Pulmonary Health Hub

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

On Jan. 13, 2 days after a drive-through vaccination “superstation” opened in San Diego, six people were treated for anaphylaxis after they received the Moderna vaccine, leading the California state epidemiologist to recommend pausing the administration of that particular lot.
 

A group of allergy and immunology experts and public health officials reviewed the cases, as well as an incident that occurred the day before, and concluded that at least some of the responses were angioedema, or swelling — a serious allergic reaction — but none were actually anaphylaxis. No similar clusters had occurred with the same vaccine lot in other states, and California resumed using the doses.

Yet questions remain about the reactions and the mechanisms for them. Some might have been triggered by an allergy to a vaccine component, most likely the polyethylene glycol (PEG) that stabilizes the lipid surrounding the mRNA, the key vaccine component in both the Moderna and Pfizer vaccines. Another possible explanation is that some could be pseudoallergic reactions to a blood protein known as complement, a little-understood process that resembles an antigen-based reaction but doesn’t leave an immune memory and might not recur.

Cases of complement-activation-related pseudoallergy look like a severe allergic reaction but occur through a different mechanism and don’t require previous exposure to an allergen.

“It has the same signs and symptoms and is treated the same way, but it occurs through a different pathway,” explained Neal Halsey, MD, director emeritus of the Institute for Vaccine Safety and emeritus professor at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

Pseudoallergies are not well understood, but they have been associated with reactions to the contrast media used in imaging, such as with MRI. “If people have had an anaphylaxis-type reaction following the injection of contrast-dye material, that is a strong signal that it might be a complement-activation-related pseudoallergy,” said Dr. Halsey, a member of the Clinical Immunization Safety Assessment Network. “Those are the people who definitely need to consider seeing an allergist before getting the COVID vaccines.”

When Aleena Banerji, MD, clinical director of the allergy and clinical immunology unit at Massachusetts General Hospital in Boston, talks to patients about vaccine reactions, she addresses the risk for COVID-19 infection. All of the people who developed allergies after the Pfizer and Moderna vaccines recovered, but more than 445,000 Americans have died from COVID-19.

Most people with common allergies, such as to food or oral medications, don’t need to worry about reactions, said Dr. Banerji, lead author of a review that assessed the risk for allergic reactions to the Pfizer and Moderna vaccines.
 

Investigating reactions

As investigators search for the answers to what causes reactions, transparency is crucial to trust, said Kathryn Edwards, MD, principal investigator of the Clinical Immunization Safety Assessment Project, a vaccine safety network funded by the Centers for Disease Control and Prevention.

“Unless the public knows that we’re really investigating and we’re taking this seriously, then I think the vaccine hesitancy is going to increase,” said Dr. Edwards, professor of pediatrics at Vanderbilt University Medical Center and scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn.

First reports of anaphylaxis came quickly after COVID-19 vaccinations began. In the 2 weeks before the holidays, almost 2 million health care workers received the Pfizer vaccine, and 21 of them developed anaphylaxis, according to CDC researchers who reviewed case reports from the Vaccine Adverse Event Reporting System (VAERS). That rate of about 1 in 100,000 is 10 times higher than the occurrence with other vaccines. No deaths from anaphylaxis were reported.

As the vaccinations ramped up, the rate declined. As of Jan. 18, 50 cases of anaphylaxis were reported to VAERS after the administration of 9,943,247 Pfizer doses, for a rate of 5.0 per million, according to data presented at the Jan. 27 meeting of the CDC Advisory Committee on Immunization Practices. And 21 cases of anaphylaxis were reported to VAERS after the administration of 7,581,429 Moderna doses, for a rate of 2.8 per million.

The anaphylaxis occurred almost exclusively in women; only three of the VAERS anaphylaxis reports were from men. Only 24% had a history of anaphylaxis.

The earlier CDC report explored the potential link to allergies. One person with anaphylaxis had a history of allergy to iodinated contrast media, and others had allergies to various medications, vaccines, foods, and animals. The researchers reported 86 nonanaphylaxis allergic reactions and 61 nonallergic adverse events among the 175 case reports they reviewed as possible cases of severe allergic reaction.

Of 1,266 reports that VAERS received from Dec. 21 to Jan. 10, the CDC identified 108 possible cases of severe allergic reaction after the Moderna vaccine. Only 10 met the case definition of anaphylaxis put forward by the Brighton Collaboration, a vaccine safety organization. All but one case involved a history of allergies or allergic reactions; only five had a previously experienced anaphylaxis.

There were 47 nonanaphylaxis allergic reactions.

The San Diego cluster also met the Brighton case definition for anaphylaxis, Dr. Edwards reported. This discrepancy highlights the difficulties in characterizing vaccine reactions.

Measuring a pseudoallergic reaction is a challenge. It requires that a blood sample be drawn soon after the incident and then frozen to protect heat-sensitive blood markers, Dr. Edwards explained.

And as vaccinations rise, so do adverse-event reports. But unlike in clinical trials, there is no control group for comparison. That is why vaccine safety experts urge caution when evaluating events and, where possible, advise looking at background rates.

“A major way to determine whether the adverse event is causally related is to assess the incidence of the adverse event in vaccines versus nonvaccines,” said Walter Orenstein, MD, who directed the U.S. Immunization Program from 1988 to 2004 and is now associate director of the Emory Vaccine Center and professor of infectious diseases at Emory University in Atlanta. Public health officials could then identify vaccine risk factors, he said.

When a reaction occurs almost immediately after vaccination, vaccine safety investigators look for probable triggers. If allergy to PEG is the culprit in anaphylactic reactions, then the individuals would have had a previous exposure, perhaps from injectable medications, Dr. Edwards said.

It might be feasible to perform a skin test for allergy to PEG. “If the skin testing is negative, that doesn’t completely rule out allergy, but it can be used in the decision-making about giving the first or second vaccine dose,” Dr. Banerji said.

Other vaccines, such as childhood vaccines, contain polysorbate as a stabilizer, which has a similar chemical structure, and it’s not clear why someone would react to PEG but not to polysorbate, Dr. Edwards said.

Meanwhile, other illnesses and even deaths sometimes occur in the days after vaccination, but that doesn’t mean the vaccine caused them, cautioned Steve Black, MD, emeritus professor of pediatrics at Cincinnati Children’s Hospital and cofounder of the Global Vaccine Data Network, an international vaccine safety collaboration.

“Different events and clusters of events will occur by chance alone, as these events can occur without vaccines. We need to not immediately assume that they’re due to the vaccine,” he said. “You don’t want to undermine the whole vaccine program every time something comes up and assume that it’s associated with the vaccine.”

The CDC only has three contraindications for the vaccines:

• Severe allergic reaction (such as anaphylaxis) after a previous dose of an mRNA COVID-19 vaccine or any of its components.
• Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG).
• Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with PEG).

People who have had an immediate allergic reaction to other vaccines or injectable therapies should consider consulting with an allergist or immunologist before getting the Pfizer or Moderna vaccines, the CDC advises.

The CDC also says that people with a history of anaphylaxis from any cause should be observed for 30 minutes after vaccination. Vaccination protocol calls for everyone else to wait on site for 15 minutes after vaccination.

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

On Jan. 13, 2 days after a drive-through vaccination “superstation” opened in San Diego, six people were treated for anaphylaxis after they received the Moderna vaccine, leading the California state epidemiologist to recommend pausing the administration of that particular lot.
 

A group of allergy and immunology experts and public health officials reviewed the cases, as well as an incident that occurred the day before, and concluded that at least some of the responses were angioedema, or swelling — a serious allergic reaction — but none were actually anaphylaxis. No similar clusters had occurred with the same vaccine lot in other states, and California resumed using the doses.

Yet questions remain about the reactions and the mechanisms for them. Some might have been triggered by an allergy to a vaccine component, most likely the polyethylene glycol (PEG) that stabilizes the lipid surrounding the mRNA, the key vaccine component in both the Moderna and Pfizer vaccines. Another possible explanation is that some could be pseudoallergic reactions to a blood protein known as complement, a little-understood process that resembles an antigen-based reaction but doesn’t leave an immune memory and might not recur.

Cases of complement-activation-related pseudoallergy look like a severe allergic reaction but occur through a different mechanism and don’t require previous exposure to an allergen.

“It has the same signs and symptoms and is treated the same way, but it occurs through a different pathway,” explained Neal Halsey, MD, director emeritus of the Institute for Vaccine Safety and emeritus professor at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

Pseudoallergies are not well understood, but they have been associated with reactions to the contrast media used in imaging, such as with MRI. “If people have had an anaphylaxis-type reaction following the injection of contrast-dye material, that is a strong signal that it might be a complement-activation-related pseudoallergy,” said Dr. Halsey, a member of the Clinical Immunization Safety Assessment Network. “Those are the people who definitely need to consider seeing an allergist before getting the COVID vaccines.”

When Aleena Banerji, MD, clinical director of the allergy and clinical immunology unit at Massachusetts General Hospital in Boston, talks to patients about vaccine reactions, she addresses the risk for COVID-19 infection. All of the people who developed allergies after the Pfizer and Moderna vaccines recovered, but more than 445,000 Americans have died from COVID-19.

Most people with common allergies, such as to food or oral medications, don’t need to worry about reactions, said Dr. Banerji, lead author of a review that assessed the risk for allergic reactions to the Pfizer and Moderna vaccines.
 

Investigating reactions

As investigators search for the answers to what causes reactions, transparency is crucial to trust, said Kathryn Edwards, MD, principal investigator of the Clinical Immunization Safety Assessment Project, a vaccine safety network funded by the Centers for Disease Control and Prevention.

“Unless the public knows that we’re really investigating and we’re taking this seriously, then I think the vaccine hesitancy is going to increase,” said Dr. Edwards, professor of pediatrics at Vanderbilt University Medical Center and scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn.

First reports of anaphylaxis came quickly after COVID-19 vaccinations began. In the 2 weeks before the holidays, almost 2 million health care workers received the Pfizer vaccine, and 21 of them developed anaphylaxis, according to CDC researchers who reviewed case reports from the Vaccine Adverse Event Reporting System (VAERS). That rate of about 1 in 100,000 is 10 times higher than the occurrence with other vaccines. No deaths from anaphylaxis were reported.

As the vaccinations ramped up, the rate declined. As of Jan. 18, 50 cases of anaphylaxis were reported to VAERS after the administration of 9,943,247 Pfizer doses, for a rate of 5.0 per million, according to data presented at the Jan. 27 meeting of the CDC Advisory Committee on Immunization Practices. And 21 cases of anaphylaxis were reported to VAERS after the administration of 7,581,429 Moderna doses, for a rate of 2.8 per million.

The anaphylaxis occurred almost exclusively in women; only three of the VAERS anaphylaxis reports were from men. Only 24% had a history of anaphylaxis.

The earlier CDC report explored the potential link to allergies. One person with anaphylaxis had a history of allergy to iodinated contrast media, and others had allergies to various medications, vaccines, foods, and animals. The researchers reported 86 nonanaphylaxis allergic reactions and 61 nonallergic adverse events among the 175 case reports they reviewed as possible cases of severe allergic reaction.

Of 1,266 reports that VAERS received from Dec. 21 to Jan. 10, the CDC identified 108 possible cases of severe allergic reaction after the Moderna vaccine. Only 10 met the case definition of anaphylaxis put forward by the Brighton Collaboration, a vaccine safety organization. All but one case involved a history of allergies or allergic reactions; only five had a previously experienced anaphylaxis.

There were 47 nonanaphylaxis allergic reactions.

The San Diego cluster also met the Brighton case definition for anaphylaxis, Dr. Edwards reported. This discrepancy highlights the difficulties in characterizing vaccine reactions.

Measuring a pseudoallergic reaction is a challenge. It requires that a blood sample be drawn soon after the incident and then frozen to protect heat-sensitive blood markers, Dr. Edwards explained.

And as vaccinations rise, so do adverse-event reports. But unlike in clinical trials, there is no control group for comparison. That is why vaccine safety experts urge caution when evaluating events and, where possible, advise looking at background rates.

“A major way to determine whether the adverse event is causally related is to assess the incidence of the adverse event in vaccines versus nonvaccines,” said Walter Orenstein, MD, who directed the U.S. Immunization Program from 1988 to 2004 and is now associate director of the Emory Vaccine Center and professor of infectious diseases at Emory University in Atlanta. Public health officials could then identify vaccine risk factors, he said.

When a reaction occurs almost immediately after vaccination, vaccine safety investigators look for probable triggers. If allergy to PEG is the culprit in anaphylactic reactions, then the individuals would have had a previous exposure, perhaps from injectable medications, Dr. Edwards said.

It might be feasible to perform a skin test for allergy to PEG. “If the skin testing is negative, that doesn’t completely rule out allergy, but it can be used in the decision-making about giving the first or second vaccine dose,” Dr. Banerji said.

Other vaccines, such as childhood vaccines, contain polysorbate as a stabilizer, which has a similar chemical structure, and it’s not clear why someone would react to PEG but not to polysorbate, Dr. Edwards said.

Meanwhile, other illnesses and even deaths sometimes occur in the days after vaccination, but that doesn’t mean the vaccine caused them, cautioned Steve Black, MD, emeritus professor of pediatrics at Cincinnati Children’s Hospital and cofounder of the Global Vaccine Data Network, an international vaccine safety collaboration.

“Different events and clusters of events will occur by chance alone, as these events can occur without vaccines. We need to not immediately assume that they’re due to the vaccine,” he said. “You don’t want to undermine the whole vaccine program every time something comes up and assume that it’s associated with the vaccine.”

The CDC only has three contraindications for the vaccines:

• Severe allergic reaction (such as anaphylaxis) after a previous dose of an mRNA COVID-19 vaccine or any of its components.
• Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG).
• Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with PEG).

People who have had an immediate allergic reaction to other vaccines or injectable therapies should consider consulting with an allergist or immunologist before getting the Pfizer or Moderna vaccines, the CDC advises.

The CDC also says that people with a history of anaphylaxis from any cause should be observed for 30 minutes after vaccination. Vaccination protocol calls for everyone else to wait on site for 15 minutes after vaccination.

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

On Jan. 13, 2 days after a drive-through vaccination “superstation” opened in San Diego, six people were treated for anaphylaxis after they received the Moderna vaccine, leading the California state epidemiologist to recommend pausing the administration of that particular lot.
 

A group of allergy and immunology experts and public health officials reviewed the cases, as well as an incident that occurred the day before, and concluded that at least some of the responses were angioedema, or swelling — a serious allergic reaction — but none were actually anaphylaxis. No similar clusters had occurred with the same vaccine lot in other states, and California resumed using the doses.

Yet questions remain about the reactions and the mechanisms for them. Some might have been triggered by an allergy to a vaccine component, most likely the polyethylene glycol (PEG) that stabilizes the lipid surrounding the mRNA, the key vaccine component in both the Moderna and Pfizer vaccines. Another possible explanation is that some could be pseudoallergic reactions to a blood protein known as complement, a little-understood process that resembles an antigen-based reaction but doesn’t leave an immune memory and might not recur.

Cases of complement-activation-related pseudoallergy look like a severe allergic reaction but occur through a different mechanism and don’t require previous exposure to an allergen.

“It has the same signs and symptoms and is treated the same way, but it occurs through a different pathway,” explained Neal Halsey, MD, director emeritus of the Institute for Vaccine Safety and emeritus professor at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

Pseudoallergies are not well understood, but they have been associated with reactions to the contrast media used in imaging, such as with MRI. “If people have had an anaphylaxis-type reaction following the injection of contrast-dye material, that is a strong signal that it might be a complement-activation-related pseudoallergy,” said Dr. Halsey, a member of the Clinical Immunization Safety Assessment Network. “Those are the people who definitely need to consider seeing an allergist before getting the COVID vaccines.”

When Aleena Banerji, MD, clinical director of the allergy and clinical immunology unit at Massachusetts General Hospital in Boston, talks to patients about vaccine reactions, she addresses the risk for COVID-19 infection. All of the people who developed allergies after the Pfizer and Moderna vaccines recovered, but more than 445,000 Americans have died from COVID-19.

Most people with common allergies, such as to food or oral medications, don’t need to worry about reactions, said Dr. Banerji, lead author of a review that assessed the risk for allergic reactions to the Pfizer and Moderna vaccines.
 

Investigating reactions

As investigators search for the answers to what causes reactions, transparency is crucial to trust, said Kathryn Edwards, MD, principal investigator of the Clinical Immunization Safety Assessment Project, a vaccine safety network funded by the Centers for Disease Control and Prevention.

“Unless the public knows that we’re really investigating and we’re taking this seriously, then I think the vaccine hesitancy is going to increase,” said Dr. Edwards, professor of pediatrics at Vanderbilt University Medical Center and scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn.

First reports of anaphylaxis came quickly after COVID-19 vaccinations began. In the 2 weeks before the holidays, almost 2 million health care workers received the Pfizer vaccine, and 21 of them developed anaphylaxis, according to CDC researchers who reviewed case reports from the Vaccine Adverse Event Reporting System (VAERS). That rate of about 1 in 100,000 is 10 times higher than the occurrence with other vaccines. No deaths from anaphylaxis were reported.

As the vaccinations ramped up, the rate declined. As of Jan. 18, 50 cases of anaphylaxis were reported to VAERS after the administration of 9,943,247 Pfizer doses, for a rate of 5.0 per million, according to data presented at the Jan. 27 meeting of the CDC Advisory Committee on Immunization Practices. And 21 cases of anaphylaxis were reported to VAERS after the administration of 7,581,429 Moderna doses, for a rate of 2.8 per million.

The anaphylaxis occurred almost exclusively in women; only three of the VAERS anaphylaxis reports were from men. Only 24% had a history of anaphylaxis.

The earlier CDC report explored the potential link to allergies. One person with anaphylaxis had a history of allergy to iodinated contrast media, and others had allergies to various medications, vaccines, foods, and animals. The researchers reported 86 nonanaphylaxis allergic reactions and 61 nonallergic adverse events among the 175 case reports they reviewed as possible cases of severe allergic reaction.

Of 1,266 reports that VAERS received from Dec. 21 to Jan. 10, the CDC identified 108 possible cases of severe allergic reaction after the Moderna vaccine. Only 10 met the case definition of anaphylaxis put forward by the Brighton Collaboration, a vaccine safety organization. All but one case involved a history of allergies or allergic reactions; only five had a previously experienced anaphylaxis.

There were 47 nonanaphylaxis allergic reactions.

The San Diego cluster also met the Brighton case definition for anaphylaxis, Dr. Edwards reported. This discrepancy highlights the difficulties in characterizing vaccine reactions.

Measuring a pseudoallergic reaction is a challenge. It requires that a blood sample be drawn soon after the incident and then frozen to protect heat-sensitive blood markers, Dr. Edwards explained.

And as vaccinations rise, so do adverse-event reports. But unlike in clinical trials, there is no control group for comparison. That is why vaccine safety experts urge caution when evaluating events and, where possible, advise looking at background rates.

“A major way to determine whether the adverse event is causally related is to assess the incidence of the adverse event in vaccines versus nonvaccines,” said Walter Orenstein, MD, who directed the U.S. Immunization Program from 1988 to 2004 and is now associate director of the Emory Vaccine Center and professor of infectious diseases at Emory University in Atlanta. Public health officials could then identify vaccine risk factors, he said.

When a reaction occurs almost immediately after vaccination, vaccine safety investigators look for probable triggers. If allergy to PEG is the culprit in anaphylactic reactions, then the individuals would have had a previous exposure, perhaps from injectable medications, Dr. Edwards said.

It might be feasible to perform a skin test for allergy to PEG. “If the skin testing is negative, that doesn’t completely rule out allergy, but it can be used in the decision-making about giving the first or second vaccine dose,” Dr. Banerji said.

Other vaccines, such as childhood vaccines, contain polysorbate as a stabilizer, which has a similar chemical structure, and it’s not clear why someone would react to PEG but not to polysorbate, Dr. Edwards said.

Meanwhile, other illnesses and even deaths sometimes occur in the days after vaccination, but that doesn’t mean the vaccine caused them, cautioned Steve Black, MD, emeritus professor of pediatrics at Cincinnati Children’s Hospital and cofounder of the Global Vaccine Data Network, an international vaccine safety collaboration.

“Different events and clusters of events will occur by chance alone, as these events can occur without vaccines. We need to not immediately assume that they’re due to the vaccine,” he said. “You don’t want to undermine the whole vaccine program every time something comes up and assume that it’s associated with the vaccine.”

The CDC only has three contraindications for the vaccines:

• Severe allergic reaction (such as anaphylaxis) after a previous dose of an mRNA COVID-19 vaccine or any of its components.
• Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG).
• Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with PEG).

People who have had an immediate allergic reaction to other vaccines or injectable therapies should consider consulting with an allergist or immunologist before getting the Pfizer or Moderna vaccines, the CDC advises.

The CDC also says that people with a history of anaphylaxis from any cause should be observed for 30 minutes after vaccination. Vaccination protocol calls for everyone else to wait on site for 15 minutes after vaccination.

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

Aerosolized high-molecular-weight hyaluronan (HMW-HA) may improve acute exacerbations of chronic obstructive pulmonary disease (COPD), findings of a new study suggest.

HMW-HA was associated with a significantly shorter duration of noninvasive positive-pressure ventilation (NIPPV), lower systemic inflammatory markers, and lower measured peak airway pressure, compared with placebo, reported lead author Flavia Galdi, MD, of Campus Bio-Medico University Hospital, Rome, and colleagues.

“HMW-HA is a naturally occurring sugar that is abundant in the extracellular matrix, including in the lung,” the investigators wrote in Respiratory Research. “[It] has been used routinely, together with hypertonic saline, in cystic fibrosis patients [for several years] with no reported side effects; rather, it improves tolerability and decreases the need for bronchodilators in these patients.”

According to Robert A. Sandhaus, MD, PhD, FCCP, of National Jewish Health, Denver, the role of hyaluronan in lung disease was first recognized decades ago.

“Data stretching back into the 1970s has identified decreases in hyaluronan content in emphysematous lung tissue, protection of lung connective tissue from proteolysis by hyaluronan, and potential therapeutic roles for hyaluronan in a variety of disease, especially of the lungs,” he said in an interview.

For patients with COPD, treatment with HMW-HA may provide benefit by counteracting an imbalance in diseased lung tissue, wrote Dr. Galdi and colleagues.

“Emerging evidence suggests that imbalance between declining HMW-HA levels, and increasing smaller fragments of hyaluronan may contribute to chronic airway disease pathogenesis,” they wrote. “This has led to the hypothesis that exogenous supplementation of HMW-HA may restore hyaluronan homeostasis in favor of undegraded molecules, inhibit inflammation and loss of lung function, and ameliorate COPD progression.”

To test this hypothesis, the investigators screened 44 patients with a history of acute exacerbations of COPD necessitating NIPPV, ultimately excluding 3 patients because of heart failure. Following 1:1 randomization, 20 patients received HMW-HA while 21 received placebo, each twice daily, in conjunction with NIPPV and standard medical therapy. Treatment continued until NIPPV failure or liberation from NIPPV. Most patients received NIPPV in the hospital; however, home/chronic NIPPV was given to four patients in the placebo group and three patients in the HMW-HA group.

The primary outcome was duration of NIPPV. Secondary outcomes included markers of systemic inflammation associated with acute exacerbations of COPD and respiratory physiology parameters. Adverse events were also reported.

Results showed that patients treated with HMW-HA were liberated sooner from NIPPV than were those who received placebo (mean, 5.2 vs 6.4 days; P < .037). Similarly, patients in the HMW-HA group had significantly shorter hospital stay, on average, than those in the placebo group (mean, 7.2 vs 10.2 days; P = .039). Median values followed a similar pattern.

“These data suggest that HMW-HA shortened the duration of acute respiratory failure, need for NIPPV and, consequently, hospital length of stay in these patients,” the investigators wrote.

Secondary outcomes further supported these therapeutic benefits. Compared with placebo, HMW-HA was associated with significantly lower peak pressure and greater improvements in both pCO2/FiO2 ratio and inflammatory markers. No adverse events were reported.

Further analyses involving human bronchial epithelial cell cultures offered some mechanistic insight. Using micro-optical coherence tomography imaging, the investigators found that HMW-HA treatment was associated with “a prominent effect on mucociliary transport” in cell cultures derived from COPD patients and in healthy nonsmoker cell cultures exposed to cigarette smoke extract.

“Our study shows for the first time the therapeutic potential of an extracellular matrix molecule in acute exacerbation of human lung disease,” the investigators concluded, noting a “clinically meaningful salutary effect” on duration of NIPPV.

Dr. Galdi and colleagues went on to predict that benefits in a real-world patient population could be even more meaningful.

“Since the serum samples were collected at the end of NIPPV, HMW-HA–treated patients were on average sampled a day earlier than placebo-treated patients (because they were liberated from NIPPV a day earlier on average),” the investigators wrote. “Thus, HMW-HA treatment effects may have been underestimated in our study.”

According to Dr. Sandhaus, “The current report, while a relatively small single-center study, is well controlled and the results suggest that inhaled hyaluronan decreased time on noninvasive ventilation, decreased hospital stay duration, and decreased some mediators of inflammation.”

He also suggested that HMW-HA may have a role in the prophylactic setting.

“The limitations of this pilot study are appropriately explored by the authors but do not dampen the exciting possibility that this therapeutic approach may hold promise not only in severe exacerbations of COPD but potentially for the prevention of such exacerbations,” Dr. Sandhaus said.

Jerome O. Cantor, MD, FCCP, of St. John’s University, New York, who previously conducted a pilot study for using lower molecular weight hyaluronan in COPD and published a review on the subject, said that more studies are necessary.

“Further clinical trials are needed to better determine the role of hyaluronan as an adjunct to existing therapies for COPD exacerbations,” he said.

The study was supported by the National Institutes of Health. The investigators and Dr. Sandhaus declared no conflicts of interest. Dr. Cantor disclosed a relationship with MatRx Therapeutics.

Aerosolized high-molecular-weight hyaluronan (HMW-HA) may improve acute exacerbations of chronic obstructive pulmonary disease (COPD), findings of a new study suggest.

HMW-HA was associated with a significantly shorter duration of noninvasive positive-pressure ventilation (NIPPV), lower systemic inflammatory markers, and lower measured peak airway pressure, compared with placebo, reported lead author Flavia Galdi, MD, of Campus Bio-Medico University Hospital, Rome, and colleagues.

“HMW-HA is a naturally occurring sugar that is abundant in the extracellular matrix, including in the lung,” the investigators wrote in Respiratory Research. “[It] has been used routinely, together with hypertonic saline, in cystic fibrosis patients [for several years] with no reported side effects; rather, it improves tolerability and decreases the need for bronchodilators in these patients.”

According to Robert A. Sandhaus, MD, PhD, FCCP, of National Jewish Health, Denver, the role of hyaluronan in lung disease was first recognized decades ago.

“Data stretching back into the 1970s has identified decreases in hyaluronan content in emphysematous lung tissue, protection of lung connective tissue from proteolysis by hyaluronan, and potential therapeutic roles for hyaluronan in a variety of disease, especially of the lungs,” he said in an interview.

For patients with COPD, treatment with HMW-HA may provide benefit by counteracting an imbalance in diseased lung tissue, wrote Dr. Galdi and colleagues.

“Emerging evidence suggests that imbalance between declining HMW-HA levels, and increasing smaller fragments of hyaluronan may contribute to chronic airway disease pathogenesis,” they wrote. “This has led to the hypothesis that exogenous supplementation of HMW-HA may restore hyaluronan homeostasis in favor of undegraded molecules, inhibit inflammation and loss of lung function, and ameliorate COPD progression.”

To test this hypothesis, the investigators screened 44 patients with a history of acute exacerbations of COPD necessitating NIPPV, ultimately excluding 3 patients because of heart failure. Following 1:1 randomization, 20 patients received HMW-HA while 21 received placebo, each twice daily, in conjunction with NIPPV and standard medical therapy. Treatment continued until NIPPV failure or liberation from NIPPV. Most patients received NIPPV in the hospital; however, home/chronic NIPPV was given to four patients in the placebo group and three patients in the HMW-HA group.

The primary outcome was duration of NIPPV. Secondary outcomes included markers of systemic inflammation associated with acute exacerbations of COPD and respiratory physiology parameters. Adverse events were also reported.

Results showed that patients treated with HMW-HA were liberated sooner from NIPPV than were those who received placebo (mean, 5.2 vs 6.4 days; P < .037). Similarly, patients in the HMW-HA group had significantly shorter hospital stay, on average, than those in the placebo group (mean, 7.2 vs 10.2 days; P = .039). Median values followed a similar pattern.

“These data suggest that HMW-HA shortened the duration of acute respiratory failure, need for NIPPV and, consequently, hospital length of stay in these patients,” the investigators wrote.

Secondary outcomes further supported these therapeutic benefits. Compared with placebo, HMW-HA was associated with significantly lower peak pressure and greater improvements in both pCO2/FiO2 ratio and inflammatory markers. No adverse events were reported.

Further analyses involving human bronchial epithelial cell cultures offered some mechanistic insight. Using micro-optical coherence tomography imaging, the investigators found that HMW-HA treatment was associated with “a prominent effect on mucociliary transport” in cell cultures derived from COPD patients and in healthy nonsmoker cell cultures exposed to cigarette smoke extract.

“Our study shows for the first time the therapeutic potential of an extracellular matrix molecule in acute exacerbation of human lung disease,” the investigators concluded, noting a “clinically meaningful salutary effect” on duration of NIPPV.

Dr. Galdi and colleagues went on to predict that benefits in a real-world patient population could be even more meaningful.

“Since the serum samples were collected at the end of NIPPV, HMW-HA–treated patients were on average sampled a day earlier than placebo-treated patients (because they were liberated from NIPPV a day earlier on average),” the investigators wrote. “Thus, HMW-HA treatment effects may have been underestimated in our study.”

According to Dr. Sandhaus, “The current report, while a relatively small single-center study, is well controlled and the results suggest that inhaled hyaluronan decreased time on noninvasive ventilation, decreased hospital stay duration, and decreased some mediators of inflammation.”

He also suggested that HMW-HA may have a role in the prophylactic setting.

“The limitations of this pilot study are appropriately explored by the authors but do not dampen the exciting possibility that this therapeutic approach may hold promise not only in severe exacerbations of COPD but potentially for the prevention of such exacerbations,” Dr. Sandhaus said.

Jerome O. Cantor, MD, FCCP, of St. John’s University, New York, who previously conducted a pilot study for using lower molecular weight hyaluronan in COPD and published a review on the subject, said that more studies are necessary.

“Further clinical trials are needed to better determine the role of hyaluronan as an adjunct to existing therapies for COPD exacerbations,” he said.

The study was supported by the National Institutes of Health. The investigators and Dr. Sandhaus declared no conflicts of interest. Dr. Cantor disclosed a relationship with MatRx Therapeutics.

Aerosolized high-molecular-weight hyaluronan (HMW-HA) may improve acute exacerbations of chronic obstructive pulmonary disease (COPD), findings of a new study suggest.

HMW-HA was associated with a significantly shorter duration of noninvasive positive-pressure ventilation (NIPPV), lower systemic inflammatory markers, and lower measured peak airway pressure, compared with placebo, reported lead author Flavia Galdi, MD, of Campus Bio-Medico University Hospital, Rome, and colleagues.

“HMW-HA is a naturally occurring sugar that is abundant in the extracellular matrix, including in the lung,” the investigators wrote in Respiratory Research. “[It] has been used routinely, together with hypertonic saline, in cystic fibrosis patients [for several years] with no reported side effects; rather, it improves tolerability and decreases the need for bronchodilators in these patients.”

According to Robert A. Sandhaus, MD, PhD, FCCP, of National Jewish Health, Denver, the role of hyaluronan in lung disease was first recognized decades ago.

“Data stretching back into the 1970s has identified decreases in hyaluronan content in emphysematous lung tissue, protection of lung connective tissue from proteolysis by hyaluronan, and potential therapeutic roles for hyaluronan in a variety of disease, especially of the lungs,” he said in an interview.

For patients with COPD, treatment with HMW-HA may provide benefit by counteracting an imbalance in diseased lung tissue, wrote Dr. Galdi and colleagues.

“Emerging evidence suggests that imbalance between declining HMW-HA levels, and increasing smaller fragments of hyaluronan may contribute to chronic airway disease pathogenesis,” they wrote. “This has led to the hypothesis that exogenous supplementation of HMW-HA may restore hyaluronan homeostasis in favor of undegraded molecules, inhibit inflammation and loss of lung function, and ameliorate COPD progression.”

To test this hypothesis, the investigators screened 44 patients with a history of acute exacerbations of COPD necessitating NIPPV, ultimately excluding 3 patients because of heart failure. Following 1:1 randomization, 20 patients received HMW-HA while 21 received placebo, each twice daily, in conjunction with NIPPV and standard medical therapy. Treatment continued until NIPPV failure or liberation from NIPPV. Most patients received NIPPV in the hospital; however, home/chronic NIPPV was given to four patients in the placebo group and three patients in the HMW-HA group.

The primary outcome was duration of NIPPV. Secondary outcomes included markers of systemic inflammation associated with acute exacerbations of COPD and respiratory physiology parameters. Adverse events were also reported.

Results showed that patients treated with HMW-HA were liberated sooner from NIPPV than were those who received placebo (mean, 5.2 vs 6.4 days; P < .037). Similarly, patients in the HMW-HA group had significantly shorter hospital stay, on average, than those in the placebo group (mean, 7.2 vs 10.2 days; P = .039). Median values followed a similar pattern.

“These data suggest that HMW-HA shortened the duration of acute respiratory failure, need for NIPPV and, consequently, hospital length of stay in these patients,” the investigators wrote.

Secondary outcomes further supported these therapeutic benefits. Compared with placebo, HMW-HA was associated with significantly lower peak pressure and greater improvements in both pCO2/FiO2 ratio and inflammatory markers. No adverse events were reported.

Further analyses involving human bronchial epithelial cell cultures offered some mechanistic insight. Using micro-optical coherence tomography imaging, the investigators found that HMW-HA treatment was associated with “a prominent effect on mucociliary transport” in cell cultures derived from COPD patients and in healthy nonsmoker cell cultures exposed to cigarette smoke extract.

“Our study shows for the first time the therapeutic potential of an extracellular matrix molecule in acute exacerbation of human lung disease,” the investigators concluded, noting a “clinically meaningful salutary effect” on duration of NIPPV.

Dr. Galdi and colleagues went on to predict that benefits in a real-world patient population could be even more meaningful.

“Since the serum samples were collected at the end of NIPPV, HMW-HA–treated patients were on average sampled a day earlier than placebo-treated patients (because they were liberated from NIPPV a day earlier on average),” the investigators wrote. “Thus, HMW-HA treatment effects may have been underestimated in our study.”

According to Dr. Sandhaus, “The current report, while a relatively small single-center study, is well controlled and the results suggest that inhaled hyaluronan decreased time on noninvasive ventilation, decreased hospital stay duration, and decreased some mediators of inflammation.”

He also suggested that HMW-HA may have a role in the prophylactic setting.

“The limitations of this pilot study are appropriately explored by the authors but do not dampen the exciting possibility that this therapeutic approach may hold promise not only in severe exacerbations of COPD but potentially for the prevention of such exacerbations,” Dr. Sandhaus said.

Jerome O. Cantor, MD, FCCP, of St. John’s University, New York, who previously conducted a pilot study for using lower molecular weight hyaluronan in COPD and published a review on the subject, said that more studies are necessary.

“Further clinical trials are needed to better determine the role of hyaluronan as an adjunct to existing therapies for COPD exacerbations,” he said.

The study was supported by the National Institutes of Health. The investigators and Dr. Sandhaus declared no conflicts of interest. Dr. Cantor disclosed a relationship with MatRx Therapeutics.

New COVID-19 cases in children dropped for the third consecutive week, even as children continue to make up a larger share of all cases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

New child cases totaled almost 118,000 for the week of Jan. 29-Feb. 4, continuing the decline that began right after the United States topped 200,000 cases for the only time Jan. 8-14, the AAP and the CHA said in their weekly COVID-19 report.

For the latest week, however, children represented 16.0% of all new COVID-19 cases, continuing a 5-week increase that began in early December 2020, after the proportion had dropped to 12.6%, based on data collected from the health departments of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam. During the week of Sept. 11-17, children made up 16.9% of all cases, the highest level seen during the pandemic.

The 2.93 million cases that have been reported in children make up 12.9% of all cases since the pandemic began, and the overall rate of pediatric coronavirus infection is 3,899 cases per 100,000 children in the population. Taking a step down from the national level, 30 states are above that rate and 18 are below it, along with D.C., New York City, Puerto Rico, and Guam (New York and Texas are excluded), the AAP and CHA reported.

There were 12 new COVID-19–related child deaths in the 43 states, along with New York City and Guam, that are reporting such data, bringing the total to 227. Nationally, 0.06% of all deaths have occurred in children, with rates ranging from 0.00% (11 states) to 0.26% (Nebraska) in the 45 jurisdictions, the AAP/CHA report shows.

Child hospitalizations rose to 1.9% of all hospitalizations after holding at 1.8% since mid-November in 25 reporting jurisdictions (24 states and New York City), but the hospitalization rate among children with COVID held at 0.8%, where it has been for the last 4 weeks. Hospitalization rates as high as 3.8% were recorded early in the pandemic, the AAP and CHA noted.

[email protected]

New COVID-19 cases in children dropped for the third consecutive week, even as children continue to make up a larger share of all cases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

New child cases totaled almost 118,000 for the week of Jan. 29-Feb. 4, continuing the decline that began right after the United States topped 200,000 cases for the only time Jan. 8-14, the AAP and the CHA said in their weekly COVID-19 report.

For the latest week, however, children represented 16.0% of all new COVID-19 cases, continuing a 5-week increase that began in early December 2020, after the proportion had dropped to 12.6%, based on data collected from the health departments of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam. During the week of Sept. 11-17, children made up 16.9% of all cases, the highest level seen during the pandemic.

The 2.93 million cases that have been reported in children make up 12.9% of all cases since the pandemic began, and the overall rate of pediatric coronavirus infection is 3,899 cases per 100,000 children in the population. Taking a step down from the national level, 30 states are above that rate and 18 are below it, along with D.C., New York City, Puerto Rico, and Guam (New York and Texas are excluded), the AAP and CHA reported.

There were 12 new COVID-19–related child deaths in the 43 states, along with New York City and Guam, that are reporting such data, bringing the total to 227. Nationally, 0.06% of all deaths have occurred in children, with rates ranging from 0.00% (11 states) to 0.26% (Nebraska) in the 45 jurisdictions, the AAP/CHA report shows.

Child hospitalizations rose to 1.9% of all hospitalizations after holding at 1.8% since mid-November in 25 reporting jurisdictions (24 states and New York City), but the hospitalization rate among children with COVID held at 0.8%, where it has been for the last 4 weeks. Hospitalization rates as high as 3.8% were recorded early in the pandemic, the AAP and CHA noted.

[email protected]

New COVID-19 cases in children dropped for the third consecutive week, even as children continue to make up a larger share of all cases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

New child cases totaled almost 118,000 for the week of Jan. 29-Feb. 4, continuing the decline that began right after the United States topped 200,000 cases for the only time Jan. 8-14, the AAP and the CHA said in their weekly COVID-19 report.

For the latest week, however, children represented 16.0% of all new COVID-19 cases, continuing a 5-week increase that began in early December 2020, after the proportion had dropped to 12.6%, based on data collected from the health departments of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam. During the week of Sept. 11-17, children made up 16.9% of all cases, the highest level seen during the pandemic.

The 2.93 million cases that have been reported in children make up 12.9% of all cases since the pandemic began, and the overall rate of pediatric coronavirus infection is 3,899 cases per 100,000 children in the population. Taking a step down from the national level, 30 states are above that rate and 18 are below it, along with D.C., New York City, Puerto Rico, and Guam (New York and Texas are excluded), the AAP and CHA reported.

There were 12 new COVID-19–related child deaths in the 43 states, along with New York City and Guam, that are reporting such data, bringing the total to 227. Nationally, 0.06% of all deaths have occurred in children, with rates ranging from 0.00% (11 states) to 0.26% (Nebraska) in the 45 jurisdictions, the AAP/CHA report shows.

Child hospitalizations rose to 1.9% of all hospitalizations after holding at 1.8% since mid-November in 25 reporting jurisdictions (24 states and New York City), but the hospitalization rate among children with COVID held at 0.8%, where it has been for the last 4 weeks. Hospitalization rates as high as 3.8% were recorded early in the pandemic, the AAP and CHA noted.

[email protected]

The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.

The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.

The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.

While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%. 

A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”

Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”

The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.

“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.

The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.

“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
 

“Category 5” storm

The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.

This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report. 

As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.

Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.

In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.

Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.

“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.

Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.

“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.

Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.

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

The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.

The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.

The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.

While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%. 

A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”

Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”

The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.

“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.

The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.

“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
 

“Category 5” storm

The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.

This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report. 

As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.

Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.

In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.

Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.

“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.

Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.

“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.

Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.

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

The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.

The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.

The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.

While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%. 

A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”

Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”

The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.

“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.

The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.

“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
 

“Category 5” storm

The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.

This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report. 

As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.

Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.

In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.

Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.

“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.

Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.

“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.

Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.

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

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

A version of this article first appeared on WebMD.com.

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

A version of this article first appeared on WebMD.com.

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

A version of this article first appeared on WebMD.com.

The Food and Drug Administration has revised its emergency use authorization for COVID-19 convalescent plasma on the basis of the latest available data.

The revision states that only high-titer COVID-19 convalescent plasma can be used and only in hospitalized patients who are early in the disease course and those with impaired humoral immunity who cannot produce an adequate antibody response.

The revisions stem from new clinical trial data analyzed or reported since the original EUA was issued in August 2020. The original EUA did not have these restrictions.

“This and other changes to the EUA represent important updates to the use of convalescent plasma for the treatment of COVID-19 patients,” Peter Marks, MD, PhD, director, FDA Center for Biologics Evaluation and Research, said in a statement announcing the revisions.

“COVID-19 convalescent plasma used according to the revised EUA may have efficacy, and its known and potential benefits outweigh its known and potential risks,” the FDA said.

The agency said it revoked use of low-titer COVID-19 convalescent plasma on the basis of new data from clinical trials, including randomized, controlled trials, that have failed to demonstrate that low-titer convalescent plasma may be effective in the treatment of hospitalized patients with COVID-19.

The FDA’s updated fact sheet for health care providers on the use of COVID-19 convalescent plasma also notes that transfusion of COVID-19 convalescent plasma late in the disease course, following respiratory failure requiring intubation and mechanical ventilation, hasn’t been found to have clinical benefit.

The revised EUA also includes several additional tests that can be used to manufacture COVID-19 convalescent plasma.

“With this update, nine tests are now included in the EUA for testing plasma donations for anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release,” the FDA said.

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

The Food and Drug Administration has revised its emergency use authorization for COVID-19 convalescent plasma on the basis of the latest available data.

The revision states that only high-titer COVID-19 convalescent plasma can be used and only in hospitalized patients who are early in the disease course and those with impaired humoral immunity who cannot produce an adequate antibody response.

The revisions stem from new clinical trial data analyzed or reported since the original EUA was issued in August 2020. The original EUA did not have these restrictions.

“This and other changes to the EUA represent important updates to the use of convalescent plasma for the treatment of COVID-19 patients,” Peter Marks, MD, PhD, director, FDA Center for Biologics Evaluation and Research, said in a statement announcing the revisions.

“COVID-19 convalescent plasma used according to the revised EUA may have efficacy, and its known and potential benefits outweigh its known and potential risks,” the FDA said.

The agency said it revoked use of low-titer COVID-19 convalescent plasma on the basis of new data from clinical trials, including randomized, controlled trials, that have failed to demonstrate that low-titer convalescent plasma may be effective in the treatment of hospitalized patients with COVID-19.

The FDA’s updated fact sheet for health care providers on the use of COVID-19 convalescent plasma also notes that transfusion of COVID-19 convalescent plasma late in the disease course, following respiratory failure requiring intubation and mechanical ventilation, hasn’t been found to have clinical benefit.

The revised EUA also includes several additional tests that can be used to manufacture COVID-19 convalescent plasma.

“With this update, nine tests are now included in the EUA for testing plasma donations for anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release,” the FDA said.

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

The Food and Drug Administration has revised its emergency use authorization for COVID-19 convalescent plasma on the basis of the latest available data.

The revision states that only high-titer COVID-19 convalescent plasma can be used and only in hospitalized patients who are early in the disease course and those with impaired humoral immunity who cannot produce an adequate antibody response.

The revisions stem from new clinical trial data analyzed or reported since the original EUA was issued in August 2020. The original EUA did not have these restrictions.

“This and other changes to the EUA represent important updates to the use of convalescent plasma for the treatment of COVID-19 patients,” Peter Marks, MD, PhD, director, FDA Center for Biologics Evaluation and Research, said in a statement announcing the revisions.

“COVID-19 convalescent plasma used according to the revised EUA may have efficacy, and its known and potential benefits outweigh its known and potential risks,” the FDA said.

The agency said it revoked use of low-titer COVID-19 convalescent plasma on the basis of new data from clinical trials, including randomized, controlled trials, that have failed to demonstrate that low-titer convalescent plasma may be effective in the treatment of hospitalized patients with COVID-19.

The FDA’s updated fact sheet for health care providers on the use of COVID-19 convalescent plasma also notes that transfusion of COVID-19 convalescent plasma late in the disease course, following respiratory failure requiring intubation and mechanical ventilation, hasn’t been found to have clinical benefit.

The revised EUA also includes several additional tests that can be used to manufacture COVID-19 convalescent plasma.

“With this update, nine tests are now included in the EUA for testing plasma donations for anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release,” the FDA said.

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

Monoclonal antibodies (mAbs) to treat COVID-19 are in ample supply, but scant evidence on their effectiveness, paltry reimbursement, and a lack of a planned infrastructure to administer them has led to major underutilization of these potentially useful therapies, according to a new report from The National Academies of Sciences, Engineering, and Medicine.

The 35-page report described missed opportunities to work with states and hospitals to establish trust with clinicians and patients and to set up an infusion infrastructure to funnel patients to sites. Though the therapies still need more study, they should be an option for the right patient at the right time, said the National Academies experts in their report, Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics.

“No potentially eligible patient should be left uninformed, and no eligible patient should be denied access, if there are doses available and the patient and doctor agree it is a reasonable course,” they concluded. The report also noted that underuse, and in particular underuse by members of vulnerable and underserved communities “raises concerns about exacerbating already dramatic health disparities.”

The federal government has spent $375 million on Eli Lilly’s bamlanivimab and $450 million on Regeneron’s casirivimab plus imdevimab cocktail, and agreed last month to spend as much as $2.6 billion more on up to 1.25 million additional doses.

Some 785,000 doses of the two therapeutics have been produced and about a half million have been distributed to states. But about three quarters have gone unused. The U.S. Department of Health & Human Services has launched an online treatment locater to try to spur interest in the therapies.

But the federal government hasn’t addressed some of the basic barriers to use of the monoclonals, said the National Academies experts.

“Lack of awareness, interest, and confidence in COVID-19 mAb therapies among patients and providers are major issues,” they said in the report. Patients who have tested positive might not want to travel to an infusion site, while others might not have access to health care or only seek such treatments when it’s too late. Some who are eligible might not have the time, resources, or transportation to go to a site and sit through a 2-hour treatment.

In addition, “the supply and availability of infusion centers and personnel was identified as a greater constraint than the supply of COVID-19 mAbs,” said the report.
 

Cost a big impediment

While the federal government has covered the cost of the therapies, hospitals and patients inevitably incur related costs.

“The fragmented payment system in the United States has not provided adequate support to cover the spectrum of costs associated with COVID-19 mAb therapies,” said the report. That is compounded by chronic underfunding and restrictions on federally qualified health centers for community health, the report said.

Patients may have to pay for testing, office visits, follow-up appointments, transportation to and from the infusion site, and potentially a copay for the administration of the drug.

While Medicare pays hospitals $309 per infusion, that might not be enough, especially if a hospital or other site had to build out a new infusion center, the report shows. For clinicians, the administrative payment under Medicare Part B does “not cover the total practice cost to furnish infusion services, resulting in a substantial cost-reimbursement disparity,” the report states.

In addition, there are no specific codes for observing patients during the 2-hour procedure.

“The established Medicare payment rate for furnishing COVID-19 mAb therapies does not cover the cost associated with coordinating care for those patients, nor does it justify the risk and opportunity costs associated with investing in infrastructure modifications to safely integrate COVID-19 patients into existing facilities or building temporary infusion capacity,” the report concluded.
 

More data needed

The U.S. Food and Drug Administration issued emergency-use authorizations (EUAs) for the two monoclonal therapies based on phase 2 trial data, and that leaves a lot of uncertainty, noted the National Academies.

In trials, both therapies reduced COVID-19-related hospitalizations and emergency room visits within 28 days after treatment among patients at high risk of progression, compared with those who received placebo.

But clinicians aren’t certain about who should use the monoclonals, said the report. The underuse has in turn led to trouble collecting data – either through ongoing trials or in starting new trials.

The National Academies recommended allocating the monoclonal antibodies in a way that would give rise to better data collection to inform clinicians. Payers could support the development of a core data platform or registry, or Medicare could develop pilot trials, said the report.

Lilly and UnitedHealth Group are collaborating on a study in high-risk Medicare patients, according to Reuters. Patients who test positive will be given bamlanivimab at home.

“Building infusion capacity and developing the evidence base about the impact of COVID-19 mAbs on clinical outcomes other than hospitalization, including mortality, are the most promising strategies for increasing effective utilization moving forward,” stated the National Academies report.

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

Monoclonal antibodies (mAbs) to treat COVID-19 are in ample supply, but scant evidence on their effectiveness, paltry reimbursement, and a lack of a planned infrastructure to administer them has led to major underutilization of these potentially useful therapies, according to a new report from The National Academies of Sciences, Engineering, and Medicine.

The 35-page report described missed opportunities to work with states and hospitals to establish trust with clinicians and patients and to set up an infusion infrastructure to funnel patients to sites. Though the therapies still need more study, they should be an option for the right patient at the right time, said the National Academies experts in their report, Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics.

“No potentially eligible patient should be left uninformed, and no eligible patient should be denied access, if there are doses available and the patient and doctor agree it is a reasonable course,” they concluded. The report also noted that underuse, and in particular underuse by members of vulnerable and underserved communities “raises concerns about exacerbating already dramatic health disparities.”

The federal government has spent $375 million on Eli Lilly’s bamlanivimab and $450 million on Regeneron’s casirivimab plus imdevimab cocktail, and agreed last month to spend as much as $2.6 billion more on up to 1.25 million additional doses.

Some 785,000 doses of the two therapeutics have been produced and about a half million have been distributed to states. But about three quarters have gone unused. The U.S. Department of Health & Human Services has launched an online treatment locater to try to spur interest in the therapies.

But the federal government hasn’t addressed some of the basic barriers to use of the monoclonals, said the National Academies experts.

“Lack of awareness, interest, and confidence in COVID-19 mAb therapies among patients and providers are major issues,” they said in the report. Patients who have tested positive might not want to travel to an infusion site, while others might not have access to health care or only seek such treatments when it’s too late. Some who are eligible might not have the time, resources, or transportation to go to a site and sit through a 2-hour treatment.

In addition, “the supply and availability of infusion centers and personnel was identified as a greater constraint than the supply of COVID-19 mAbs,” said the report.
 

Cost a big impediment

While the federal government has covered the cost of the therapies, hospitals and patients inevitably incur related costs.

“The fragmented payment system in the United States has not provided adequate support to cover the spectrum of costs associated with COVID-19 mAb therapies,” said the report. That is compounded by chronic underfunding and restrictions on federally qualified health centers for community health, the report said.

Patients may have to pay for testing, office visits, follow-up appointments, transportation to and from the infusion site, and potentially a copay for the administration of the drug.

While Medicare pays hospitals $309 per infusion, that might not be enough, especially if a hospital or other site had to build out a new infusion center, the report shows. For clinicians, the administrative payment under Medicare Part B does “not cover the total practice cost to furnish infusion services, resulting in a substantial cost-reimbursement disparity,” the report states.

In addition, there are no specific codes for observing patients during the 2-hour procedure.

“The established Medicare payment rate for furnishing COVID-19 mAb therapies does not cover the cost associated with coordinating care for those patients, nor does it justify the risk and opportunity costs associated with investing in infrastructure modifications to safely integrate COVID-19 patients into existing facilities or building temporary infusion capacity,” the report concluded.
 

More data needed

The U.S. Food and Drug Administration issued emergency-use authorizations (EUAs) for the two monoclonal therapies based on phase 2 trial data, and that leaves a lot of uncertainty, noted the National Academies.

In trials, both therapies reduced COVID-19-related hospitalizations and emergency room visits within 28 days after treatment among patients at high risk of progression, compared with those who received placebo.

But clinicians aren’t certain about who should use the monoclonals, said the report. The underuse has in turn led to trouble collecting data – either through ongoing trials or in starting new trials.

The National Academies recommended allocating the monoclonal antibodies in a way that would give rise to better data collection to inform clinicians. Payers could support the development of a core data platform or registry, or Medicare could develop pilot trials, said the report.

Lilly and UnitedHealth Group are collaborating on a study in high-risk Medicare patients, according to Reuters. Patients who test positive will be given bamlanivimab at home.

“Building infusion capacity and developing the evidence base about the impact of COVID-19 mAbs on clinical outcomes other than hospitalization, including mortality, are the most promising strategies for increasing effective utilization moving forward,” stated the National Academies report.

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

Monoclonal antibodies (mAbs) to treat COVID-19 are in ample supply, but scant evidence on their effectiveness, paltry reimbursement, and a lack of a planned infrastructure to administer them has led to major underutilization of these potentially useful therapies, according to a new report from The National Academies of Sciences, Engineering, and Medicine.

The 35-page report described missed opportunities to work with states and hospitals to establish trust with clinicians and patients and to set up an infusion infrastructure to funnel patients to sites. Though the therapies still need more study, they should be an option for the right patient at the right time, said the National Academies experts in their report, Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics.

“No potentially eligible patient should be left uninformed, and no eligible patient should be denied access, if there are doses available and the patient and doctor agree it is a reasonable course,” they concluded. The report also noted that underuse, and in particular underuse by members of vulnerable and underserved communities “raises concerns about exacerbating already dramatic health disparities.”

The federal government has spent $375 million on Eli Lilly’s bamlanivimab and $450 million on Regeneron’s casirivimab plus imdevimab cocktail, and agreed last month to spend as much as $2.6 billion more on up to 1.25 million additional doses.

Some 785,000 doses of the two therapeutics have been produced and about a half million have been distributed to states. But about three quarters have gone unused. The U.S. Department of Health & Human Services has launched an online treatment locater to try to spur interest in the therapies.

But the federal government hasn’t addressed some of the basic barriers to use of the monoclonals, said the National Academies experts.

“Lack of awareness, interest, and confidence in COVID-19 mAb therapies among patients and providers are major issues,” they said in the report. Patients who have tested positive might not want to travel to an infusion site, while others might not have access to health care or only seek such treatments when it’s too late. Some who are eligible might not have the time, resources, or transportation to go to a site and sit through a 2-hour treatment.

In addition, “the supply and availability of infusion centers and personnel was identified as a greater constraint than the supply of COVID-19 mAbs,” said the report.
 

Cost a big impediment

While the federal government has covered the cost of the therapies, hospitals and patients inevitably incur related costs.

“The fragmented payment system in the United States has not provided adequate support to cover the spectrum of costs associated with COVID-19 mAb therapies,” said the report. That is compounded by chronic underfunding and restrictions on federally qualified health centers for community health, the report said.

Patients may have to pay for testing, office visits, follow-up appointments, transportation to and from the infusion site, and potentially a copay for the administration of the drug.

While Medicare pays hospitals $309 per infusion, that might not be enough, especially if a hospital or other site had to build out a new infusion center, the report shows. For clinicians, the administrative payment under Medicare Part B does “not cover the total practice cost to furnish infusion services, resulting in a substantial cost-reimbursement disparity,” the report states.

In addition, there are no specific codes for observing patients during the 2-hour procedure.

“The established Medicare payment rate for furnishing COVID-19 mAb therapies does not cover the cost associated with coordinating care for those patients, nor does it justify the risk and opportunity costs associated with investing in infrastructure modifications to safely integrate COVID-19 patients into existing facilities or building temporary infusion capacity,” the report concluded.
 

More data needed

The U.S. Food and Drug Administration issued emergency-use authorizations (EUAs) for the two monoclonal therapies based on phase 2 trial data, and that leaves a lot of uncertainty, noted the National Academies.

In trials, both therapies reduced COVID-19-related hospitalizations and emergency room visits within 28 days after treatment among patients at high risk of progression, compared with those who received placebo.

But clinicians aren’t certain about who should use the monoclonals, said the report. The underuse has in turn led to trouble collecting data – either through ongoing trials or in starting new trials.

The National Academies recommended allocating the monoclonal antibodies in a way that would give rise to better data collection to inform clinicians. Payers could support the development of a core data platform or registry, or Medicare could develop pilot trials, said the report.

Lilly and UnitedHealth Group are collaborating on a study in high-risk Medicare patients, according to Reuters. Patients who test positive will be given bamlanivimab at home.

“Building infusion capacity and developing the evidence base about the impact of COVID-19 mAbs on clinical outcomes other than hospitalization, including mortality, are the most promising strategies for increasing effective utilization moving forward,” stated the National Academies report.

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

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

COVID-19 cases are continuing to fall in the United States, according to the New York Times tracker, though the number of deaths from the disease again neared 4,000 on Feb. 3.

janiecbros/iStock/Getty Images Plus

The United States has averaged 141,146 cases a day in the past week, down 30% from the average 2 weeks ago. For the first time since November 2020, the country is averaging fewer than 150,000 cases a day, according to the tracker.

However, Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention, warned that new COVID-19 variants popping up widely could threaten that progress.

“Although we have seen declines in cases and admissions and a recent slowing of deaths, cases remain extraordinarily high, still twice as high as the peak number of cases over the summer. And the continued proliferation of variants, variants that likely have increased transmissibility, that spread more easily, threatens to reverse these recent trends.

“Based on contact tracing of recent variant cases, not wearing masks and participating in in-person social gatherings have contributed to the variants’ spread,” she said at a White House COVID-19 briefing on Feb. 3, 2021.

The number of cases worldwide neared 104 million on Feb. 3 and the U.S. numbers made up 26.4 million of that total.

As of Feb. 4, COVID-19 had killed at least 454,000 people and infected about 26.6 million in the United States since January 2020, according to the Johns Hopkins University tracker.

The Johns Hopkins tracker found that, per capita, North Dakota, South Dakota, and Rhode Island have reported the most cases while New Jersey and New York have recorded the most deaths.

According to the COVID tracking project, hospitalizations for COVID-19 nationwide were down to 91,440 on Feb. 3.

The tracking report noted, “compared to last week, the number of people currently hospitalized with COVID-19 is down by 10% or more in 38 states.”

Even in hard-hit Los Angeles County, infections and case numbers are on the decline, according to the Los Angeles Times. However, officials, warn the numbers remain well above presurge levels. Over the past week, 201 city residents have died every day.

Reuters also reports that Anthony S. Fauci, MD, the government’s top infectious disease expert, said despite some good news in the numbers, Americans should continue to follow social distancing guidelines. He added that double-masking may add protection.

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

COVID-19 cases are continuing to fall in the United States, according to the New York Times tracker, though the number of deaths from the disease again neared 4,000 on Feb. 3.

janiecbros/iStock/Getty Images Plus

The United States has averaged 141,146 cases a day in the past week, down 30% from the average 2 weeks ago. For the first time since November 2020, the country is averaging fewer than 150,000 cases a day, according to the tracker.

However, Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention, warned that new COVID-19 variants popping up widely could threaten that progress.

“Although we have seen declines in cases and admissions and a recent slowing of deaths, cases remain extraordinarily high, still twice as high as the peak number of cases over the summer. And the continued proliferation of variants, variants that likely have increased transmissibility, that spread more easily, threatens to reverse these recent trends.

“Based on contact tracing of recent variant cases, not wearing masks and participating in in-person social gatherings have contributed to the variants’ spread,” she said at a White House COVID-19 briefing on Feb. 3, 2021.

The number of cases worldwide neared 104 million on Feb. 3 and the U.S. numbers made up 26.4 million of that total.

As of Feb. 4, COVID-19 had killed at least 454,000 people and infected about 26.6 million in the United States since January 2020, according to the Johns Hopkins University tracker.

The Johns Hopkins tracker found that, per capita, North Dakota, South Dakota, and Rhode Island have reported the most cases while New Jersey and New York have recorded the most deaths.

According to the COVID tracking project, hospitalizations for COVID-19 nationwide were down to 91,440 on Feb. 3.

The tracking report noted, “compared to last week, the number of people currently hospitalized with COVID-19 is down by 10% or more in 38 states.”

Even in hard-hit Los Angeles County, infections and case numbers are on the decline, according to the Los Angeles Times. However, officials, warn the numbers remain well above presurge levels. Over the past week, 201 city residents have died every day.

Reuters also reports that Anthony S. Fauci, MD, the government’s top infectious disease expert, said despite some good news in the numbers, Americans should continue to follow social distancing guidelines. He added that double-masking may add protection.

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

COVID-19 cases are continuing to fall in the United States, according to the New York Times tracker, though the number of deaths from the disease again neared 4,000 on Feb. 3.

janiecbros/iStock/Getty Images Plus

The United States has averaged 141,146 cases a day in the past week, down 30% from the average 2 weeks ago. For the first time since November 2020, the country is averaging fewer than 150,000 cases a day, according to the tracker.

However, Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention, warned that new COVID-19 variants popping up widely could threaten that progress.

“Although we have seen declines in cases and admissions and a recent slowing of deaths, cases remain extraordinarily high, still twice as high as the peak number of cases over the summer. And the continued proliferation of variants, variants that likely have increased transmissibility, that spread more easily, threatens to reverse these recent trends.

“Based on contact tracing of recent variant cases, not wearing masks and participating in in-person social gatherings have contributed to the variants’ spread,” she said at a White House COVID-19 briefing on Feb. 3, 2021.

The number of cases worldwide neared 104 million on Feb. 3 and the U.S. numbers made up 26.4 million of that total.

As of Feb. 4, COVID-19 had killed at least 454,000 people and infected about 26.6 million in the United States since January 2020, according to the Johns Hopkins University tracker.

The Johns Hopkins tracker found that, per capita, North Dakota, South Dakota, and Rhode Island have reported the most cases while New Jersey and New York have recorded the most deaths.

According to the COVID tracking project, hospitalizations for COVID-19 nationwide were down to 91,440 on Feb. 3.

The tracking report noted, “compared to last week, the number of people currently hospitalized with COVID-19 is down by 10% or more in 38 states.”

Even in hard-hit Los Angeles County, infections and case numbers are on the decline, according to the Los Angeles Times. However, officials, warn the numbers remain well above presurge levels. Over the past week, 201 city residents have died every day.

Reuters also reports that Anthony S. Fauci, MD, the government’s top infectious disease expert, said despite some good news in the numbers, Americans should continue to follow social distancing guidelines. He added that double-masking may add protection.

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