and capacity make comparative studies difficult. The sarcopenic obese patient needs as much attention as the cachectic one as their wasting is from within.



4. In sarcopenic obesity and cancer the presence of sarcopenia is likely to lead to which of the following?

A. Earlier death

B. Decreased capacity for therapy

C. Less treatment focus compared to nonsarcopenic patients

D. All of the above

Answer: D

The presence of sarcopenia correlates to all of the above particularly as the obese patient is thought to require less intensive attention than others.

Case

The patient is a 65-year-old white female who recently was discovered to have a 2-cm spiculated lung mass in the right upper lobe. She is undergoing an evaluation at present but her main complaint today is that of profound weakness and fatigue. Her appetite and energy level are noticeably less; her family ascribes this to anxiety and depression. Her other medical problems include diabetes, hypertension, osteoporosis, and obesity. The patient believes that she’s lost about 20-25 pounds recently, though her family is skeptical, adding that “she’s been heavy all her life.” Her body mass index is 40. What additional interventions would you add to her workup?

SandraMatic/Thinkstock

Background

Sarcopenic obesity occurs as a natural consequence of aging. As a general rule, as many as half the women and a quarter of the men over age 80 years are affected. A total of about 18 million people are involved.

One thought as to etiology is that as one ages, proteolysis outdoes protein synthesis. Fat then replaces the body’s muscle, permeates the viscera, and becomes the prominent body form. Chronic lipodeposition leads to chronic inflammation which, in turn, augments protein catabolism. The elderly become less energetic and less active, and the muscle mass decreases further. A vicious cycle develops. Concurrently with obesity, patients suffer with the onset of dyslipidemia, osteoarthritis, osteoporosis (due to vitamin D deficiency), insulin resistance, and an overall increase in frailty.

Sarcopenic obesity also plays a prognostic role in the management of cancer patients where the presence of sarcopenia correlates with earlier death and decreased capacity for therapy. Patients seen as obese are less likely to receive the intensive care (particularly nutritional support) that patients seen as a higher risk receive. The cancer cachexia is less pronounced. The obesity seen externally masks the wasting within.

Diagnosis and treatment

Sarcopenic obesity suffers from an inexact definition. According to the World Health Organization, obesity is defined, officially, as a body mass index of greater than 30 kg/m². Muscle mass is an important part of this entity, too, but the inclusion of muscle function in this definition brings, seemingly, a point of conjecture. Is muscle function necessary? By what scale do you measure it? This imprecision makes comparative research in the field somewhat more difficult.

As clinical acumen remains the major diagnostic approach to this disease, confirmatory testing for sarcopenic obesity comprises MRIs/CTs and dual energy x-ray absorptiometry (DXA) scans. Presently DXA is used to assess bone density in the diagnosis of osteoporosis. It also reveals the decreased lean appendicular (extremity) muscle mass which, along with the increased BMI, forms the basic diagnosis of sarcopenic obesity. DXA scans are favored over CTs for the assessment of appendicular lean muscle mass. DXA scans provide a relatively inexpensive method of estimating fat, muscle, and additionally, bone density. CTs are less favored because of their radiation exposure as well as their high cost. Assessing muscle strength, using handgrip dynomometry, is available though not widely advocated.

Of the myriad modalities tried in sarcopenic obesity, many have shortcomings. No particular diet format can be advocated. Hypocaloric diets, with or without protein supplementation, offer little advantage to a good physical exercise program. The administration of vitamin D, with calcium, can be of benefit to those sarcopenically obese patients suffering with osteoporosis. Other medications, as exemplified by testosterone, vitamin K, myostatin inhibitors, or mesenchymal stem cells, are either anecdotal or dubious in nature. More research is definitely needed.

The key component for the treatment of sarcopenic obesity is exercise, both aerobic and resistant. Physical exercise recruits muscle satellite cells into the muscle fibers strengthening their composition. Growth factors are also released that stimulate the production of muscle satellite cells. Muscle mass becomes augmented and fortified. Aerobic exercise counteracts the negative metabolic effects of lipids. Resistance training is felt to improve strength when in combination with aerobic exercise, compared with aerobic exercise alone. Research has shown that high-speed resistance training, over a 12-week period, had shown a greater improvement in muscle power and capacity when compared to low-speed training. It was also recommended that patients exercise only until fatigued, not until “failure,” as a stopping point. Programs must be customized to fit the individual.

Sarcopenic obesity is a form of deconditioning that occurs naturally with age but is compounded by cancer. Research into this disease is confounded by a lack of accepted definitions. Radiographic workup and lifestyle changes are the mainstay of medical management. The foremost diagnostic tool remains, as always, clinical suspicion.
 

Dr. Killeen is a physician in Tampa, Fla. He practices internal medicine, hematology, and oncology, and has worked in hospice and hospital medicine.

Recommended reading

Gruber ES et al. Sarcopenia and Sarcopenic Obesity are independent adverse prognostic factors in resectable pancreatic ductal adenocarcinoma. PLoS One. 2019;14(5): e02115915.10.1371/journal.pone.0215915 [PMID 31059520].

Lombardo M et al. Sarcopenic Obesity: Etiology and lifestyle therapy. Eur Rev Med Pharmacol Sci. 2019; 23: 7152-62.

Petroni M et al. Prevention and treatment of Sarcopenic Obesity in women. Nutrients. 2019; Jun 8.10.3390/nu1161302 [PMID 31181771].

Barcos VE, Arribas L. Sarcopenic Obesity: Hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann Oncol. 2018;29(suppl. 2):ii1-ii9.

Zhang X et al. Association of Sarcopenic Obesity with the risk of all-cause mortality among adults over a broad range of different settings: An update meta-analysis. BMC Geriatr. 2018;19:183-97.
 

Key points

• • In sarcopenic obesity a patient’s muscle loss in mass can be clouded, overshadowed by the obese body habitus. The major diagnostic tool initially is clinical suspicion.
• • The diagnostic tests for sarcopenic obesity are DXA and CT scans.
• • The best treatment for sarcopenic obesity is a good exercise plan.

Quiz

1. What is the best treatment for sarcopenic obesity?

A. Testosterone

B. Vitamin K

C. Myostatin inhibitors

D. None of the above

Answer: D

There is no particular pharmaceutical treatment, to date, for sarcopenic obesity. Only an exercise program has proved to be of benefit. Those for whom fatigue might be problematic could benefit perhaps by doing “energy banking” or taking programmed naps/rest periods prior to exercise.



2. DXA scans are favored over CT scans because of which of the following?

A. Less cost

B. Capacity to diagnose osteoporosis

C. Less radiation exposure

D. All of the above

Answer: D

DXA scans offer all of the above advantages over CT scans. Also, patients with sarcopenic obesity found to be osteoporotic could be started on vitamin D and calcium supplementation.



3. Which of the following hamper the diagnosis and treatment of sarcopenic obesity?

A. The issue of muscle function

B. Difficulties in comparative research studies

C. Remembering that muscle wasting can occur without external evidence of cachexia

D. All of the above

Answer: D

Obtaining a precise definition of sarcopenic obesity and dealing with the issue of muscle strength and capacity make comparative studies difficult. The sarcopenic obese patient needs as much attention as the cachectic one as their wasting is from within.



4. In sarcopenic obesity and cancer the presence of sarcopenia is likely to lead to which of the following?

A. Earlier death

B. Decreased capacity for therapy

C. Less treatment focus compared to nonsarcopenic patients

D. All of the above

Answer: D

The presence of sarcopenia correlates to all of the above particularly as the obese patient is thought to require less intensive attention than others.

A new nationwide U.S. observational study suggests that ACE inhibitors may protect against severe illness in older people with COVID-19, prompting the start of a randomized clinical trial to test the strategy.

In addition, a new meta-analysis of all the available data on the use of ACE inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19–infected patients has concluded that these drugs are not associated with more severe disease and do not increase susceptibility to infection.

The observational study, which was published on the MedRxiv preprint server on May 19 and has not yet been peer reviewed, was conducted by the health insurance company United Heath Group and by Yale University, New Haven, Conn.

The investigators analyzed data from 10,000 patients from across the United States who had tested positive for COVID-19, who were enrolled in Medicare Advantage insurance plans or were commercially insured, and who had received a prescription for one or more antihypertensive medications.

Results showed that the use of ACE inhibitors was associated with an almost 40% lower risk for COVID-19 hospitalization for older people enrolled in Medicare Advantage plans. No such benefit was seen in the younger commercially insured patients or in either group with ARBs.

Courtesy Yale University

At a telephone media briefing on the study, senior investigator Harlan M. Krumholz, MD, said: “We don’t believe this is enough info to change practice, but we do think this is an interesting and intriguing result.

“These findings merit a clinical trial to formally test whether ACE inhibitors – which are cheap, widely available, and well-tolerated drugs – can reduce hospitalization of patients infected with COVID-19,” added Dr. Krumholz, professor of medicine at Yale and director of the Yale New Haven Hospital Center for Outcomes Research.

A pragmatic clinical trial is now being planned. In this trial, 10,000 older people who test positive for COVID-19 will be randomly assigned to receive either a low dose of an ACE inhibitor or placebo. It is hoped that recruitment for the trial will begin in June of 2020. It is open to all eligible Americans who are older than 50 years, who test negative for COVID-19, and who are not taking medications for hypertension. Prospective patients can sign up at a dedicated website.

The randomized trial, also conducted by United Health Group and Yale, is said to be “one of the first virtual COVID-19 clinical trials to be launched at scale.”

For the observational study, the researchers identified 2,263 people who were receiving medication for hypertension and who tested positive for COVID-19. Of these, approximately two-thirds were older, Medicare Advantage enrollees; one-third were younger, commercially insured individuals.

In a propensity score–matched analysis, the investigators matched 441 patients who were taking ACE inhibitors to 441 patients who were taking other antihypertensive agents; and 412 patients who were receiving an ARB to 412 patients who were receiving other antihypertensive agents.

Results showed that during a median of 30 days after testing positive, 12.7% of the cohort were hospitalized for COVID-19. In propensity score–matched analyses, neither ACE inhibitors (hazard ratio [HR], 0.77; P = .18) nor ARBs (HR, 0.88; P =.48) were significantly associated with risk for hospitalization.

However, in analyses stratified by the insurance group, ACE inhibitors (but not ARBs) were associated with a significant lower risk for hospitalization among the Medicare group (HR, 0.61; P = .02) but not among the commercially insured group (HR, 2.14; P = .12).

A second study examined outcomes of 7,933 individuals with hypertension who were hospitalized with COVID-19 (92% of these patients were Medicare Advantage enrollees). Of these, 14.2% died, 59.5% survived to discharge, and 26.3% underwent ongoing hospitalization. In propensity score–matched analyses, use of neither an ACE inhibitor (HR, 0.97; P = .74) nor an ARB (HR, 1.15; P = .15) was associated with risk of in-hospital mortality.

The researchers said their findings are consistent with prior evidence from randomized clinical trials suggesting a reduced risk for pneumonia with ACE inhibitors that is not observed with ARBs.

They also cited some preclinical evidence that they said suggests a possible protective role for ACE inhibitors in COVID-19: that ACE inhibitors, but not ARBs, are associated with the upregulation of ACE2 receptors, which modulate the local interactions of the renin-angiotensin-aldosterone system in the lung tissue.

“The presence of ACE2 receptors, therefore, exerts a protective effect against the development of acute lung injury in infections with SARS coronaviruses, which lead to dysregulation of these mechanisms and endothelial damage,” they added. “Further, our observations do not support theoretical concerns of adverse outcomes due to enhanced virulence of SARS coronaviruses due to overexpression of ACE2 receptors in cell cultures – an indirect binding site for these viruses.”

The authors also noted that their findings have “important implications” for four ongoing randomized trials of ACE inhibitors/ARBs in COVID-19, “as none of them align with the observations of our study.”

They pointed out that of the four ongoing trials, three are testing the use of ACE inhibitors or ARBs in the treatment of hospitalized COVID-19 patients, and one is testing the use of a 10-day course of ARBs after a positive SARS-CoV-2 test to prevent hospitalization.
 

Experts cautious

However, two cardiovascular experts who were asked to comment on this latest study were not overly optimistic about the data.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, said: “This report adds to the growing number of observational studies that show varying effects of ACE inhibitors and ARBs in increasing or decreasing hospitalizations for COVID-19 and the likelihood of in-hospital mortality. Overall, this new report differs from others in the remarkable effects of insurance coverage: In particular, for ACE inhibitors, there was a 40% reduction in fatal events in Medicare patients but a twofold increase in patients using commercial insurance – albeit the test for heterogeneity when comparing the two groups did not quite reach statistical significance.

“In essence, these authors are saying that ACE inhibitors are highly protective in patients aged 65 or older but bordering on harmful in patients aged below 65. I agree that it’s worthwhile to check this finding in a prospective trial ... but this hypothesis does seem to be a reach.”

Dr. Weber noted that both ACE inhibitors and ARBs increase the level of the ACE2 enzyme to which the COVID-19 virus binds in the lungs.

“The ACE inhibitors do so by inhibiting the enzyme’s action and thus stimulate further enzyme production; the ARBs block the effects of angiotensin II, which results in high angiotensin II levels that also upregulate ACE2 production,” he said. “Perhaps the ACE inhibitors, by binding to the ACE enzyme, can in some way interfere with the enzyme’s uptake of the COVID virus and thus provide some measure of clinical protection. This is possible, but why would this effect be apparent only in older people?”

Catherine Hackett/MDedge News

John McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, added: “This looks like a subgroup of a subgroup type analysis based on small numbers of events – I think there were only 77 hospitalizations among the 722 patients treated with an ACE inhibitor, and the Medicare Advantage subgroup was only 581 of those 722 patients.

“The hazard ratio had wide 95% CI [confidence interval] and a modest P value,” Dr. McMurray added. “So yes, interesting and hypothesis-generating, but not definitive.”
 

New meta-analysis

The new meta-analysis of all data so far available on ACE inhibitor and ARB use for patients with COVID-19 was published online in Annals of Internal Medicine on May 15.

The analysis is a living, systematic review with ongoing literature surveillance and critical appraisal, which will be updated as new data become available. It included 14 observational studies.

The authors, led by Katherine M. Mackey, MD, VA Portland Health Care System, Oregon, concluded: “High-certainty evidence suggests that ACE-inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate certainty evidence suggested no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.”

In an accompanying editorial, William G. Kussmaul III, MD, Drexel University, Philadelphia, said that initial fears that these drugs may be harmful for patients with COVID-19 now seem to have been unfounded.

“We now have reasonable reassurance that drugs that alter the renin-angiotensin system do not pose substantial threats as either COVID-19 risk factors or severity multipliers,” he wrote.
 

A version of this article originally appeared on Medscape.com.

A new nationwide U.S. observational study suggests that ACE inhibitors may protect against severe illness in older people with COVID-19, prompting the start of a randomized clinical trial to test the strategy.

In addition, a new meta-analysis of all the available data on the use of ACE inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19–infected patients has concluded that these drugs are not associated with more severe disease and do not increase susceptibility to infection.

The observational study, which was published on the MedRxiv preprint server on May 19 and has not yet been peer reviewed, was conducted by the health insurance company United Heath Group and by Yale University, New Haven, Conn.

The investigators analyzed data from 10,000 patients from across the United States who had tested positive for COVID-19, who were enrolled in Medicare Advantage insurance plans or were commercially insured, and who had received a prescription for one or more antihypertensive medications.

Results showed that the use of ACE inhibitors was associated with an almost 40% lower risk for COVID-19 hospitalization for older people enrolled in Medicare Advantage plans. No such benefit was seen in the younger commercially insured patients or in either group with ARBs.

Courtesy Yale University

At a telephone media briefing on the study, senior investigator Harlan M. Krumholz, MD, said: “We don’t believe this is enough info to change practice, but we do think this is an interesting and intriguing result.

“These findings merit a clinical trial to formally test whether ACE inhibitors – which are cheap, widely available, and well-tolerated drugs – can reduce hospitalization of patients infected with COVID-19,” added Dr. Krumholz, professor of medicine at Yale and director of the Yale New Haven Hospital Center for Outcomes Research.

A pragmatic clinical trial is now being planned. In this trial, 10,000 older people who test positive for COVID-19 will be randomly assigned to receive either a low dose of an ACE inhibitor or placebo. It is hoped that recruitment for the trial will begin in June of 2020. It is open to all eligible Americans who are older than 50 years, who test negative for COVID-19, and who are not taking medications for hypertension. Prospective patients can sign up at a dedicated website.

The randomized trial, also conducted by United Health Group and Yale, is said to be “one of the first virtual COVID-19 clinical trials to be launched at scale.”

For the observational study, the researchers identified 2,263 people who were receiving medication for hypertension and who tested positive for COVID-19. Of these, approximately two-thirds were older, Medicare Advantage enrollees; one-third were younger, commercially insured individuals.

In a propensity score–matched analysis, the investigators matched 441 patients who were taking ACE inhibitors to 441 patients who were taking other antihypertensive agents; and 412 patients who were receiving an ARB to 412 patients who were receiving other antihypertensive agents.

Results showed that during a median of 30 days after testing positive, 12.7% of the cohort were hospitalized for COVID-19. In propensity score–matched analyses, neither ACE inhibitors (hazard ratio [HR], 0.77; P = .18) nor ARBs (HR, 0.88; P =.48) were significantly associated with risk for hospitalization.

However, in analyses stratified by the insurance group, ACE inhibitors (but not ARBs) were associated with a significant lower risk for hospitalization among the Medicare group (HR, 0.61; P = .02) but not among the commercially insured group (HR, 2.14; P = .12).

A second study examined outcomes of 7,933 individuals with hypertension who were hospitalized with COVID-19 (92% of these patients were Medicare Advantage enrollees). Of these, 14.2% died, 59.5% survived to discharge, and 26.3% underwent ongoing hospitalization. In propensity score–matched analyses, use of neither an ACE inhibitor (HR, 0.97; P = .74) nor an ARB (HR, 1.15; P = .15) was associated with risk of in-hospital mortality.

The researchers said their findings are consistent with prior evidence from randomized clinical trials suggesting a reduced risk for pneumonia with ACE inhibitors that is not observed with ARBs.

They also cited some preclinical evidence that they said suggests a possible protective role for ACE inhibitors in COVID-19: that ACE inhibitors, but not ARBs, are associated with the upregulation of ACE2 receptors, which modulate the local interactions of the renin-angiotensin-aldosterone system in the lung tissue.

“The presence of ACE2 receptors, therefore, exerts a protective effect against the development of acute lung injury in infections with SARS coronaviruses, which lead to dysregulation of these mechanisms and endothelial damage,” they added. “Further, our observations do not support theoretical concerns of adverse outcomes due to enhanced virulence of SARS coronaviruses due to overexpression of ACE2 receptors in cell cultures – an indirect binding site for these viruses.”

The authors also noted that their findings have “important implications” for four ongoing randomized trials of ACE inhibitors/ARBs in COVID-19, “as none of them align with the observations of our study.”

They pointed out that of the four ongoing trials, three are testing the use of ACE inhibitors or ARBs in the treatment of hospitalized COVID-19 patients, and one is testing the use of a 10-day course of ARBs after a positive SARS-CoV-2 test to prevent hospitalization.
 

Experts cautious

However, two cardiovascular experts who were asked to comment on this latest study were not overly optimistic about the data.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, said: “This report adds to the growing number of observational studies that show varying effects of ACE inhibitors and ARBs in increasing or decreasing hospitalizations for COVID-19 and the likelihood of in-hospital mortality. Overall, this new report differs from others in the remarkable effects of insurance coverage: In particular, for ACE inhibitors, there was a 40% reduction in fatal events in Medicare patients but a twofold increase in patients using commercial insurance – albeit the test for heterogeneity when comparing the two groups did not quite reach statistical significance.

“In essence, these authors are saying that ACE inhibitors are highly protective in patients aged 65 or older but bordering on harmful in patients aged below 65. I agree that it’s worthwhile to check this finding in a prospective trial ... but this hypothesis does seem to be a reach.”

Dr. Weber noted that both ACE inhibitors and ARBs increase the level of the ACE2 enzyme to which the COVID-19 virus binds in the lungs.

“The ACE inhibitors do so by inhibiting the enzyme’s action and thus stimulate further enzyme production; the ARBs block the effects of angiotensin II, which results in high angiotensin II levels that also upregulate ACE2 production,” he said. “Perhaps the ACE inhibitors, by binding to the ACE enzyme, can in some way interfere with the enzyme’s uptake of the COVID virus and thus provide some measure of clinical protection. This is possible, but why would this effect be apparent only in older people?”

Catherine Hackett/MDedge News

John McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, added: “This looks like a subgroup of a subgroup type analysis based on small numbers of events – I think there were only 77 hospitalizations among the 722 patients treated with an ACE inhibitor, and the Medicare Advantage subgroup was only 581 of those 722 patients.

“The hazard ratio had wide 95% CI [confidence interval] and a modest P value,” Dr. McMurray added. “So yes, interesting and hypothesis-generating, but not definitive.”
 

New meta-analysis

The new meta-analysis of all data so far available on ACE inhibitor and ARB use for patients with COVID-19 was published online in Annals of Internal Medicine on May 15.

The analysis is a living, systematic review with ongoing literature surveillance and critical appraisal, which will be updated as new data become available. It included 14 observational studies.

The authors, led by Katherine M. Mackey, MD, VA Portland Health Care System, Oregon, concluded: “High-certainty evidence suggests that ACE-inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate certainty evidence suggested no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.”

In an accompanying editorial, William G. Kussmaul III, MD, Drexel University, Philadelphia, said that initial fears that these drugs may be harmful for patients with COVID-19 now seem to have been unfounded.

“We now have reasonable reassurance that drugs that alter the renin-angiotensin system do not pose substantial threats as either COVID-19 risk factors or severity multipliers,” he wrote.
 

A version of this article originally appeared on Medscape.com.

A new nationwide U.S. observational study suggests that ACE inhibitors may protect against severe illness in older people with COVID-19, prompting the start of a randomized clinical trial to test the strategy.

In addition, a new meta-analysis of all the available data on the use of ACE inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19–infected patients has concluded that these drugs are not associated with more severe disease and do not increase susceptibility to infection.

The observational study, which was published on the MedRxiv preprint server on May 19 and has not yet been peer reviewed, was conducted by the health insurance company United Heath Group and by Yale University, New Haven, Conn.

The investigators analyzed data from 10,000 patients from across the United States who had tested positive for COVID-19, who were enrolled in Medicare Advantage insurance plans or were commercially insured, and who had received a prescription for one or more antihypertensive medications.

Results showed that the use of ACE inhibitors was associated with an almost 40% lower risk for COVID-19 hospitalization for older people enrolled in Medicare Advantage plans. No such benefit was seen in the younger commercially insured patients or in either group with ARBs.

Courtesy Yale University

At a telephone media briefing on the study, senior investigator Harlan M. Krumholz, MD, said: “We don’t believe this is enough info to change practice, but we do think this is an interesting and intriguing result.

“These findings merit a clinical trial to formally test whether ACE inhibitors – which are cheap, widely available, and well-tolerated drugs – can reduce hospitalization of patients infected with COVID-19,” added Dr. Krumholz, professor of medicine at Yale and director of the Yale New Haven Hospital Center for Outcomes Research.

A pragmatic clinical trial is now being planned. In this trial, 10,000 older people who test positive for COVID-19 will be randomly assigned to receive either a low dose of an ACE inhibitor or placebo. It is hoped that recruitment for the trial will begin in June of 2020. It is open to all eligible Americans who are older than 50 years, who test negative for COVID-19, and who are not taking medications for hypertension. Prospective patients can sign up at a dedicated website.

The randomized trial, also conducted by United Health Group and Yale, is said to be “one of the first virtual COVID-19 clinical trials to be launched at scale.”

For the observational study, the researchers identified 2,263 people who were receiving medication for hypertension and who tested positive for COVID-19. Of these, approximately two-thirds were older, Medicare Advantage enrollees; one-third were younger, commercially insured individuals.

In a propensity score–matched analysis, the investigators matched 441 patients who were taking ACE inhibitors to 441 patients who were taking other antihypertensive agents; and 412 patients who were receiving an ARB to 412 patients who were receiving other antihypertensive agents.

Results showed that during a median of 30 days after testing positive, 12.7% of the cohort were hospitalized for COVID-19. In propensity score–matched analyses, neither ACE inhibitors (hazard ratio [HR], 0.77; P = .18) nor ARBs (HR, 0.88; P =.48) were significantly associated with risk for hospitalization.

However, in analyses stratified by the insurance group, ACE inhibitors (but not ARBs) were associated with a significant lower risk for hospitalization among the Medicare group (HR, 0.61; P = .02) but not among the commercially insured group (HR, 2.14; P = .12).

A second study examined outcomes of 7,933 individuals with hypertension who were hospitalized with COVID-19 (92% of these patients were Medicare Advantage enrollees). Of these, 14.2% died, 59.5% survived to discharge, and 26.3% underwent ongoing hospitalization. In propensity score–matched analyses, use of neither an ACE inhibitor (HR, 0.97; P = .74) nor an ARB (HR, 1.15; P = .15) was associated with risk of in-hospital mortality.

The researchers said their findings are consistent with prior evidence from randomized clinical trials suggesting a reduced risk for pneumonia with ACE inhibitors that is not observed with ARBs.

They also cited some preclinical evidence that they said suggests a possible protective role for ACE inhibitors in COVID-19: that ACE inhibitors, but not ARBs, are associated with the upregulation of ACE2 receptors, which modulate the local interactions of the renin-angiotensin-aldosterone system in the lung tissue.

“The presence of ACE2 receptors, therefore, exerts a protective effect against the development of acute lung injury in infections with SARS coronaviruses, which lead to dysregulation of these mechanisms and endothelial damage,” they added. “Further, our observations do not support theoretical concerns of adverse outcomes due to enhanced virulence of SARS coronaviruses due to overexpression of ACE2 receptors in cell cultures – an indirect binding site for these viruses.”

The authors also noted that their findings have “important implications” for four ongoing randomized trials of ACE inhibitors/ARBs in COVID-19, “as none of them align with the observations of our study.”

They pointed out that of the four ongoing trials, three are testing the use of ACE inhibitors or ARBs in the treatment of hospitalized COVID-19 patients, and one is testing the use of a 10-day course of ARBs after a positive SARS-CoV-2 test to prevent hospitalization.
 

Experts cautious

However, two cardiovascular experts who were asked to comment on this latest study were not overly optimistic about the data.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, said: “This report adds to the growing number of observational studies that show varying effects of ACE inhibitors and ARBs in increasing or decreasing hospitalizations for COVID-19 and the likelihood of in-hospital mortality. Overall, this new report differs from others in the remarkable effects of insurance coverage: In particular, for ACE inhibitors, there was a 40% reduction in fatal events in Medicare patients but a twofold increase in patients using commercial insurance – albeit the test for heterogeneity when comparing the two groups did not quite reach statistical significance.

“In essence, these authors are saying that ACE inhibitors are highly protective in patients aged 65 or older but bordering on harmful in patients aged below 65. I agree that it’s worthwhile to check this finding in a prospective trial ... but this hypothesis does seem to be a reach.”

Dr. Weber noted that both ACE inhibitors and ARBs increase the level of the ACE2 enzyme to which the COVID-19 virus binds in the lungs.

“The ACE inhibitors do so by inhibiting the enzyme’s action and thus stimulate further enzyme production; the ARBs block the effects of angiotensin II, which results in high angiotensin II levels that also upregulate ACE2 production,” he said. “Perhaps the ACE inhibitors, by binding to the ACE enzyme, can in some way interfere with the enzyme’s uptake of the COVID virus and thus provide some measure of clinical protection. This is possible, but why would this effect be apparent only in older people?”

Catherine Hackett/MDedge News

John McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, added: “This looks like a subgroup of a subgroup type analysis based on small numbers of events – I think there were only 77 hospitalizations among the 722 patients treated with an ACE inhibitor, and the Medicare Advantage subgroup was only 581 of those 722 patients.

“The hazard ratio had wide 95% CI [confidence interval] and a modest P value,” Dr. McMurray added. “So yes, interesting and hypothesis-generating, but not definitive.”
 

New meta-analysis

The new meta-analysis of all data so far available on ACE inhibitor and ARB use for patients with COVID-19 was published online in Annals of Internal Medicine on May 15.

The analysis is a living, systematic review with ongoing literature surveillance and critical appraisal, which will be updated as new data become available. It included 14 observational studies.

The authors, led by Katherine M. Mackey, MD, VA Portland Health Care System, Oregon, concluded: “High-certainty evidence suggests that ACE-inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate certainty evidence suggested no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.”

In an accompanying editorial, William G. Kussmaul III, MD, Drexel University, Philadelphia, said that initial fears that these drugs may be harmful for patients with COVID-19 now seem to have been unfounded.

“We now have reasonable reassurance that drugs that alter the renin-angiotensin system do not pose substantial threats as either COVID-19 risk factors or severity multipliers,” he wrote.
 

A version of this article originally appeared on Medscape.com.

The drastic drop in admissions for acute myocardial infarctions (AMI) during the COVID-19 pandemic in Italy has seen a parallel rise in MI fatality rates in those who do present to hospitals, according to a new report. This gives credence to suggestions that people have avoided hospitals during the pandemic despite life-threatening emergencies.

Salvatore De Rosa, MD, PhD, and colleagues reported their results in the European Heart Journal.

“These data return a frightening picture of about half of AMI patients not reaching out to the hospital at all, which will probably significantly increase mortality for AMI and bring with it a number of patients with post-MI heart failure, despite the fact that acute coronary syndrome management protocols were promptly implemented,” Dr. De Rosa, of Magna Graecia University in Catanzaro, Italy, and associates wrote.
 

Hospitalizations down

The study counted AMIs at 54 hospital coronary care units nationwide for the week of March 12-19, 2020, at the height of the coronavirus outbreak in northern Italy, and compared that with an equivalent week in 2019. The researchers reported 319 AMIs during the week in 2020, compared with 618 in the equivalent 2019 week, a 48% reduction (P < .001). Although the outbreak was worst in northern Italy, the decline in admissions occurred throughout the country.

An analysis of subtype determined the decline in the incidence of ST-segment elevation MI lagged significantly behind that of non-STEMI. STEMI declined from 268 in 2019 to 197 in 2020, a 27% reduction, while hospitalizations for non-STEMI went from 350 to 122, a 65% reduction.

The researchers also found substantial reductions in hospitalizations for heart failure, by 47%, and atrial fibrillation, by 53%. Incidentally, the mean age of atrial fibrillation patients was considerably younger in 2020: 64.6 vs. 70 years.
 

Death, complications up

AMI patients who managed to get to the hospital during the pandemic also had worse outcomes. Mortality for STEMI cases more than tripled, to 14% during the outbreak, compared with 4% in 2019 (P < .001) and complication rates increased by 80% to 19% (P = .025). Twenty-one STEMI patients were positive for COVID-19 and more than a quarter (29%) died, which was more than two and a half times the 12% death rate in non–COVID-19 STEMI patients.

Analysis of the STEMI group also found that the care gap for women with heart disease worsened significantly during the pandemic, as they comprised 20.3% of cases this year, compared with 25.4% before the pandemic. Also, the reduction in admissions for STEMI during the pandemic was statistically significant at 41% for women, but not for men at 18%.

Non-STEMI patients fared better overall than STEMI patients, but their outcomes also worsened during the pandemic. Non-STEMI patients were significantly less likely to have percutaneous coronary intervention during the pandemic than previously; the rate declined by 13%, from 77% to 66%. The non-STEMI mortality rate nearly doubled, although not statistically significantly, from 1.7% to 3.3%, whereas complication rates actually more than doubled, from 5.1% to 10.7%, a significant difference. Twelve (9.8%) of the non-STEMI patients were COVID-19 positive, but none died.
 

Trend extends beyond borders

Dr. De Rosa and colleagues noted that their findings are in line with studies that reported similar declines for STEMI interventions in the United States and Spain during the pandemic (J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.011; REC Interv Cardiol. 2020. doi: 10.24875/RECIC.M20000120).

Additionally, a group at Kaiser Permanente in Northern California also reported a 50% decline in the incidence of AMI hospitalizations during the pandemic (N Engl J Med. 2020 May 19. doi: 10.1056/NEJMc2015630). Likewise, a study of aortic dissections in New York reported a sharp decline in procedures during the pandemic in the city, from 13 to 3 a month (J Am Coll Cardiol. 2020 May 15. doi: 10.1016/j.jacc.2020.05.022)

The researchers in Italy didn’t aim to determine the reasons for the decline in AMI hospitalizations, but Dr. De Rosa and colleagues speculated on the following explanations: Fear of contagion in response to media reports, concentration of resources to address COVID-19 may have engendered a sense to defer less urgent care among patients and health care systems, and a true reduction in acute cardiovascular disease because people under stay-at-home orders had low physical stress.

“The concern is fewer MIs most likely means people are dying at home or presenting later as this study suggests,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix, in interpreting the results of the Italian study.

That could be a result of a mixed message from the media about accessing health care during the pandemic. “What it suggests to a lot of us is that the media has transmitted this notion that hospitals are busy taking care of COVID-19 patients, but we never said don’t come to hospital if you’re having a heart attack,” Dr. Gulati said. “I think we created some sort of fear that patients if they didn’t have COVID-19 they didn’t want to bother physicians.”

Dr. Gulati, whose practice focuses on women with CVD, said the study’s findings that interventions in women dropped more precipitously than men were concerning. “We know already that women don’t do as well after a heart attack, compared to men, and now we see it worsen it even further when women aren’t presenting,” she said. “We’re worried that this is going to increase the gap.”

Dr. DeRosa and colleagues have no relevant financial relationships to disclose.

SOURCE: De Rosa S et al. Euro Heart J. 2020 May 15. doi: 10.1093/eurheartj/ehaa409.

The drastic drop in admissions for acute myocardial infarctions (AMI) during the COVID-19 pandemic in Italy has seen a parallel rise in MI fatality rates in those who do present to hospitals, according to a new report. This gives credence to suggestions that people have avoided hospitals during the pandemic despite life-threatening emergencies.

Salvatore De Rosa, MD, PhD, and colleagues reported their results in the European Heart Journal.

“These data return a frightening picture of about half of AMI patients not reaching out to the hospital at all, which will probably significantly increase mortality for AMI and bring with it a number of patients with post-MI heart failure, despite the fact that acute coronary syndrome management protocols were promptly implemented,” Dr. De Rosa, of Magna Graecia University in Catanzaro, Italy, and associates wrote.
 

Hospitalizations down

The study counted AMIs at 54 hospital coronary care units nationwide for the week of March 12-19, 2020, at the height of the coronavirus outbreak in northern Italy, and compared that with an equivalent week in 2019. The researchers reported 319 AMIs during the week in 2020, compared with 618 in the equivalent 2019 week, a 48% reduction (P < .001). Although the outbreak was worst in northern Italy, the decline in admissions occurred throughout the country.

An analysis of subtype determined the decline in the incidence of ST-segment elevation MI lagged significantly behind that of non-STEMI. STEMI declined from 268 in 2019 to 197 in 2020, a 27% reduction, while hospitalizations for non-STEMI went from 350 to 122, a 65% reduction.

The researchers also found substantial reductions in hospitalizations for heart failure, by 47%, and atrial fibrillation, by 53%. Incidentally, the mean age of atrial fibrillation patients was considerably younger in 2020: 64.6 vs. 70 years.
 

Death, complications up

AMI patients who managed to get to the hospital during the pandemic also had worse outcomes. Mortality for STEMI cases more than tripled, to 14% during the outbreak, compared with 4% in 2019 (P < .001) and complication rates increased by 80% to 19% (P = .025). Twenty-one STEMI patients were positive for COVID-19 and more than a quarter (29%) died, which was more than two and a half times the 12% death rate in non–COVID-19 STEMI patients.

Analysis of the STEMI group also found that the care gap for women with heart disease worsened significantly during the pandemic, as they comprised 20.3% of cases this year, compared with 25.4% before the pandemic. Also, the reduction in admissions for STEMI during the pandemic was statistically significant at 41% for women, but not for men at 18%.

Non-STEMI patients fared better overall than STEMI patients, but their outcomes also worsened during the pandemic. Non-STEMI patients were significantly less likely to have percutaneous coronary intervention during the pandemic than previously; the rate declined by 13%, from 77% to 66%. The non-STEMI mortality rate nearly doubled, although not statistically significantly, from 1.7% to 3.3%, whereas complication rates actually more than doubled, from 5.1% to 10.7%, a significant difference. Twelve (9.8%) of the non-STEMI patients were COVID-19 positive, but none died.
 

Trend extends beyond borders

Dr. De Rosa and colleagues noted that their findings are in line with studies that reported similar declines for STEMI interventions in the United States and Spain during the pandemic (J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.011; REC Interv Cardiol. 2020. doi: 10.24875/RECIC.M20000120).

Additionally, a group at Kaiser Permanente in Northern California also reported a 50% decline in the incidence of AMI hospitalizations during the pandemic (N Engl J Med. 2020 May 19. doi: 10.1056/NEJMc2015630). Likewise, a study of aortic dissections in New York reported a sharp decline in procedures during the pandemic in the city, from 13 to 3 a month (J Am Coll Cardiol. 2020 May 15. doi: 10.1016/j.jacc.2020.05.022)

The researchers in Italy didn’t aim to determine the reasons for the decline in AMI hospitalizations, but Dr. De Rosa and colleagues speculated on the following explanations: Fear of contagion in response to media reports, concentration of resources to address COVID-19 may have engendered a sense to defer less urgent care among patients and health care systems, and a true reduction in acute cardiovascular disease because people under stay-at-home orders had low physical stress.

“The concern is fewer MIs most likely means people are dying at home or presenting later as this study suggests,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix, in interpreting the results of the Italian study.

That could be a result of a mixed message from the media about accessing health care during the pandemic. “What it suggests to a lot of us is that the media has transmitted this notion that hospitals are busy taking care of COVID-19 patients, but we never said don’t come to hospital if you’re having a heart attack,” Dr. Gulati said. “I think we created some sort of fear that patients if they didn’t have COVID-19 they didn’t want to bother physicians.”

Dr. Gulati, whose practice focuses on women with CVD, said the study’s findings that interventions in women dropped more precipitously than men were concerning. “We know already that women don’t do as well after a heart attack, compared to men, and now we see it worsen it even further when women aren’t presenting,” she said. “We’re worried that this is going to increase the gap.”

Dr. DeRosa and colleagues have no relevant financial relationships to disclose.

SOURCE: De Rosa S et al. Euro Heart J. 2020 May 15. doi: 10.1093/eurheartj/ehaa409.

The drastic drop in admissions for acute myocardial infarctions (AMI) during the COVID-19 pandemic in Italy has seen a parallel rise in MI fatality rates in those who do present to hospitals, according to a new report. This gives credence to suggestions that people have avoided hospitals during the pandemic despite life-threatening emergencies.

Salvatore De Rosa, MD, PhD, and colleagues reported their results in the European Heart Journal.

“These data return a frightening picture of about half of AMI patients not reaching out to the hospital at all, which will probably significantly increase mortality for AMI and bring with it a number of patients with post-MI heart failure, despite the fact that acute coronary syndrome management protocols were promptly implemented,” Dr. De Rosa, of Magna Graecia University in Catanzaro, Italy, and associates wrote.
 

Hospitalizations down

The study counted AMIs at 54 hospital coronary care units nationwide for the week of March 12-19, 2020, at the height of the coronavirus outbreak in northern Italy, and compared that with an equivalent week in 2019. The researchers reported 319 AMIs during the week in 2020, compared with 618 in the equivalent 2019 week, a 48% reduction (P < .001). Although the outbreak was worst in northern Italy, the decline in admissions occurred throughout the country.

An analysis of subtype determined the decline in the incidence of ST-segment elevation MI lagged significantly behind that of non-STEMI. STEMI declined from 268 in 2019 to 197 in 2020, a 27% reduction, while hospitalizations for non-STEMI went from 350 to 122, a 65% reduction.

The researchers also found substantial reductions in hospitalizations for heart failure, by 47%, and atrial fibrillation, by 53%. Incidentally, the mean age of atrial fibrillation patients was considerably younger in 2020: 64.6 vs. 70 years.
 

Death, complications up

AMI patients who managed to get to the hospital during the pandemic also had worse outcomes. Mortality for STEMI cases more than tripled, to 14% during the outbreak, compared with 4% in 2019 (P < .001) and complication rates increased by 80% to 19% (P = .025). Twenty-one STEMI patients were positive for COVID-19 and more than a quarter (29%) died, which was more than two and a half times the 12% death rate in non–COVID-19 STEMI patients.

Analysis of the STEMI group also found that the care gap for women with heart disease worsened significantly during the pandemic, as they comprised 20.3% of cases this year, compared with 25.4% before the pandemic. Also, the reduction in admissions for STEMI during the pandemic was statistically significant at 41% for women, but not for men at 18%.

Non-STEMI patients fared better overall than STEMI patients, but their outcomes also worsened during the pandemic. Non-STEMI patients were significantly less likely to have percutaneous coronary intervention during the pandemic than previously; the rate declined by 13%, from 77% to 66%. The non-STEMI mortality rate nearly doubled, although not statistically significantly, from 1.7% to 3.3%, whereas complication rates actually more than doubled, from 5.1% to 10.7%, a significant difference. Twelve (9.8%) of the non-STEMI patients were COVID-19 positive, but none died.
 

Trend extends beyond borders

Dr. De Rosa and colleagues noted that their findings are in line with studies that reported similar declines for STEMI interventions in the United States and Spain during the pandemic (J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.011; REC Interv Cardiol. 2020. doi: 10.24875/RECIC.M20000120).

Additionally, a group at Kaiser Permanente in Northern California also reported a 50% decline in the incidence of AMI hospitalizations during the pandemic (N Engl J Med. 2020 May 19. doi: 10.1056/NEJMc2015630). Likewise, a study of aortic dissections in New York reported a sharp decline in procedures during the pandemic in the city, from 13 to 3 a month (J Am Coll Cardiol. 2020 May 15. doi: 10.1016/j.jacc.2020.05.022)

The researchers in Italy didn’t aim to determine the reasons for the decline in AMI hospitalizations, but Dr. De Rosa and colleagues speculated on the following explanations: Fear of contagion in response to media reports, concentration of resources to address COVID-19 may have engendered a sense to defer less urgent care among patients and health care systems, and a true reduction in acute cardiovascular disease because people under stay-at-home orders had low physical stress.

“The concern is fewer MIs most likely means people are dying at home or presenting later as this study suggests,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix, in interpreting the results of the Italian study.

That could be a result of a mixed message from the media about accessing health care during the pandemic. “What it suggests to a lot of us is that the media has transmitted this notion that hospitals are busy taking care of COVID-19 patients, but we never said don’t come to hospital if you’re having a heart attack,” Dr. Gulati said. “I think we created some sort of fear that patients if they didn’t have COVID-19 they didn’t want to bother physicians.”

Dr. Gulati, whose practice focuses on women with CVD, said the study’s findings that interventions in women dropped more precipitously than men were concerning. “We know already that women don’t do as well after a heart attack, compared to men, and now we see it worsen it even further when women aren’t presenting,” she said. “We’re worried that this is going to increase the gap.”

Dr. DeRosa and colleagues have no relevant financial relationships to disclose.

SOURCE: De Rosa S et al. Euro Heart J. 2020 May 15. doi: 10.1093/eurheartj/ehaa409.

Coronavirus disease of 2019 (COVID-19) may lead to subacute thyroiditis in some patients, which is suspected to have viral or postviral origin, especially with upper respiratory tract infections, according to a case study in the Journal of Clinical Endocrinology & Metabolism.

Alessandro Brancatella, a PhD student at the University Hospital Pisa (Italy), and colleagues described the case of an 18-year-old woman who was tested Feb. 21 for SARS-CoV-2 infection after her father was hospitalized because of COVID-19. Her results were positive for the virus, and not long after, she developed mild symptoms. By March 13 and again on March 14, test swabs for SARS-CoV-2 were both negative.

On March 17, she presented with fever, fatigue, palpitations, and neck pain that radiated to her jaw. Testing and physical examination pointed to subacute thyroiditis, and she was soon diagnosed and treated with prednisone. Her neck pain and fever disappeared within 2 days, and the remaining symptoms went away within a week.

The authors noted that the woman’s thyroid had been evaluated before she tested positive for SARS-CoV-2, and at that time, thyroid disease was ruled out. They also pointed out that, although the exact etiology for subacute thyroiditis is unknown, “it is common opinion that the disease is due to a viral infection or to a post-viral inflammatory reaction in genetically predisposed subjects.” They cited examples of viruses with suspected causal associations, including mumps, Epstein-Barr virus, and HIV, and they suggested that, based on the timing of the woman’s subacute thyroiditis and the normal results of her thyroid evaluation before developing COVID-19, SARS-CoV-2 be added to that list.

“To our knowledge, this is the first case of [subacute thyroiditis] related to SARS-CoV-2,” they concluded. “We therefore believe that physicians should be alerted about the possibility of this additional clinical manifestation related to SARS-CoV-2 infection.”

One author reported funding from the University of Pisa.

[email protected]

SOURCE: Brancatella A et al. J Clin Endocrinol Metab. 2020 May 21. doi: 10.1210/clinem/dgaa276.

Coronavirus disease of 2019 (COVID-19) may lead to subacute thyroiditis in some patients, which is suspected to have viral or postviral origin, especially with upper respiratory tract infections, according to a case study in the Journal of Clinical Endocrinology & Metabolism.

Alessandro Brancatella, a PhD student at the University Hospital Pisa (Italy), and colleagues described the case of an 18-year-old woman who was tested Feb. 21 for SARS-CoV-2 infection after her father was hospitalized because of COVID-19. Her results were positive for the virus, and not long after, she developed mild symptoms. By March 13 and again on March 14, test swabs for SARS-CoV-2 were both negative.

On March 17, she presented with fever, fatigue, palpitations, and neck pain that radiated to her jaw. Testing and physical examination pointed to subacute thyroiditis, and she was soon diagnosed and treated with prednisone. Her neck pain and fever disappeared within 2 days, and the remaining symptoms went away within a week.

The authors noted that the woman’s thyroid had been evaluated before she tested positive for SARS-CoV-2, and at that time, thyroid disease was ruled out. They also pointed out that, although the exact etiology for subacute thyroiditis is unknown, “it is common opinion that the disease is due to a viral infection or to a post-viral inflammatory reaction in genetically predisposed subjects.” They cited examples of viruses with suspected causal associations, including mumps, Epstein-Barr virus, and HIV, and they suggested that, based on the timing of the woman’s subacute thyroiditis and the normal results of her thyroid evaluation before developing COVID-19, SARS-CoV-2 be added to that list.

“To our knowledge, this is the first case of [subacute thyroiditis] related to SARS-CoV-2,” they concluded. “We therefore believe that physicians should be alerted about the possibility of this additional clinical manifestation related to SARS-CoV-2 infection.”

One author reported funding from the University of Pisa.

[email protected]

SOURCE: Brancatella A et al. J Clin Endocrinol Metab. 2020 May 21. doi: 10.1210/clinem/dgaa276.

Coronavirus disease of 2019 (COVID-19) may lead to subacute thyroiditis in some patients, which is suspected to have viral or postviral origin, especially with upper respiratory tract infections, according to a case study in the Journal of Clinical Endocrinology & Metabolism.

Alessandro Brancatella, a PhD student at the University Hospital Pisa (Italy), and colleagues described the case of an 18-year-old woman who was tested Feb. 21 for SARS-CoV-2 infection after her father was hospitalized because of COVID-19. Her results were positive for the virus, and not long after, she developed mild symptoms. By March 13 and again on March 14, test swabs for SARS-CoV-2 were both negative.

On March 17, she presented with fever, fatigue, palpitations, and neck pain that radiated to her jaw. Testing and physical examination pointed to subacute thyroiditis, and she was soon diagnosed and treated with prednisone. Her neck pain and fever disappeared within 2 days, and the remaining symptoms went away within a week.

The authors noted that the woman’s thyroid had been evaluated before she tested positive for SARS-CoV-2, and at that time, thyroid disease was ruled out. They also pointed out that, although the exact etiology for subacute thyroiditis is unknown, “it is common opinion that the disease is due to a viral infection or to a post-viral inflammatory reaction in genetically predisposed subjects.” They cited examples of viruses with suspected causal associations, including mumps, Epstein-Barr virus, and HIV, and they suggested that, based on the timing of the woman’s subacute thyroiditis and the normal results of her thyroid evaluation before developing COVID-19, SARS-CoV-2 be added to that list.

“To our knowledge, this is the first case of [subacute thyroiditis] related to SARS-CoV-2,” they concluded. “We therefore believe that physicians should be alerted about the possibility of this additional clinical manifestation related to SARS-CoV-2 infection.”

One author reported funding from the University of Pisa.

[email protected]

SOURCE: Brancatella A et al. J Clin Endocrinol Metab. 2020 May 21. doi: 10.1210/clinem/dgaa276.

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

[email protected]

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

[email protected]

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

[email protected]

The American Heart Association/American Stroke Association has developed a “conceptual framework” to assist emergency medical service (EMS) providers and in-hospital triage teams handle suspected cases of acute stroke during the ongoing COVID-19 crisis and future pandemics. A key goal is to ensure timely transfer of patients while minimizing the risk of infectious exposure for EMS personnel, coworkers, and other patients, the writing group says.

“Acute ischemic stroke is still a highly devastating disease and the Time Is Brain paradigm remains true during the COVID-19 pandemic as well,” said writing group chair Mayank Goyal, MD, of the University of Calgary (Alta.)

“We have highly effective and proven treatments available. As such, treatment delays due to additional screening requirements and personal protection equipment (PPE) should be kept at a minimum,” Dr. Goyal said.

“Practicing COVID-19 stroke work flows, through simulation training, can help to reduce treatment delays, minimize the risk of infectious exposure for patients and staff, and help alleviate stress,” he added.
 

A new layer of complexity

The guidance statement, Prehospital Triage of Acute Stroke Patients During the COVID-19 Pandemic, was published online May 13 in the journal Stroke.

“The need to limit infectious spread during the COVID-19 pandemic has added a new layer of complexity to prehospital stroke triage and transfer,” the writing group noted. “Timely and enhanced” communication between EMS, hospitals, and local coordinating authorities are critical, especially ambulance-and facility-based telestroke networks, they wrote.

The main factors to guide the triage decision are the likelihood of a large vessel occlusion; the magnitude of additional delays because of interhospital transfer and work flow efficiency at the primary stroke center or acute stroke ready hospital; the need for advanced critical care resources; and the available bed, staff, and PPE resources at the hospitals.

The group said it “seems reasonable” to lower the threshold to bypass hospitals that can’t provide acute stroke treatment in favor of transporting to a hospital that is “stroke ready,” particularly in patients likely to require advanced care. They cautioned, however, that taking all acute stroke patients to a comprehensive stroke center could overwhelm these centers and lead to clustering of COVID-19 patients.

They said it is equally important to ensure “necessary transfers” of stroke patients who would benefit from endovascular therapy or neurocritical care and avoid unnecessary patient transfers. “Doing so will likely require local hospital boards and health care authorities to collaborate and establish local guidelines and protocols,” the writing group said.

“During the COVID-19 pandemic, it is more important than ever to ensure that stroke patients are taken to the right hospital that can meet their urgent needs at the outset,” Dr. Goyal commented in an AHA news release.

The writing group emphasized that the principles put forth in the document are intended as suggestions rather than strict rules and will be adapted and updated to meet the evolving needs during the COVID-19 crisis and future pandemics.

“The process of improving stroke work flow and getting the correct patient to the correct hospital fast is dependent on training, protocols, simulation, technology, and – probably most importantly – teamwork. These principles are extremely important during the current pandemic but will be useful in improving stroke care afterwards as well,” Dr. Goyal said.

This research had no commercial funding. Members of the writing committee are on several AHA/ASA Council Science Subcommittees, including the Emergency Neurovascular Care, the Telestroke, and the Neurovascular Intervention committees. Goyal is a consultant for Medtronic, Stryker, Microvention, GE Healthcare, and Mentice. A complete list of author disclosures is available with the original article.

This article first appeared on Medscape.com.

The American Heart Association/American Stroke Association has developed a “conceptual framework” to assist emergency medical service (EMS) providers and in-hospital triage teams handle suspected cases of acute stroke during the ongoing COVID-19 crisis and future pandemics. A key goal is to ensure timely transfer of patients while minimizing the risk of infectious exposure for EMS personnel, coworkers, and other patients, the writing group says.

“Acute ischemic stroke is still a highly devastating disease and the Time Is Brain paradigm remains true during the COVID-19 pandemic as well,” said writing group chair Mayank Goyal, MD, of the University of Calgary (Alta.)

“We have highly effective and proven treatments available. As such, treatment delays due to additional screening requirements and personal protection equipment (PPE) should be kept at a minimum,” Dr. Goyal said.

“Practicing COVID-19 stroke work flows, through simulation training, can help to reduce treatment delays, minimize the risk of infectious exposure for patients and staff, and help alleviate stress,” he added.
 

A new layer of complexity

The guidance statement, Prehospital Triage of Acute Stroke Patients During the COVID-19 Pandemic, was published online May 13 in the journal Stroke.

“The need to limit infectious spread during the COVID-19 pandemic has added a new layer of complexity to prehospital stroke triage and transfer,” the writing group noted. “Timely and enhanced” communication between EMS, hospitals, and local coordinating authorities are critical, especially ambulance-and facility-based telestroke networks, they wrote.

The main factors to guide the triage decision are the likelihood of a large vessel occlusion; the magnitude of additional delays because of interhospital transfer and work flow efficiency at the primary stroke center or acute stroke ready hospital; the need for advanced critical care resources; and the available bed, staff, and PPE resources at the hospitals.

The group said it “seems reasonable” to lower the threshold to bypass hospitals that can’t provide acute stroke treatment in favor of transporting to a hospital that is “stroke ready,” particularly in patients likely to require advanced care. They cautioned, however, that taking all acute stroke patients to a comprehensive stroke center could overwhelm these centers and lead to clustering of COVID-19 patients.

They said it is equally important to ensure “necessary transfers” of stroke patients who would benefit from endovascular therapy or neurocritical care and avoid unnecessary patient transfers. “Doing so will likely require local hospital boards and health care authorities to collaborate and establish local guidelines and protocols,” the writing group said.

“During the COVID-19 pandemic, it is more important than ever to ensure that stroke patients are taken to the right hospital that can meet their urgent needs at the outset,” Dr. Goyal commented in an AHA news release.

The writing group emphasized that the principles put forth in the document are intended as suggestions rather than strict rules and will be adapted and updated to meet the evolving needs during the COVID-19 crisis and future pandemics.

“The process of improving stroke work flow and getting the correct patient to the correct hospital fast is dependent on training, protocols, simulation, technology, and – probably most importantly – teamwork. These principles are extremely important during the current pandemic but will be useful in improving stroke care afterwards as well,” Dr. Goyal said.

This research had no commercial funding. Members of the writing committee are on several AHA/ASA Council Science Subcommittees, including the Emergency Neurovascular Care, the Telestroke, and the Neurovascular Intervention committees. Goyal is a consultant for Medtronic, Stryker, Microvention, GE Healthcare, and Mentice. A complete list of author disclosures is available with the original article.

This article first appeared on Medscape.com.

The American Heart Association/American Stroke Association has developed a “conceptual framework” to assist emergency medical service (EMS) providers and in-hospital triage teams handle suspected cases of acute stroke during the ongoing COVID-19 crisis and future pandemics. A key goal is to ensure timely transfer of patients while minimizing the risk of infectious exposure for EMS personnel, coworkers, and other patients, the writing group says.

“Acute ischemic stroke is still a highly devastating disease and the Time Is Brain paradigm remains true during the COVID-19 pandemic as well,” said writing group chair Mayank Goyal, MD, of the University of Calgary (Alta.)

“We have highly effective and proven treatments available. As such, treatment delays due to additional screening requirements and personal protection equipment (PPE) should be kept at a minimum,” Dr. Goyal said.

“Practicing COVID-19 stroke work flows, through simulation training, can help to reduce treatment delays, minimize the risk of infectious exposure for patients and staff, and help alleviate stress,” he added.
 

A new layer of complexity

The guidance statement, Prehospital Triage of Acute Stroke Patients During the COVID-19 Pandemic, was published online May 13 in the journal Stroke.

“The need to limit infectious spread during the COVID-19 pandemic has added a new layer of complexity to prehospital stroke triage and transfer,” the writing group noted. “Timely and enhanced” communication between EMS, hospitals, and local coordinating authorities are critical, especially ambulance-and facility-based telestroke networks, they wrote.

The main factors to guide the triage decision are the likelihood of a large vessel occlusion; the magnitude of additional delays because of interhospital transfer and work flow efficiency at the primary stroke center or acute stroke ready hospital; the need for advanced critical care resources; and the available bed, staff, and PPE resources at the hospitals.

The group said it “seems reasonable” to lower the threshold to bypass hospitals that can’t provide acute stroke treatment in favor of transporting to a hospital that is “stroke ready,” particularly in patients likely to require advanced care. They cautioned, however, that taking all acute stroke patients to a comprehensive stroke center could overwhelm these centers and lead to clustering of COVID-19 patients.

They said it is equally important to ensure “necessary transfers” of stroke patients who would benefit from endovascular therapy or neurocritical care and avoid unnecessary patient transfers. “Doing so will likely require local hospital boards and health care authorities to collaborate and establish local guidelines and protocols,” the writing group said.

“During the COVID-19 pandemic, it is more important than ever to ensure that stroke patients are taken to the right hospital that can meet their urgent needs at the outset,” Dr. Goyal commented in an AHA news release.

The writing group emphasized that the principles put forth in the document are intended as suggestions rather than strict rules and will be adapted and updated to meet the evolving needs during the COVID-19 crisis and future pandemics.

“The process of improving stroke work flow and getting the correct patient to the correct hospital fast is dependent on training, protocols, simulation, technology, and – probably most importantly – teamwork. These principles are extremely important during the current pandemic but will be useful in improving stroke care afterwards as well,” Dr. Goyal said.

This research had no commercial funding. Members of the writing committee are on several AHA/ASA Council Science Subcommittees, including the Emergency Neurovascular Care, the Telestroke, and the Neurovascular Intervention committees. Goyal is a consultant for Medtronic, Stryker, Microvention, GE Healthcare, and Mentice. A complete list of author disclosures is available with the original article.

This article first appeared on Medscape.com.