The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.

According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.

The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.

“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.

This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.

“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.

To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.

Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.

The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.

Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.

Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.

Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).

“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.

“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.

“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.

There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.

Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.

The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.

According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.

The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.

“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.

This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.

“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.

To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.

Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.

The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.

Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.

Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.

Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).

“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.

“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.

“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.

There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.

Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.

The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.

According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.

The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.

“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.

This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.

“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.

To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.

Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.

The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.

Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.

Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.

Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).

“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.

“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.

“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.

There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.

Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.

After hinting that new guidelines on outdoor mask-wearing were coming, the Centers for Disease Control and Prevention on April 27 officially gave a green light to fully vaccinated people gathering outside in uncrowded activities without the masks that have become so common during the COVID-19 pandemic.

It is a minor – but still significant – step toward the end of pandemic restrictions.

“Over the past year, we have spent a lot of time telling Americans what they cannot do, what they should not do,” CDC director Rochelle Walensky, MD, MPH, said at a White House press briefing. “Today, I’m going to tell you some of the things you can do if you are fully vaccinated.”

President Joe Biden affirmed the new guidelines at a press conference soon after the CDC briefing ended.

“Starting today, if you are fully vaccinated and you’re outdoors and not in a big crowd, you no longer need to wear a mask,” he said, adding “the bottom line is clear: If you’re vaccinated, you can do more things, more safely, both outdoors as well as indoors.”

President Biden emphasized the role science played in the decision, saying “The CDC is able to make this announcement because our scientists are convinced by the data that the odds of getting or giving the virus to others is very, very low if you’ve both been fully vaccinated and are out in the open air.”

President Biden also said these new guidelines should be an incentive for more people to get vaccinated. “This is another great reason to go get vaccinated now. Now,” he said.

The CDC has long advised that outdoor activities are safer than indoor activities.

“Most of transmission is happening indoors rather than outdoors. Less than 10% of documented transmissions in many studies have occurred outdoors,” said Dr. Walensky. “We also know there’s almost a 20-fold increased risk of transmission in the indoor setting, than the outdoor setting.”

Dr. Walensky said the lower risks outdoors, combined with growing vaccination coverage and falling COVID cases around the country, motivated the change.

The new guidelines come as the share of people in the United States who are vaccinated is growing. About 37% of all eligible Americans are fully vaccinated, according to the CDC. Nearly 54% have had at least one dose.

The new guidelines say unvaccinated people should continue to wear masks outdoors when gathering with others or dining at an outdoor restaurant.

And vaccinated people should continue to wear masks outdoors in crowded settings where social distancing might not always be possible, like a concert or sporting event. People are considered fully vaccinated when they are 2 weeks past their last shot

The CDC guidelines say people who live in the same house don’t need to wear masks if they’re exercising or hanging out together outdoors.

You also don’t need a mask if you’re attending a small, outdoor gathering with fully vaccinated family and friends, whether you’re vaccinated or not.

The new guidelines also say it’s OK for fully vaccinated people to take their masks off outdoors when gathering in a small group of vaccinated and unvaccinated people, but suggest that unvaccinated people should still wear a mask.



Reporter Marcia Frellick contributed to this report.

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

After hinting that new guidelines on outdoor mask-wearing were coming, the Centers for Disease Control and Prevention on April 27 officially gave a green light to fully vaccinated people gathering outside in uncrowded activities without the masks that have become so common during the COVID-19 pandemic.

It is a minor – but still significant – step toward the end of pandemic restrictions.

“Over the past year, we have spent a lot of time telling Americans what they cannot do, what they should not do,” CDC director Rochelle Walensky, MD, MPH, said at a White House press briefing. “Today, I’m going to tell you some of the things you can do if you are fully vaccinated.”

President Joe Biden affirmed the new guidelines at a press conference soon after the CDC briefing ended.

“Starting today, if you are fully vaccinated and you’re outdoors and not in a big crowd, you no longer need to wear a mask,” he said, adding “the bottom line is clear: If you’re vaccinated, you can do more things, more safely, both outdoors as well as indoors.”

President Biden emphasized the role science played in the decision, saying “The CDC is able to make this announcement because our scientists are convinced by the data that the odds of getting or giving the virus to others is very, very low if you’ve both been fully vaccinated and are out in the open air.”

President Biden also said these new guidelines should be an incentive for more people to get vaccinated. “This is another great reason to go get vaccinated now. Now,” he said.

The CDC has long advised that outdoor activities are safer than indoor activities.

“Most of transmission is happening indoors rather than outdoors. Less than 10% of documented transmissions in many studies have occurred outdoors,” said Dr. Walensky. “We also know there’s almost a 20-fold increased risk of transmission in the indoor setting, than the outdoor setting.”

Dr. Walensky said the lower risks outdoors, combined with growing vaccination coverage and falling COVID cases around the country, motivated the change.

The new guidelines come as the share of people in the United States who are vaccinated is growing. About 37% of all eligible Americans are fully vaccinated, according to the CDC. Nearly 54% have had at least one dose.

The new guidelines say unvaccinated people should continue to wear masks outdoors when gathering with others or dining at an outdoor restaurant.

And vaccinated people should continue to wear masks outdoors in crowded settings where social distancing might not always be possible, like a concert or sporting event. People are considered fully vaccinated when they are 2 weeks past their last shot

The CDC guidelines say people who live in the same house don’t need to wear masks if they’re exercising or hanging out together outdoors.

You also don’t need a mask if you’re attending a small, outdoor gathering with fully vaccinated family and friends, whether you’re vaccinated or not.

The new guidelines also say it’s OK for fully vaccinated people to take their masks off outdoors when gathering in a small group of vaccinated and unvaccinated people, but suggest that unvaccinated people should still wear a mask.



Reporter Marcia Frellick contributed to this report.

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

After hinting that new guidelines on outdoor mask-wearing were coming, the Centers for Disease Control and Prevention on April 27 officially gave a green light to fully vaccinated people gathering outside in uncrowded activities without the masks that have become so common during the COVID-19 pandemic.

It is a minor – but still significant – step toward the end of pandemic restrictions.

“Over the past year, we have spent a lot of time telling Americans what they cannot do, what they should not do,” CDC director Rochelle Walensky, MD, MPH, said at a White House press briefing. “Today, I’m going to tell you some of the things you can do if you are fully vaccinated.”

President Joe Biden affirmed the new guidelines at a press conference soon after the CDC briefing ended.

“Starting today, if you are fully vaccinated and you’re outdoors and not in a big crowd, you no longer need to wear a mask,” he said, adding “the bottom line is clear: If you’re vaccinated, you can do more things, more safely, both outdoors as well as indoors.”

President Biden emphasized the role science played in the decision, saying “The CDC is able to make this announcement because our scientists are convinced by the data that the odds of getting or giving the virus to others is very, very low if you’ve both been fully vaccinated and are out in the open air.”

President Biden also said these new guidelines should be an incentive for more people to get vaccinated. “This is another great reason to go get vaccinated now. Now,” he said.

The CDC has long advised that outdoor activities are safer than indoor activities.

“Most of transmission is happening indoors rather than outdoors. Less than 10% of documented transmissions in many studies have occurred outdoors,” said Dr. Walensky. “We also know there’s almost a 20-fold increased risk of transmission in the indoor setting, than the outdoor setting.”

Dr. Walensky said the lower risks outdoors, combined with growing vaccination coverage and falling COVID cases around the country, motivated the change.

The new guidelines come as the share of people in the United States who are vaccinated is growing. About 37% of all eligible Americans are fully vaccinated, according to the CDC. Nearly 54% have had at least one dose.

The new guidelines say unvaccinated people should continue to wear masks outdoors when gathering with others or dining at an outdoor restaurant.

And vaccinated people should continue to wear masks outdoors in crowded settings where social distancing might not always be possible, like a concert or sporting event. People are considered fully vaccinated when they are 2 weeks past their last shot

The CDC guidelines say people who live in the same house don’t need to wear masks if they’re exercising or hanging out together outdoors.

You also don’t need a mask if you’re attending a small, outdoor gathering with fully vaccinated family and friends, whether you’re vaccinated or not.

The new guidelines also say it’s OK for fully vaccinated people to take their masks off outdoors when gathering in a small group of vaccinated and unvaccinated people, but suggest that unvaccinated people should still wear a mask.



Reporter Marcia Frellick contributed to this report.

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

On April 23, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion for the IL-13 inhibitor tralokinumab (Adtralza) for the treatment of adults with moderate to severe atopic dermatitis (AD) who are eligible for systemic therapy.

The new opinion represents the final stages before the European Commission decides whether tralokinumab will be authorized for use throughout the European Union. The final decision should be made in the next few months.

If ultimately authorized, tralokinumab would become the first approved fully human monoclonal antibody targeting the interleukin-13 cytokine, a key factor that drives the signs and symptoms of AD. Tralokinumab has previously shown to target IL-13 with high affinity and subsequently improve symptoms associated with the inflammatory skin disease.

The EMA accepted the marketing application for tralokinumab back in June 2020. Submitted alongside the marketing application were data from the ECZTRA 1, 2, and 3 pivotal randomized, placebo-controlled trials.

In the ECZTRA trials, treatment with tralokinumab, either alone or with topical corticosteroids, was associated with significant improvements in the Investigator Global Assessment score of clear or almost clear skin and at least a 75% improvement in the Eczema Area and Severity Index score. Safety of tralokinumab in these trials was comparable with that reported with placebo.

Interim data from the open-label extension trial, ECZTEND, also showed that treatment with tralokinumab was associated with durable efficacy in adult patients with moderate to severe AD. Patients in this study were previously enrolled in the ECZTRA 1 and 2 parent trials and had received the IL-13 inhibitor for up to 2 years. Data from this trial were presented at the 2021 American Academy of Dermatology Virtual Meeting Experience.

Pending the European Commission’s final decision, the Marketing Authorization Application for use of tralokinumab in adults with moderate to severe AD will be valid in across all European Union member states in addition to Iceland, Norway, and Liechtenstein. Other regulatory filings for the drug are currently underway with health authorities from various countries worldwide.

Back in July 2020, the Food and Drug Administration accepted a Biologics License Application for tralokinumab for the treatment of moderate to severe AD in adults. Data from the pivotal ECZTRA 1, 2, and ECZTRA 3 trials were submitted to the FDA.

The FDA expects to make a final decision in the second quarter of this year on whether to approve tralokinumab in the United States for the adult AD indication.

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

On April 23, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion for the IL-13 inhibitor tralokinumab (Adtralza) for the treatment of adults with moderate to severe atopic dermatitis (AD) who are eligible for systemic therapy.

The new opinion represents the final stages before the European Commission decides whether tralokinumab will be authorized for use throughout the European Union. The final decision should be made in the next few months.

If ultimately authorized, tralokinumab would become the first approved fully human monoclonal antibody targeting the interleukin-13 cytokine, a key factor that drives the signs and symptoms of AD. Tralokinumab has previously shown to target IL-13 with high affinity and subsequently improve symptoms associated with the inflammatory skin disease.

The EMA accepted the marketing application for tralokinumab back in June 2020. Submitted alongside the marketing application were data from the ECZTRA 1, 2, and 3 pivotal randomized, placebo-controlled trials.

In the ECZTRA trials, treatment with tralokinumab, either alone or with topical corticosteroids, was associated with significant improvements in the Investigator Global Assessment score of clear or almost clear skin and at least a 75% improvement in the Eczema Area and Severity Index score. Safety of tralokinumab in these trials was comparable with that reported with placebo.

Interim data from the open-label extension trial, ECZTEND, also showed that treatment with tralokinumab was associated with durable efficacy in adult patients with moderate to severe AD. Patients in this study were previously enrolled in the ECZTRA 1 and 2 parent trials and had received the IL-13 inhibitor for up to 2 years. Data from this trial were presented at the 2021 American Academy of Dermatology Virtual Meeting Experience.

Pending the European Commission’s final decision, the Marketing Authorization Application for use of tralokinumab in adults with moderate to severe AD will be valid in across all European Union member states in addition to Iceland, Norway, and Liechtenstein. Other regulatory filings for the drug are currently underway with health authorities from various countries worldwide.

Back in July 2020, the Food and Drug Administration accepted a Biologics License Application for tralokinumab for the treatment of moderate to severe AD in adults. Data from the pivotal ECZTRA 1, 2, and ECZTRA 3 trials were submitted to the FDA.

The FDA expects to make a final decision in the second quarter of this year on whether to approve tralokinumab in the United States for the adult AD indication.

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

On April 23, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion for the IL-13 inhibitor tralokinumab (Adtralza) for the treatment of adults with moderate to severe atopic dermatitis (AD) who are eligible for systemic therapy.

The new opinion represents the final stages before the European Commission decides whether tralokinumab will be authorized for use throughout the European Union. The final decision should be made in the next few months.

If ultimately authorized, tralokinumab would become the first approved fully human monoclonal antibody targeting the interleukin-13 cytokine, a key factor that drives the signs and symptoms of AD. Tralokinumab has previously shown to target IL-13 with high affinity and subsequently improve symptoms associated with the inflammatory skin disease.

The EMA accepted the marketing application for tralokinumab back in June 2020. Submitted alongside the marketing application were data from the ECZTRA 1, 2, and 3 pivotal randomized, placebo-controlled trials.

In the ECZTRA trials, treatment with tralokinumab, either alone or with topical corticosteroids, was associated with significant improvements in the Investigator Global Assessment score of clear or almost clear skin and at least a 75% improvement in the Eczema Area and Severity Index score. Safety of tralokinumab in these trials was comparable with that reported with placebo.

Interim data from the open-label extension trial, ECZTEND, also showed that treatment with tralokinumab was associated with durable efficacy in adult patients with moderate to severe AD. Patients in this study were previously enrolled in the ECZTRA 1 and 2 parent trials and had received the IL-13 inhibitor for up to 2 years. Data from this trial were presented at the 2021 American Academy of Dermatology Virtual Meeting Experience.

Pending the European Commission’s final decision, the Marketing Authorization Application for use of tralokinumab in adults with moderate to severe AD will be valid in across all European Union member states in addition to Iceland, Norway, and Liechtenstein. Other regulatory filings for the drug are currently underway with health authorities from various countries worldwide.

Back in July 2020, the Food and Drug Administration accepted a Biologics License Application for tralokinumab for the treatment of moderate to severe AD in adults. Data from the pivotal ECZTRA 1, 2, and ECZTRA 3 trials were submitted to the FDA.

The FDA expects to make a final decision in the second quarter of this year on whether to approve tralokinumab in the United States for the adult AD indication.

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

The Pfizer and Moderna COVID-19 vaccines appear to be safe in pregnant patients, according to preliminary findings published in the New England Journal of Medicine.

The Centers for Disease Control and Prevention have said pregnant people have an increased risk of being severely ill from COVID-19; however, this group was excluded from major clinical trials that led up to the current vaccine approvals.

But based on the new findings, Rochelle Walensky, MD, director of the CDC, announced during a White House COVID-19 briefing that the CDC recommends that pregnant people receive the COVID-19 vaccine.

The new study, which analyzed data between Dec. 14, 2020, and Feb. 28, 2021, from three federal databases, adds to a pool of limited data about the safety and efficacy of the vaccine in pregnant persons. Researchers did not include people who received the Johnson & Johnson vaccine because it received emergency use authorization on Feb. 27, just 1 day before they study’s cutoff.

“Our hope is that these initial data will be reassuring to pregnant people and their health care providers as well as the public, and contribute to increasing vaccination rates,” study author Christine Olson, MD, said in an interview. “While the data are preliminary and will continue to be analyzed as more reports become available, our findings are reassuring.”

For the study, Dr. Olson and colleagues analyzed v-safe survey data, data from those enrolled in the v-safe pregnancy registry, and Vaccine Adverse Event Reporting System (VAERS) reports.

Researchers found that 86% of pregnancies resulted in a live birth, 12.6 % resulted in spontaneous abortions, and 0.1% resulted in stillbirth. They also found that, among the live births, 9.4% were preterm, 3.2% of babies were small for their gestational age, and 2.2% had congenital anomalies.

Researchers also found that injection-site pain, fatigue, and headaches were reported more frequently in pregnant patients than among those who were not pregnant. Among VAERS reports, they found that 70% of adverse events were nonpregnancy specific. Nearly 30% involved pregnancy- or neonatal-specific adverse events. The most frequently reported pregnancy-related events were spontaneous abortions, followed by stillbirths, premature rupture of membranes and vaginal bleeding.

“I think the results are actually quite reassuring as the proportion of the pregnancy outcomes, such as pregnancy loss and health effects to the newborns, are really quite consistent with what we’d expect in the background rate of the population,” Dr. Walensky said in a podcast accompanying the study. “So this study adds to growing evidence confirming that pregnant people develop a robust immune response to COVID-19 vaccination without so far seeing any adverse events to the mom or the fetus.”

Researchers said limitations of the study include the accuracy of self-reported data, and there being limited information on other potential risk factors for adverse pregnancies and neonatal outcomes. They acknowledged that continuous monitoring is needed to look at maternal safety and pregnancy outcomes in earlier stages of pregnancy and during the preconception period.

David Jaspan, DO, chair of the department of obstetrics and gynecology at Einstein Medical Center, Philadelphia, who was not involved with the study, said in an interview that, despite the limitations, the study provides much-needed insight on the vaccine’s safety and efficacy in pregnant patients.

“In December we had no data for any pregnant patient,” Dr. Jaspan said. “And now just 4 short months later, this paper [has data from] at least had 35,000 people. We can’t answer every question, but we have more answers today than we had just 4 months ago.”

Dr. Olson hopes the present data is enough to help inform decision-making of pregnant patients and their health care providers when it comes to deciding to get the COVID-19 vaccination.

The study author and experts interviewed disclosed no relevant financial relationships.

The Pfizer and Moderna COVID-19 vaccines appear to be safe in pregnant patients, according to preliminary findings published in the New England Journal of Medicine.

The Centers for Disease Control and Prevention have said pregnant people have an increased risk of being severely ill from COVID-19; however, this group was excluded from major clinical trials that led up to the current vaccine approvals.

But based on the new findings, Rochelle Walensky, MD, director of the CDC, announced during a White House COVID-19 briefing that the CDC recommends that pregnant people receive the COVID-19 vaccine.

The new study, which analyzed data between Dec. 14, 2020, and Feb. 28, 2021, from three federal databases, adds to a pool of limited data about the safety and efficacy of the vaccine in pregnant persons. Researchers did not include people who received the Johnson & Johnson vaccine because it received emergency use authorization on Feb. 27, just 1 day before they study’s cutoff.

“Our hope is that these initial data will be reassuring to pregnant people and their health care providers as well as the public, and contribute to increasing vaccination rates,” study author Christine Olson, MD, said in an interview. “While the data are preliminary and will continue to be analyzed as more reports become available, our findings are reassuring.”

For the study, Dr. Olson and colleagues analyzed v-safe survey data, data from those enrolled in the v-safe pregnancy registry, and Vaccine Adverse Event Reporting System (VAERS) reports.

Researchers found that 86% of pregnancies resulted in a live birth, 12.6 % resulted in spontaneous abortions, and 0.1% resulted in stillbirth. They also found that, among the live births, 9.4% were preterm, 3.2% of babies were small for their gestational age, and 2.2% had congenital anomalies.

Researchers also found that injection-site pain, fatigue, and headaches were reported more frequently in pregnant patients than among those who were not pregnant. Among VAERS reports, they found that 70% of adverse events were nonpregnancy specific. Nearly 30% involved pregnancy- or neonatal-specific adverse events. The most frequently reported pregnancy-related events were spontaneous abortions, followed by stillbirths, premature rupture of membranes and vaginal bleeding.

“I think the results are actually quite reassuring as the proportion of the pregnancy outcomes, such as pregnancy loss and health effects to the newborns, are really quite consistent with what we’d expect in the background rate of the population,” Dr. Walensky said in a podcast accompanying the study. “So this study adds to growing evidence confirming that pregnant people develop a robust immune response to COVID-19 vaccination without so far seeing any adverse events to the mom or the fetus.”

Researchers said limitations of the study include the accuracy of self-reported data, and there being limited information on other potential risk factors for adverse pregnancies and neonatal outcomes. They acknowledged that continuous monitoring is needed to look at maternal safety and pregnancy outcomes in earlier stages of pregnancy and during the preconception period.

David Jaspan, DO, chair of the department of obstetrics and gynecology at Einstein Medical Center, Philadelphia, who was not involved with the study, said in an interview that, despite the limitations, the study provides much-needed insight on the vaccine’s safety and efficacy in pregnant patients.

“In December we had no data for any pregnant patient,” Dr. Jaspan said. “And now just 4 short months later, this paper [has data from] at least had 35,000 people. We can’t answer every question, but we have more answers today than we had just 4 months ago.”

Dr. Olson hopes the present data is enough to help inform decision-making of pregnant patients and their health care providers when it comes to deciding to get the COVID-19 vaccination.

The study author and experts interviewed disclosed no relevant financial relationships.

The Pfizer and Moderna COVID-19 vaccines appear to be safe in pregnant patients, according to preliminary findings published in the New England Journal of Medicine.

The Centers for Disease Control and Prevention have said pregnant people have an increased risk of being severely ill from COVID-19; however, this group was excluded from major clinical trials that led up to the current vaccine approvals.

But based on the new findings, Rochelle Walensky, MD, director of the CDC, announced during a White House COVID-19 briefing that the CDC recommends that pregnant people receive the COVID-19 vaccine.

The new study, which analyzed data between Dec. 14, 2020, and Feb. 28, 2021, from three federal databases, adds to a pool of limited data about the safety and efficacy of the vaccine in pregnant persons. Researchers did not include people who received the Johnson & Johnson vaccine because it received emergency use authorization on Feb. 27, just 1 day before they study’s cutoff.

“Our hope is that these initial data will be reassuring to pregnant people and their health care providers as well as the public, and contribute to increasing vaccination rates,” study author Christine Olson, MD, said in an interview. “While the data are preliminary and will continue to be analyzed as more reports become available, our findings are reassuring.”

For the study, Dr. Olson and colleagues analyzed v-safe survey data, data from those enrolled in the v-safe pregnancy registry, and Vaccine Adverse Event Reporting System (VAERS) reports.

Researchers found that 86% of pregnancies resulted in a live birth, 12.6 % resulted in spontaneous abortions, and 0.1% resulted in stillbirth. They also found that, among the live births, 9.4% were preterm, 3.2% of babies were small for their gestational age, and 2.2% had congenital anomalies.

Researchers also found that injection-site pain, fatigue, and headaches were reported more frequently in pregnant patients than among those who were not pregnant. Among VAERS reports, they found that 70% of adverse events were nonpregnancy specific. Nearly 30% involved pregnancy- or neonatal-specific adverse events. The most frequently reported pregnancy-related events were spontaneous abortions, followed by stillbirths, premature rupture of membranes and vaginal bleeding.

“I think the results are actually quite reassuring as the proportion of the pregnancy outcomes, such as pregnancy loss and health effects to the newborns, are really quite consistent with what we’d expect in the background rate of the population,” Dr. Walensky said in a podcast accompanying the study. “So this study adds to growing evidence confirming that pregnant people develop a robust immune response to COVID-19 vaccination without so far seeing any adverse events to the mom or the fetus.”

Researchers said limitations of the study include the accuracy of self-reported data, and there being limited information on other potential risk factors for adverse pregnancies and neonatal outcomes. They acknowledged that continuous monitoring is needed to look at maternal safety and pregnancy outcomes in earlier stages of pregnancy and during the preconception period.

David Jaspan, DO, chair of the department of obstetrics and gynecology at Einstein Medical Center, Philadelphia, who was not involved with the study, said in an interview that, despite the limitations, the study provides much-needed insight on the vaccine’s safety and efficacy in pregnant patients.

“In December we had no data for any pregnant patient,” Dr. Jaspan said. “And now just 4 short months later, this paper [has data from] at least had 35,000 people. We can’t answer every question, but we have more answers today than we had just 4 months ago.”

Dr. Olson hopes the present data is enough to help inform decision-making of pregnant patients and their health care providers when it comes to deciding to get the COVID-19 vaccination.

The study author and experts interviewed disclosed no relevant financial relationships.

The Food and Drug Administration granted an accelerated approval April 24, 2021, for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.

The new product, loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), is the first and only CD19-targeted antibody-drug conjugate approved for this disease.

DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, said in a company press release.

The company also cited data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
 

Accelerated approval based on ORR

The accelerated approval was based on overall response rate data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.

The trial was conducted in 145 patients with relapsed/refractory DLBCL who had already tried at least two lines of systemic therapy. Dr. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or chimeric antigen receptor T-cell therapy.

The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).

Patients had a median time to response of 1.3 months and the median duration of response for the 70 responders was 10.3 months.

“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.

A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.

The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In the LOTIS-2 trial, the most common (≥10%) grade 3 or higher treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).

Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.

Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase. Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
 

Warnings on effusions, infections, and skin reactions

The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.

Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.

The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

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

The Food and Drug Administration granted an accelerated approval April 24, 2021, for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.

The new product, loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), is the first and only CD19-targeted antibody-drug conjugate approved for this disease.

DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, said in a company press release.

The company also cited data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
 

Accelerated approval based on ORR

The accelerated approval was based on overall response rate data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.

The trial was conducted in 145 patients with relapsed/refractory DLBCL who had already tried at least two lines of systemic therapy. Dr. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or chimeric antigen receptor T-cell therapy.

The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).

Patients had a median time to response of 1.3 months and the median duration of response for the 70 responders was 10.3 months.

“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.

A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.

The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In the LOTIS-2 trial, the most common (≥10%) grade 3 or higher treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).

Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.

Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase. Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
 

Warnings on effusions, infections, and skin reactions

The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.

Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.

The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

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

The Food and Drug Administration granted an accelerated approval April 24, 2021, for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.

The new product, loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), is the first and only CD19-targeted antibody-drug conjugate approved for this disease.

DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, said in a company press release.

The company also cited data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
 

Accelerated approval based on ORR

The accelerated approval was based on overall response rate data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.

The trial was conducted in 145 patients with relapsed/refractory DLBCL who had already tried at least two lines of systemic therapy. Dr. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or chimeric antigen receptor T-cell therapy.

The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).

Patients had a median time to response of 1.3 months and the median duration of response for the 70 responders was 10.3 months.

“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.

A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.

The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In the LOTIS-2 trial, the most common (≥10%) grade 3 or higher treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).

Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.

Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase. Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
 

Warnings on effusions, infections, and skin reactions

The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.

Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.

The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

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

Acute kidney injury (AKI) is a frequent complication among patients hospitalized for COVID-19, with incidence rates of 39% and 52% in two independent, European case series presented recently at the International Society of Nephrology: 2021 World Congress. Many of the cases progressed to more severe, stage 3 AKI. Factors linked with incident AKI in the two reports included use of mechanical ventilation, vasopressors, or diuretics, and elevations in inflammatory markers.

Mohammed Haneefa Nizamudeen/Getty Images

The new findings confirm several U.S. reports published during the past year. In those reports, roughly a third of patients hospitalized for COVID-19 developed AKI during their hospital stay, said Jay L. Koyner, MD, during another renal conference, the National Kidney Foundation 2021 Spring Clinical Meetings.

Experience has shown it’s bad news when hospitalized COVID-19 patients develop AKI, which can prove fatal or can lead to the development or worsening of chronic kidney disease (CKD), which in some cases rapidly progresses to end-stage disease.
 

COVID-19 giving nephrologists an opportunity to improve AKI care

“COVID is giving us an opportunity to do a better job of taking care of patients who develop AKI, which is something that nephrologists have not often excelled at doing,” said Dr. Koyner, professor and director of the nephrology ICU at the University of Chicago.

“Many studies will look at how we can manage COVID-19 patients better after they develop AKI, because I suspect a large number of these patients will wind up with CKD,” Dr. Koyner said during his talk.

He cited several lessons from reports of AKI that occurs in patients hospitalized for COVID-19:

• Preexisting CKD, , and severe COVID-19 appear to be risk factors for developing COVID-related AKI.
• Patients who develop AKI during acutely severe COVID-19 may have slightly worse outcomes than patients without COVID-19 who develop AKI.
• Certain genetic susceptibilities may play a role in developing COVID-19–related AKI.
• Routine follow-up of AKI is generally inadequate and is not standardized, whether AKI develops while ill with COVID-19 or in other settings.

The most encouraging AKI takeaway from COVID-19’s first year is that its incidence among patients hospitalized with COVID-19 appears to have dropped from very high rates early on, possibly because of more routine use of steroids for critically ill patients with COVID-19 and a reduction in the use of ventilators, Dr. Koyner suggested.
 

In-hospital diuretic treatment links with AKI

One of the World Congress of Nephrology reports involved 1,248 patients admitted with confirmed COVID-19 at two tertiary care hospitals in London during March–May 2020. The average age of the patients was 69 years, 59% were men, and 17% had CKD at admission, as determined on the basis of estimated glomerular filtration rate <60 mL/min per 1.73 m².

During hospitalization, 487 patients (39%) developed AKI, including 175 (14%) with stage 3 AKI and 109 (9%) who required renal replacement therapy (dialysis or kidney transplant). The incidence of AKI peaked 5 weeks after COVID-19 admission, Paul Jewell and associates from King’s College Hospital, London, reported in a poster.

Multivariate analysis identified several demographic and clinical variables that were significantly linked with an increased risk of developing AKI: male sex (which boosted risk by 55%), Black race (79% higher risk), CKD at admission (triple the risk), being hypertensive on admission (73% higher risk), and being administered diuretics during hospitalization (69% higher risk).

The findings of a risk linked with diuretic use “supports the cautious use of diuretics in patients hospitalized with COVID-19, especially in the presence of background renal impairment,” the authors said.

For patients with incident AKI, the 30-day mortality rate was significantly increased; mortality was 59% higher among patients who developed stage 1 AKI and was roughly triple among patients who developed stage 2 or 3 AKI.
 

Second report links ventilation, vasopressors with worse AKI

A separate report from clinicians at Charité Hospital, Berlin, retrospectively analyzed 223 patients admitted with symptomatic COVID-19 to three Charité sites during March–June 2020. During hospitalization, 117 patients (52%) developed AKI, including 70 (31%) with stage 3 disease; 67 (30%) required renal replacement therapy. Half the patients with stage 3 AKI required ICU admission.

Compared with patients with less severe AKI, patients who developed stage 3 AKI were more often male, older, and had a higher body mass index.

In a multivariate model, compared with patients who developed less severe AKI, those who developed stage 3 disease also were significantly more likely to have received mechanical ventilation or vasopressor drugs and were more likely to have increased levels of leukocytes or procalcitonin, two inflammatory markers, Jan-Hendrink B. Hardenburg, MD, a Charité nephrologist, and associates reported in a poster at the meeting.

Mechanical ventilation was linked with a sixfold higher rate of stage 3 AKI, and treatment with vasopressor drugs was linked with a threefold higher rate. Elevations in procalcitonin or leukocyte levels were linked with about 60% increases in rates of stage 3 AKI. For both of these risk factors, temporal relationships were tighter; increases in both values appeared just before onset of stage 3 disease.

Dr. Joyner has been a speaker on behalf of NXStage Medical; a consultant to Astute Medical, Baxter, Mallinckrodt, Pfizer, and Sphingotec; and he has received research funding from Astute, Bioporto, NxStage, and Satellite Healthcare. Mr. Jewell and Dr. Hardenburg disclosed no relevant financial relationships.

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

Acute kidney injury (AKI) is a frequent complication among patients hospitalized for COVID-19, with incidence rates of 39% and 52% in two independent, European case series presented recently at the International Society of Nephrology: 2021 World Congress. Many of the cases progressed to more severe, stage 3 AKI. Factors linked with incident AKI in the two reports included use of mechanical ventilation, vasopressors, or diuretics, and elevations in inflammatory markers.

Mohammed Haneefa Nizamudeen/Getty Images

The new findings confirm several U.S. reports published during the past year. In those reports, roughly a third of patients hospitalized for COVID-19 developed AKI during their hospital stay, said Jay L. Koyner, MD, during another renal conference, the National Kidney Foundation 2021 Spring Clinical Meetings.

Experience has shown it’s bad news when hospitalized COVID-19 patients develop AKI, which can prove fatal or can lead to the development or worsening of chronic kidney disease (CKD), which in some cases rapidly progresses to end-stage disease.
 

COVID-19 giving nephrologists an opportunity to improve AKI care

“COVID is giving us an opportunity to do a better job of taking care of patients who develop AKI, which is something that nephrologists have not often excelled at doing,” said Dr. Koyner, professor and director of the nephrology ICU at the University of Chicago.

“Many studies will look at how we can manage COVID-19 patients better after they develop AKI, because I suspect a large number of these patients will wind up with CKD,” Dr. Koyner said during his talk.

He cited several lessons from reports of AKI that occurs in patients hospitalized for COVID-19:

• Preexisting CKD, , and severe COVID-19 appear to be risk factors for developing COVID-related AKI.
• Patients who develop AKI during acutely severe COVID-19 may have slightly worse outcomes than patients without COVID-19 who develop AKI.
• Certain genetic susceptibilities may play a role in developing COVID-19–related AKI.
• Routine follow-up of AKI is generally inadequate and is not standardized, whether AKI develops while ill with COVID-19 or in other settings.

The most encouraging AKI takeaway from COVID-19’s first year is that its incidence among patients hospitalized with COVID-19 appears to have dropped from very high rates early on, possibly because of more routine use of steroids for critically ill patients with COVID-19 and a reduction in the use of ventilators, Dr. Koyner suggested.
 

In-hospital diuretic treatment links with AKI

One of the World Congress of Nephrology reports involved 1,248 patients admitted with confirmed COVID-19 at two tertiary care hospitals in London during March–May 2020. The average age of the patients was 69 years, 59% were men, and 17% had CKD at admission, as determined on the basis of estimated glomerular filtration rate <60 mL/min per 1.73 m².

During hospitalization, 487 patients (39%) developed AKI, including 175 (14%) with stage 3 AKI and 109 (9%) who required renal replacement therapy (dialysis or kidney transplant). The incidence of AKI peaked 5 weeks after COVID-19 admission, Paul Jewell and associates from King’s College Hospital, London, reported in a poster.

Multivariate analysis identified several demographic and clinical variables that were significantly linked with an increased risk of developing AKI: male sex (which boosted risk by 55%), Black race (79% higher risk), CKD at admission (triple the risk), being hypertensive on admission (73% higher risk), and being administered diuretics during hospitalization (69% higher risk).

The findings of a risk linked with diuretic use “supports the cautious use of diuretics in patients hospitalized with COVID-19, especially in the presence of background renal impairment,” the authors said.

For patients with incident AKI, the 30-day mortality rate was significantly increased; mortality was 59% higher among patients who developed stage 1 AKI and was roughly triple among patients who developed stage 2 or 3 AKI.
 

Second report links ventilation, vasopressors with worse AKI

A separate report from clinicians at Charité Hospital, Berlin, retrospectively analyzed 223 patients admitted with symptomatic COVID-19 to three Charité sites during March–June 2020. During hospitalization, 117 patients (52%) developed AKI, including 70 (31%) with stage 3 disease; 67 (30%) required renal replacement therapy. Half the patients with stage 3 AKI required ICU admission.

Compared with patients with less severe AKI, patients who developed stage 3 AKI were more often male, older, and had a higher body mass index.

In a multivariate model, compared with patients who developed less severe AKI, those who developed stage 3 disease also were significantly more likely to have received mechanical ventilation or vasopressor drugs and were more likely to have increased levels of leukocytes or procalcitonin, two inflammatory markers, Jan-Hendrink B. Hardenburg, MD, a Charité nephrologist, and associates reported in a poster at the meeting.

Mechanical ventilation was linked with a sixfold higher rate of stage 3 AKI, and treatment with vasopressor drugs was linked with a threefold higher rate. Elevations in procalcitonin or leukocyte levels were linked with about 60% increases in rates of stage 3 AKI. For both of these risk factors, temporal relationships were tighter; increases in both values appeared just before onset of stage 3 disease.

Dr. Joyner has been a speaker on behalf of NXStage Medical; a consultant to Astute Medical, Baxter, Mallinckrodt, Pfizer, and Sphingotec; and he has received research funding from Astute, Bioporto, NxStage, and Satellite Healthcare. Mr. Jewell and Dr. Hardenburg disclosed no relevant financial relationships.

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

Acute kidney injury (AKI) is a frequent complication among patients hospitalized for COVID-19, with incidence rates of 39% and 52% in two independent, European case series presented recently at the International Society of Nephrology: 2021 World Congress. Many of the cases progressed to more severe, stage 3 AKI. Factors linked with incident AKI in the two reports included use of mechanical ventilation, vasopressors, or diuretics, and elevations in inflammatory markers.

Mohammed Haneefa Nizamudeen/Getty Images

The new findings confirm several U.S. reports published during the past year. In those reports, roughly a third of patients hospitalized for COVID-19 developed AKI during their hospital stay, said Jay L. Koyner, MD, during another renal conference, the National Kidney Foundation 2021 Spring Clinical Meetings.

Experience has shown it’s bad news when hospitalized COVID-19 patients develop AKI, which can prove fatal or can lead to the development or worsening of chronic kidney disease (CKD), which in some cases rapidly progresses to end-stage disease.
 

COVID-19 giving nephrologists an opportunity to improve AKI care

“COVID is giving us an opportunity to do a better job of taking care of patients who develop AKI, which is something that nephrologists have not often excelled at doing,” said Dr. Koyner, professor and director of the nephrology ICU at the University of Chicago.

“Many studies will look at how we can manage COVID-19 patients better after they develop AKI, because I suspect a large number of these patients will wind up with CKD,” Dr. Koyner said during his talk.

He cited several lessons from reports of AKI that occurs in patients hospitalized for COVID-19:

• Preexisting CKD, , and severe COVID-19 appear to be risk factors for developing COVID-related AKI.
• Patients who develop AKI during acutely severe COVID-19 may have slightly worse outcomes than patients without COVID-19 who develop AKI.
• Certain genetic susceptibilities may play a role in developing COVID-19–related AKI.
• Routine follow-up of AKI is generally inadequate and is not standardized, whether AKI develops while ill with COVID-19 or in other settings.

The most encouraging AKI takeaway from COVID-19’s first year is that its incidence among patients hospitalized with COVID-19 appears to have dropped from very high rates early on, possibly because of more routine use of steroids for critically ill patients with COVID-19 and a reduction in the use of ventilators, Dr. Koyner suggested.
 

In-hospital diuretic treatment links with AKI

One of the World Congress of Nephrology reports involved 1,248 patients admitted with confirmed COVID-19 at two tertiary care hospitals in London during March–May 2020. The average age of the patients was 69 years, 59% were men, and 17% had CKD at admission, as determined on the basis of estimated glomerular filtration rate <60 mL/min per 1.73 m².

During hospitalization, 487 patients (39%) developed AKI, including 175 (14%) with stage 3 AKI and 109 (9%) who required renal replacement therapy (dialysis or kidney transplant). The incidence of AKI peaked 5 weeks after COVID-19 admission, Paul Jewell and associates from King’s College Hospital, London, reported in a poster.

Multivariate analysis identified several demographic and clinical variables that were significantly linked with an increased risk of developing AKI: male sex (which boosted risk by 55%), Black race (79% higher risk), CKD at admission (triple the risk), being hypertensive on admission (73% higher risk), and being administered diuretics during hospitalization (69% higher risk).

The findings of a risk linked with diuretic use “supports the cautious use of diuretics in patients hospitalized with COVID-19, especially in the presence of background renal impairment,” the authors said.

For patients with incident AKI, the 30-day mortality rate was significantly increased; mortality was 59% higher among patients who developed stage 1 AKI and was roughly triple among patients who developed stage 2 or 3 AKI.
 

Second report links ventilation, vasopressors with worse AKI

A separate report from clinicians at Charité Hospital, Berlin, retrospectively analyzed 223 patients admitted with symptomatic COVID-19 to three Charité sites during March–June 2020. During hospitalization, 117 patients (52%) developed AKI, including 70 (31%) with stage 3 disease; 67 (30%) required renal replacement therapy. Half the patients with stage 3 AKI required ICU admission.

Compared with patients with less severe AKI, patients who developed stage 3 AKI were more often male, older, and had a higher body mass index.

In a multivariate model, compared with patients who developed less severe AKI, those who developed stage 3 disease also were significantly more likely to have received mechanical ventilation or vasopressor drugs and were more likely to have increased levels of leukocytes or procalcitonin, two inflammatory markers, Jan-Hendrink B. Hardenburg, MD, a Charité nephrologist, and associates reported in a poster at the meeting.

Mechanical ventilation was linked with a sixfold higher rate of stage 3 AKI, and treatment with vasopressor drugs was linked with a threefold higher rate. Elevations in procalcitonin or leukocyte levels were linked with about 60% increases in rates of stage 3 AKI. For both of these risk factors, temporal relationships were tighter; increases in both values appeared just before onset of stage 3 disease.

Dr. Joyner has been a speaker on behalf of NXStage Medical; a consultant to Astute Medical, Baxter, Mallinckrodt, Pfizer, and Sphingotec; and he has received research funding from Astute, Bioporto, NxStage, and Satellite Healthcare. Mr. Jewell and Dr. Hardenburg disclosed no relevant financial relationships.

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

One consequence of the ongoing opioid epidemic in the United States may be an increase in the number of hemorrhagic strokes caused by infective endocarditis, research suggests.

Intravenous drug use (IVDU) can cause this bacterial infection of the heart. In a single-center study, infective endocarditis was associated with an increase in the risk for hemorrhagic stroke as well as an increase in health care use and costs.

“Patients who are known IV drug users who have endocarditis should be more carefully screened for symptoms of cardiovascular disease,” Shahid M. Nimjee, MD, PhD, associate professor of neurosurgery and surgical director of the Comprehensive Stroke Center at the Ohio State University Wexner Medical Center, Columbus, said in a press release.

The findings were presented at the International Stroke Conference sponsored by the American Heart Association.

In the United States, 47,000 patients are treated in the hospital for endocarditis each year. Endocarditis increases the risk for stroke, which can entail significant morbidity and mortality, the authors noted.

IVDU is a risk factor for endocarditis. In the context of the opioid epidemic, Dr. Nimjee and colleagues sought to compare the risk for stroke among patients with endocarditis from IVDU with the risk among patients with endocarditis from other causes.

They retrospectively studied patients who had undergone treatment for infective endocarditis at Wexner Medical Center between Jan. 1, 2014, and July 1, 2018. They examined patients’ concomitant intravenous drug abuse and evaluated demographics, risk factors, and associated costs.
 

Dramatic increase

In all, 351 patients met the study’s inclusion criteria, and 170 (48%) had a history of IVDU-associated endocarditis. The incidence of patients with IVDU-associated endocarditis increased 630% from 2014 to 2018.

The prevalence of overall intracranial hemorrhage was increased among patients with IVDU, compared with those without (25.9% vs. 13.9%; P = .005).

This increase in prevalence included increases in intraparenchymal hemorrhage (12.4% vs. 5.1%; P = .012), subarachnoid hemorrhage (17.6% vs. 4.4%; P = .0001), and cerebral microbleeds (14.1% vs. 7.2%; P = .022).

IVDU also was associated with an increase in prevalence of infectious intracranial aneurysm (10.6% vs. 1.8%; P = .0001) and brain abscess (4.7% vs. 1.1%; P = .025).

Compared with patients with endocarditis from other causes, significantly higher numbers of patients with IVDU-associated endocarditis were homeless (5.9% vs. 1.1%; P = .014), uninsured (10.0% vs. 2.8%; P = .005), and unemployed (75.9% vs. 31.7%; P = .0001).

Medical costs were more than twice as high among patients with endocarditis from IVDU than among those with endocarditis from other causes. The difference in health care costs during admission per patient was more than $100,000.

“The wider societal impact of the opioid epidemic is not well understood,” Dr. Nimjee said in the press release. “Our research suggests that the impact of the opioid epidemic is far-reaching and contributes to increased costs in the criminal justice, health care systems, and the workplace. The increased costs can be particularly substantial for stroke care.”
 

Nationwide data desirable

“Past publications from the U.S. have shown an increase in incidence of IVDU-related endocarditis, and the current publication emphasizes this worrying trend,” Manuel Bolognese, MD, head of the stroke center at the Lucerne (Switzerland) Cantonal Hospital, said in an interview. “The higher degree of hemorrhagic strokes and brain abscesses as further complications is alarming as well and shows that IVDU-related endocarditis is becoming a more and more relevant medical problem in the U.S., with high morbidity and mortality.”

The study period is long enough to show a clear trend of increasing incidence of IVDU-related endocarditis, Dr. Bolognese said. The study’s biggest weaknesses are its retrospective design and restriction to a single center.

“Without knowing the prevalence of drug abuse and the socioeconomical situation in Columbus, it is difficult to generalize these findings to other regions in the U.S.A. or even abroad,” he said.

Also, the abstract does not provide some essential information, said Dr. Bolognese. It would be important to know which valve was affected in each patient, which bacteria were identified, whether patients also used nonopioid drugs, and what each patient’s immune status was.

A lack of sterile material such as syringes could explain the apparent association between IVDU-associated endocarditis and low socioeconomic status, said Dr. Bolognese. Delayed presentation to medical institutions because of a lack of insurance could have led to a more complicated course.

“It would be interesting to see numbers from a broader spectrum in a nationwide registry,” said Dr. Bolognese. “It might be worth studying interventions to improve the hygienic aspects (like supply of sterile material, especially in the most vulnerable groups, like homeless people) or to provide easier access to emergency health care despite lack of insurance, which could decrease the incidence of IVDU.”

Dr. Nimjee and Dr. Bolognese disclosed no relevant financial relationships.

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

One consequence of the ongoing opioid epidemic in the United States may be an increase in the number of hemorrhagic strokes caused by infective endocarditis, research suggests.

Intravenous drug use (IVDU) can cause this bacterial infection of the heart. In a single-center study, infective endocarditis was associated with an increase in the risk for hemorrhagic stroke as well as an increase in health care use and costs.

“Patients who are known IV drug users who have endocarditis should be more carefully screened for symptoms of cardiovascular disease,” Shahid M. Nimjee, MD, PhD, associate professor of neurosurgery and surgical director of the Comprehensive Stroke Center at the Ohio State University Wexner Medical Center, Columbus, said in a press release.

The findings were presented at the International Stroke Conference sponsored by the American Heart Association.

In the United States, 47,000 patients are treated in the hospital for endocarditis each year. Endocarditis increases the risk for stroke, which can entail significant morbidity and mortality, the authors noted.

IVDU is a risk factor for endocarditis. In the context of the opioid epidemic, Dr. Nimjee and colleagues sought to compare the risk for stroke among patients with endocarditis from IVDU with the risk among patients with endocarditis from other causes.

They retrospectively studied patients who had undergone treatment for infective endocarditis at Wexner Medical Center between Jan. 1, 2014, and July 1, 2018. They examined patients’ concomitant intravenous drug abuse and evaluated demographics, risk factors, and associated costs.
 

Dramatic increase

In all, 351 patients met the study’s inclusion criteria, and 170 (48%) had a history of IVDU-associated endocarditis. The incidence of patients with IVDU-associated endocarditis increased 630% from 2014 to 2018.

The prevalence of overall intracranial hemorrhage was increased among patients with IVDU, compared with those without (25.9% vs. 13.9%; P = .005).

This increase in prevalence included increases in intraparenchymal hemorrhage (12.4% vs. 5.1%; P = .012), subarachnoid hemorrhage (17.6% vs. 4.4%; P = .0001), and cerebral microbleeds (14.1% vs. 7.2%; P = .022).

IVDU also was associated with an increase in prevalence of infectious intracranial aneurysm (10.6% vs. 1.8%; P = .0001) and brain abscess (4.7% vs. 1.1%; P = .025).

Compared with patients with endocarditis from other causes, significantly higher numbers of patients with IVDU-associated endocarditis were homeless (5.9% vs. 1.1%; P = .014), uninsured (10.0% vs. 2.8%; P = .005), and unemployed (75.9% vs. 31.7%; P = .0001).

Medical costs were more than twice as high among patients with endocarditis from IVDU than among those with endocarditis from other causes. The difference in health care costs during admission per patient was more than $100,000.

“The wider societal impact of the opioid epidemic is not well understood,” Dr. Nimjee said in the press release. “Our research suggests that the impact of the opioid epidemic is far-reaching and contributes to increased costs in the criminal justice, health care systems, and the workplace. The increased costs can be particularly substantial for stroke care.”
 

Nationwide data desirable

“Past publications from the U.S. have shown an increase in incidence of IVDU-related endocarditis, and the current publication emphasizes this worrying trend,” Manuel Bolognese, MD, head of the stroke center at the Lucerne (Switzerland) Cantonal Hospital, said in an interview. “The higher degree of hemorrhagic strokes and brain abscesses as further complications is alarming as well and shows that IVDU-related endocarditis is becoming a more and more relevant medical problem in the U.S., with high morbidity and mortality.”

The study period is long enough to show a clear trend of increasing incidence of IVDU-related endocarditis, Dr. Bolognese said. The study’s biggest weaknesses are its retrospective design and restriction to a single center.

“Without knowing the prevalence of drug abuse and the socioeconomical situation in Columbus, it is difficult to generalize these findings to other regions in the U.S.A. or even abroad,” he said.

Also, the abstract does not provide some essential information, said Dr. Bolognese. It would be important to know which valve was affected in each patient, which bacteria were identified, whether patients also used nonopioid drugs, and what each patient’s immune status was.

A lack of sterile material such as syringes could explain the apparent association between IVDU-associated endocarditis and low socioeconomic status, said Dr. Bolognese. Delayed presentation to medical institutions because of a lack of insurance could have led to a more complicated course.

“It would be interesting to see numbers from a broader spectrum in a nationwide registry,” said Dr. Bolognese. “It might be worth studying interventions to improve the hygienic aspects (like supply of sterile material, especially in the most vulnerable groups, like homeless people) or to provide easier access to emergency health care despite lack of insurance, which could decrease the incidence of IVDU.”

Dr. Nimjee and Dr. Bolognese disclosed no relevant financial relationships.

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

One consequence of the ongoing opioid epidemic in the United States may be an increase in the number of hemorrhagic strokes caused by infective endocarditis, research suggests.

Intravenous drug use (IVDU) can cause this bacterial infection of the heart. In a single-center study, infective endocarditis was associated with an increase in the risk for hemorrhagic stroke as well as an increase in health care use and costs.

“Patients who are known IV drug users who have endocarditis should be more carefully screened for symptoms of cardiovascular disease,” Shahid M. Nimjee, MD, PhD, associate professor of neurosurgery and surgical director of the Comprehensive Stroke Center at the Ohio State University Wexner Medical Center, Columbus, said in a press release.

The findings were presented at the International Stroke Conference sponsored by the American Heart Association.

In the United States, 47,000 patients are treated in the hospital for endocarditis each year. Endocarditis increases the risk for stroke, which can entail significant morbidity and mortality, the authors noted.

IVDU is a risk factor for endocarditis. In the context of the opioid epidemic, Dr. Nimjee and colleagues sought to compare the risk for stroke among patients with endocarditis from IVDU with the risk among patients with endocarditis from other causes.

They retrospectively studied patients who had undergone treatment for infective endocarditis at Wexner Medical Center between Jan. 1, 2014, and July 1, 2018. They examined patients’ concomitant intravenous drug abuse and evaluated demographics, risk factors, and associated costs.
 

Dramatic increase

In all, 351 patients met the study’s inclusion criteria, and 170 (48%) had a history of IVDU-associated endocarditis. The incidence of patients with IVDU-associated endocarditis increased 630% from 2014 to 2018.

The prevalence of overall intracranial hemorrhage was increased among patients with IVDU, compared with those without (25.9% vs. 13.9%; P = .005).

This increase in prevalence included increases in intraparenchymal hemorrhage (12.4% vs. 5.1%; P = .012), subarachnoid hemorrhage (17.6% vs. 4.4%; P = .0001), and cerebral microbleeds (14.1% vs. 7.2%; P = .022).

IVDU also was associated with an increase in prevalence of infectious intracranial aneurysm (10.6% vs. 1.8%; P = .0001) and brain abscess (4.7% vs. 1.1%; P = .025).

Compared with patients with endocarditis from other causes, significantly higher numbers of patients with IVDU-associated endocarditis were homeless (5.9% vs. 1.1%; P = .014), uninsured (10.0% vs. 2.8%; P = .005), and unemployed (75.9% vs. 31.7%; P = .0001).

Medical costs were more than twice as high among patients with endocarditis from IVDU than among those with endocarditis from other causes. The difference in health care costs during admission per patient was more than $100,000.

“The wider societal impact of the opioid epidemic is not well understood,” Dr. Nimjee said in the press release. “Our research suggests that the impact of the opioid epidemic is far-reaching and contributes to increased costs in the criminal justice, health care systems, and the workplace. The increased costs can be particularly substantial for stroke care.”
 

Nationwide data desirable

“Past publications from the U.S. have shown an increase in incidence of IVDU-related endocarditis, and the current publication emphasizes this worrying trend,” Manuel Bolognese, MD, head of the stroke center at the Lucerne (Switzerland) Cantonal Hospital, said in an interview. “The higher degree of hemorrhagic strokes and brain abscesses as further complications is alarming as well and shows that IVDU-related endocarditis is becoming a more and more relevant medical problem in the U.S., with high morbidity and mortality.”

The study period is long enough to show a clear trend of increasing incidence of IVDU-related endocarditis, Dr. Bolognese said. The study’s biggest weaknesses are its retrospective design and restriction to a single center.

“Without knowing the prevalence of drug abuse and the socioeconomical situation in Columbus, it is difficult to generalize these findings to other regions in the U.S.A. or even abroad,” he said.

Also, the abstract does not provide some essential information, said Dr. Bolognese. It would be important to know which valve was affected in each patient, which bacteria were identified, whether patients also used nonopioid drugs, and what each patient’s immune status was.

A lack of sterile material such as syringes could explain the apparent association between IVDU-associated endocarditis and low socioeconomic status, said Dr. Bolognese. Delayed presentation to medical institutions because of a lack of insurance could have led to a more complicated course.

“It would be interesting to see numbers from a broader spectrum in a nationwide registry,” said Dr. Bolognese. “It might be worth studying interventions to improve the hygienic aspects (like supply of sterile material, especially in the most vulnerable groups, like homeless people) or to provide easier access to emergency health care despite lack of insurance, which could decrease the incidence of IVDU.”

Dr. Nimjee and Dr. Bolognese disclosed no relevant financial relationships.

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

After a steep rise in the beginning of the COVID-19 pandemic and a slow decline that started in the summer, telehealth consults in dermatology remain far elevated over those provided prior to the COVID-19 pandemic. But it is not clear whether the current rate will fall further, be sustained, or even climb again, according to data presented and opinions expressed in a forum on this topic at the American Academy of Dermatology Virtual Meeting Experience.

There are many unknowns, not least of which is future reimbursement from the Centers for Medicare & Medicaid Services and other third-party payers, according to several participants in a scientific session devoted to this topic. The CARES Act, which was passed in the early stages of the pandemic, provided only a temporary increase in reimbursement for telehealth. Postpandemic payments for telehealth services are yet undetermined.

Many of the assembled experts are convinced that teledermatology will continue to be offered at far higher rates than prior to the pandemic, but many issues, including physician acceptance of this approach remain unresolved. This was reflected in an AAD survey of members conducted in June 2020.

“Seventy percent of dermatologists responded that teledermatology will continue, but only 58% reported that they intend to offer it,” after the pandemic, reported Jules Lipoff, MD, assistant professor of dermatology at the University of Pennsylvania, Philadelphia, who is one of the authors of the paper that reported the results.

The low relative proportion of dermatologists planning to participate in teledermatology might at least in part reflect uncertainty about reimbursement, according to Dr. Lipoff, who is the outgoing chair of the AAD teledermatology task force

Many dermatologists might find it difficult to opt out of telehealth. In some types of care, such as follow-up visits, a combination of patient demand and institutional policy, particularly if reimbursement is adequate, might compel or at least strongly incentivize teledermatology services.

“Now that telemedicine has gotten out there, we will never go back to what once was normal practice,” Dr. Lipoff predicted. According to Dr. Lipoff, there was a great deal of data even prior to the pandemic to conclude that mobile dermatology is “an acceptable equivalent” for delivering many types of dermatologic care.

The rapid evolution in telemedicine is remarkable. According to the results of the AAD survey, 14.1% of dermatologists had experience with teledermatology prior to the COVID-19 pandemic, which increased to 96.9% by June, 2020, when the survey was conducted. Nearly 600 dermatologists completed the survey, for a 13.6% response rate.

At the beginning of the pandemic, the CARES act, along with other pandemic legislation and policy changes, changed the landscape of telemedicine by providing reimbursement commensurate with in-office visits, modifying HIPAA regulations, and permitting reciprocal licensing to allow physicians to provide care to patients who had moved out of the state. While these were among the factors that facilitated the phenomenal growth in telemedicine, nearly all of these changes were temporary or are subject to revision.

“Reimbursement [for telehealth] was very low prior to the pandemic,” noted Elizabeth K. Jones, MD, assistant professor of dermatology, Thomas Jefferson University, Philadelphia. While many physicians and policy makers were convinced that reimbursement levels had to be increased temporarily to provide medical care when in-office visits were unsafe, Dr. Jones said it is unlikely that pandemic reimbursement rates will be preserved. But recent statements from the CMS foreshadow lower rates for most video and telephone consults, she added.

Reimbursement is not the only consideration. George Han, MD, PhD, chief of teledermatology at the Icahn School of Medicine at Mount Sinai, New York, spoke about the frustration of using imperfect tools. He, like many dermatologists, have become familiar with the difficulty of making a definitive diagnosis from transmitted images of skin lesions.

As long as patients communicate with personal computers and phones under variable lighting conditions, this problem might never go away, but suboptimal quality images do not necessarily preclude other types of consults, particularly follow-up visits, according to Dr. Han, who is also system medical director for dermatology at Mount Sinai Health System.

“Now that patients know about teledermatology, they are for it,” he said. He suggested that increased efficiency of follow-up using telemedicine for both patients and physicians might increase the frequency with which these types of visits are scheduled. Citing evidence that follow-up visits increase patient retention rates, Dr. Han sees these visits among the routine uses of telemedicine when the pandemic is over.

At the height of the pandemic, teledermatology was employed broadly, but after the pandemic, Dr. Han and others predict a narrower focus. Some consults, such as those for acne or other conditions reasonably treated on the basis of patient history, appear to lend themselves to telemedicine. Others, such as a skin check for malignancy, might not.

As the role of telemedicine is sorted out and finds its equilibrium in a postpandemic world, Dr. Lipoff pointed out the need to consider populations without good-quality internet access. Without specific strategies to ensure these patients are not forgotten, he warned of “wealthier patients consuming more than their fair share” of health care resources, further widening an existing disparity.

“Is telemedicine here to stay? It is clear that, yes, it is in some way,” said Dr. Lipoff, who sees no reason for dermatology to be an exception.
 

Dr. Lipoff reported a financial relationship with AcneAway. The other investigators reported no potential conflicts of interest related to telemedicine.

After a steep rise in the beginning of the COVID-19 pandemic and a slow decline that started in the summer, telehealth consults in dermatology remain far elevated over those provided prior to the COVID-19 pandemic. But it is not clear whether the current rate will fall further, be sustained, or even climb again, according to data presented and opinions expressed in a forum on this topic at the American Academy of Dermatology Virtual Meeting Experience.

There are many unknowns, not least of which is future reimbursement from the Centers for Medicare & Medicaid Services and other third-party payers, according to several participants in a scientific session devoted to this topic. The CARES Act, which was passed in the early stages of the pandemic, provided only a temporary increase in reimbursement for telehealth. Postpandemic payments for telehealth services are yet undetermined.

Many of the assembled experts are convinced that teledermatology will continue to be offered at far higher rates than prior to the pandemic, but many issues, including physician acceptance of this approach remain unresolved. This was reflected in an AAD survey of members conducted in June 2020.

“Seventy percent of dermatologists responded that teledermatology will continue, but only 58% reported that they intend to offer it,” after the pandemic, reported Jules Lipoff, MD, assistant professor of dermatology at the University of Pennsylvania, Philadelphia, who is one of the authors of the paper that reported the results.

The low relative proportion of dermatologists planning to participate in teledermatology might at least in part reflect uncertainty about reimbursement, according to Dr. Lipoff, who is the outgoing chair of the AAD teledermatology task force

Many dermatologists might find it difficult to opt out of telehealth. In some types of care, such as follow-up visits, a combination of patient demand and institutional policy, particularly if reimbursement is adequate, might compel or at least strongly incentivize teledermatology services.

“Now that telemedicine has gotten out there, we will never go back to what once was normal practice,” Dr. Lipoff predicted. According to Dr. Lipoff, there was a great deal of data even prior to the pandemic to conclude that mobile dermatology is “an acceptable equivalent” for delivering many types of dermatologic care.

The rapid evolution in telemedicine is remarkable. According to the results of the AAD survey, 14.1% of dermatologists had experience with teledermatology prior to the COVID-19 pandemic, which increased to 96.9% by June, 2020, when the survey was conducted. Nearly 600 dermatologists completed the survey, for a 13.6% response rate.

At the beginning of the pandemic, the CARES act, along with other pandemic legislation and policy changes, changed the landscape of telemedicine by providing reimbursement commensurate with in-office visits, modifying HIPAA regulations, and permitting reciprocal licensing to allow physicians to provide care to patients who had moved out of the state. While these were among the factors that facilitated the phenomenal growth in telemedicine, nearly all of these changes were temporary or are subject to revision.

“Reimbursement [for telehealth] was very low prior to the pandemic,” noted Elizabeth K. Jones, MD, assistant professor of dermatology, Thomas Jefferson University, Philadelphia. While many physicians and policy makers were convinced that reimbursement levels had to be increased temporarily to provide medical care when in-office visits were unsafe, Dr. Jones said it is unlikely that pandemic reimbursement rates will be preserved. But recent statements from the CMS foreshadow lower rates for most video and telephone consults, she added.

Reimbursement is not the only consideration. George Han, MD, PhD, chief of teledermatology at the Icahn School of Medicine at Mount Sinai, New York, spoke about the frustration of using imperfect tools. He, like many dermatologists, have become familiar with the difficulty of making a definitive diagnosis from transmitted images of skin lesions.

As long as patients communicate with personal computers and phones under variable lighting conditions, this problem might never go away, but suboptimal quality images do not necessarily preclude other types of consults, particularly follow-up visits, according to Dr. Han, who is also system medical director for dermatology at Mount Sinai Health System.

“Now that patients know about teledermatology, they are for it,” he said. He suggested that increased efficiency of follow-up using telemedicine for both patients and physicians might increase the frequency with which these types of visits are scheduled. Citing evidence that follow-up visits increase patient retention rates, Dr. Han sees these visits among the routine uses of telemedicine when the pandemic is over.

At the height of the pandemic, teledermatology was employed broadly, but after the pandemic, Dr. Han and others predict a narrower focus. Some consults, such as those for acne or other conditions reasonably treated on the basis of patient history, appear to lend themselves to telemedicine. Others, such as a skin check for malignancy, might not.

As the role of telemedicine is sorted out and finds its equilibrium in a postpandemic world, Dr. Lipoff pointed out the need to consider populations without good-quality internet access. Without specific strategies to ensure these patients are not forgotten, he warned of “wealthier patients consuming more than their fair share” of health care resources, further widening an existing disparity.

“Is telemedicine here to stay? It is clear that, yes, it is in some way,” said Dr. Lipoff, who sees no reason for dermatology to be an exception.
 

Dr. Lipoff reported a financial relationship with AcneAway. The other investigators reported no potential conflicts of interest related to telemedicine.

After a steep rise in the beginning of the COVID-19 pandemic and a slow decline that started in the summer, telehealth consults in dermatology remain far elevated over those provided prior to the COVID-19 pandemic. But it is not clear whether the current rate will fall further, be sustained, or even climb again, according to data presented and opinions expressed in a forum on this topic at the American Academy of Dermatology Virtual Meeting Experience.

There are many unknowns, not least of which is future reimbursement from the Centers for Medicare & Medicaid Services and other third-party payers, according to several participants in a scientific session devoted to this topic. The CARES Act, which was passed in the early stages of the pandemic, provided only a temporary increase in reimbursement for telehealth. Postpandemic payments for telehealth services are yet undetermined.

Many of the assembled experts are convinced that teledermatology will continue to be offered at far higher rates than prior to the pandemic, but many issues, including physician acceptance of this approach remain unresolved. This was reflected in an AAD survey of members conducted in June 2020.

“Seventy percent of dermatologists responded that teledermatology will continue, but only 58% reported that they intend to offer it,” after the pandemic, reported Jules Lipoff, MD, assistant professor of dermatology at the University of Pennsylvania, Philadelphia, who is one of the authors of the paper that reported the results.

The low relative proportion of dermatologists planning to participate in teledermatology might at least in part reflect uncertainty about reimbursement, according to Dr. Lipoff, who is the outgoing chair of the AAD teledermatology task force

Many dermatologists might find it difficult to opt out of telehealth. In some types of care, such as follow-up visits, a combination of patient demand and institutional policy, particularly if reimbursement is adequate, might compel or at least strongly incentivize teledermatology services.

“Now that telemedicine has gotten out there, we will never go back to what once was normal practice,” Dr. Lipoff predicted. According to Dr. Lipoff, there was a great deal of data even prior to the pandemic to conclude that mobile dermatology is “an acceptable equivalent” for delivering many types of dermatologic care.

The rapid evolution in telemedicine is remarkable. According to the results of the AAD survey, 14.1% of dermatologists had experience with teledermatology prior to the COVID-19 pandemic, which increased to 96.9% by June, 2020, when the survey was conducted. Nearly 600 dermatologists completed the survey, for a 13.6% response rate.

At the beginning of the pandemic, the CARES act, along with other pandemic legislation and policy changes, changed the landscape of telemedicine by providing reimbursement commensurate with in-office visits, modifying HIPAA regulations, and permitting reciprocal licensing to allow physicians to provide care to patients who had moved out of the state. While these were among the factors that facilitated the phenomenal growth in telemedicine, nearly all of these changes were temporary or are subject to revision.

“Reimbursement [for telehealth] was very low prior to the pandemic,” noted Elizabeth K. Jones, MD, assistant professor of dermatology, Thomas Jefferson University, Philadelphia. While many physicians and policy makers were convinced that reimbursement levels had to be increased temporarily to provide medical care when in-office visits were unsafe, Dr. Jones said it is unlikely that pandemic reimbursement rates will be preserved. But recent statements from the CMS foreshadow lower rates for most video and telephone consults, she added.

Reimbursement is not the only consideration. George Han, MD, PhD, chief of teledermatology at the Icahn School of Medicine at Mount Sinai, New York, spoke about the frustration of using imperfect tools. He, like many dermatologists, have become familiar with the difficulty of making a definitive diagnosis from transmitted images of skin lesions.

As long as patients communicate with personal computers and phones under variable lighting conditions, this problem might never go away, but suboptimal quality images do not necessarily preclude other types of consults, particularly follow-up visits, according to Dr. Han, who is also system medical director for dermatology at Mount Sinai Health System.

“Now that patients know about teledermatology, they are for it,” he said. He suggested that increased efficiency of follow-up using telemedicine for both patients and physicians might increase the frequency with which these types of visits are scheduled. Citing evidence that follow-up visits increase patient retention rates, Dr. Han sees these visits among the routine uses of telemedicine when the pandemic is over.

At the height of the pandemic, teledermatology was employed broadly, but after the pandemic, Dr. Han and others predict a narrower focus. Some consults, such as those for acne or other conditions reasonably treated on the basis of patient history, appear to lend themselves to telemedicine. Others, such as a skin check for malignancy, might not.

As the role of telemedicine is sorted out and finds its equilibrium in a postpandemic world, Dr. Lipoff pointed out the need to consider populations without good-quality internet access. Without specific strategies to ensure these patients are not forgotten, he warned of “wealthier patients consuming more than their fair share” of health care resources, further widening an existing disparity.

“Is telemedicine here to stay? It is clear that, yes, it is in some way,” said Dr. Lipoff, who sees no reason for dermatology to be an exception.
 

Dr. Lipoff reported a financial relationship with AcneAway. The other investigators reported no potential conflicts of interest related to telemedicine.

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

A common cause of infant morbidity and hospitalization in developed countries, infant viral bronchiolitis, has long been bedeviled by treatment uncertainty beyond supportive care.

Rationales for most pharmacologic treatments continue to be debated, and clinical practice guidelines generally advise respiratory and hydration support, discouraging the use of chest radiography, albuterol, glucocorticoids, antibiotics, and epinephrine.

Despite evidence that the latter interventions are ineffective, they are still too often applied, according to two recent studies, one in Pediatrics, the other in JAMA Pediatrics.

“The pull of the therapeutic vacuum surrounding this disease has been noted in the pages of this journal for at least 50 years, with Wright and Beem writing in 1965 that ‘energies should not be frittered away by the annoyance of unnecessary or futile medications and procedures’ for the child with bronchiolitis,” said emergency physicians Matthew J. Lipshaw, MD, MS, of the Cincinnati Children’s Hospital Medical Center, and Todd A. Florin, MD, MSCE, of Ann and Robert H. Lurie Children’s Hospital of Chicago.

These remarks came in their editorial in Pediatrics wryly titled: “Don’t Just Do Something, Stand There” and published online to accompany a recent study of three network meta-analyses.

Led by Sarah A. Elliott, PhD, of the Alberta Research Centre for Health Evidence at the University of Alberta in Edmonton, this analysis amalgamated 150 randomized, controlled trials comparing a placebo or active comparator with any bronchodilator, glucocorticoid steroid, hypertonic saline solution, antibiotic, helium-oxygen therapy, or high-flow oxygen therapy. It then looked at the following outcomes in children aged 2 years and younger: hospital admission rate on day 1, hospital admission rate within 7 days, and total hospital length of stay.

Few treatments seemed more effective than nebulized placebo (0.9% saline) for short-term outcomes, the authors found. While nebulized epinephrine and nebulized hypertonic saline plus salbutamol appeared to reduce admission rates during the index ED presentation, and hypertonic saline, alone or in combination with epinephrine, seemed to reduce hospital stays, such treatment had no effect on admissions within 7 days of initial presentation. Furthermore, most benefits disappeared in higher-quality studies.

Concluding, albeit with weak evidence and low confidence, that some benefit might accrue with hypertonic saline with salbutamol to reduce admission rates on initial presentation to the ED, the authors called for well-designed studies on treatments in inpatients and outpatients.

According to Dr. Lipshaw, assistant professor of clinical pediatrics, the lack of benefit observed in superior studies limits the applicability of Dr. Elliott and colleagues’ results to immediate clinical practice. “These findings could be used, however, to target future high-quality studies toward the medications that they found might be useful,” he said in an interview.

For the present, other recent research augurs well for strategically reducing unnecessary care. In a paper published online in JAMA Pediatrics, Libby Haskell, MN, of the ED at Starship Children’s Hospital in Auckland, New Zealand, and associates reported on a cluster-randomized, controlled trial of targeted interventions.

Conducted in 2017 at 26 hospitals and with 3,727 babies in New Zealand and Australia, the study addressed drivers of non–evidence-based approaches with behavior-modifying approaches such as on-site clinical leads, stakeholder meetings, a train-the-trainer workshop, education, and audit and feedback.

The authors reported a 14.1% difference in rates of compliance during the first 24 hours of hospitalization favoring the intervention group for all five bronchiolitis guideline recommendations. The greatest change was seen in albuterol and chest radiography use, with other improvements in ED visits, inpatient consultations, and throughout hospitalization.

“These results provide clinicians and hospitals with clear implementation strategies to address unnecessary treatment of infants with bronchiolitis,” Dr. Haskell’s group wrote. Dr. Lipshaw agreed that multifaceted deimplementation packages including clinician and family education, audit and feedback, and clinical decision support have been successful. “Haskell et al. demonstrated that it is possible to successfully deimplement non–evidence-based practices for bronchiolitis with targeted inventions,” he said. “It would be wonderful to see their success replicated in the U.S.”


 

Why the slow adoption of guidelines?

The American Academy of Pediatrics issued bronchiolitis guidelines for babies to 23 months in 2014 and updated them in 2018. Why, then, has care in some centers been seemingly all over the map and counter to guidelines? “Both parents and clinicians are acting in what they believe to be the best interests of the child, and in the absence of high-value interventions, can feel the need to do something, even if that something is not supported by evidence,” Dr. Lipshaw said. 

Furthermore, with children in obvious distress, breathing fast and with difficulty, and sometimes unable to eat or drink, “we feel like we should have some way to make them feel better quicker. Unfortunately, none of the medications we have tried seem to be useful for most children, and we are left with supportive care measures such as suctioning their noses, giving them oxygen if their oxygen is low, and giving them fluids if they are dehydrated.”

Other physicians agree that taking a less-is-more approach can be challenging and even counterintuitive. “To families, seeing their child’s doctor ‘doing less’ can be frustrating,” admitted Diana S. Lee, MD, assistant professor of pediatrics at Icahn School of Medicine at Mount Sinai, New York.

Beyond that, altering practice behavior will need more than guidelines, Dr. Lee said in an interview. “Haskell et al. showed targeted behavior-change interventions improved compliance with bronchiolitis guidelines, but such change requires motivation and resources, and the sustainability of this effect over time remains to be seen.”

At Dr. Lipshaw’s institution, treatment depends on the attending physician, “but we have an emergency department care algorithm, which does not recommend any inhaled medications or steroids in accordance with the 2014 AAP guidelines,” he said.

Similarly at Mount Sinai, practitioners strive to follow the AAP guidelines, although their implementation has not been immediate, Dr. Lee said. “This is a situation where we must make the effort to choose not to do more, given current evidence.”

But Michelle Dunn, MD, an attending physician in the division of general pediatrics at the Children’s Hospital of Philadelphia, said the American practice norm already tends more to the observance than the breach of the guidelines, noting that since 2014 quality improvement efforts have been made throughout the country. “At our institution, we have effectively reduced the use of albuterol in patients with bronchiolitis and we use evidence-based therapy as much as possible, which in the case of bronchiolitis generally involves supportive management alone,” she said in an interview.

Still, Dr. Dunn added, many patients receive unnecessary diagnostic testing and ineffective therapies, with some providers facing psychological barriers to doing less. “However, with more and more evidence to support this, hopefully, physicians will become more comfortable with this.”

To that end, Dr. Lipshaw’s editorial urges physicians to “curb the rampant use of therapies repeatedly revealed to be ineffective,” citing team engagement, clear practice guidelines, and information technology as key factors in deimplementation. In the meantime, his mantra remains: “Don’t just do something, stand there.”

The study by Dr. Elliot and colleagues was supported by the Canadian Institutes of Health Research Knowledge Synthesis grant program. One coauthor is supported by a University of Ottawa Tier I Research Chair in Pediatric Emergency Medicine. Another is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation and the Stollery Science Laboratory. Dr. Lipshaw and Dr. Florin disclosed no financial relationships relevant to their commentary. Dr. Haskell and colleagues were supported, variously, by the National Health and Medical Research Council of New Zealand, the Center of Research Excellence for Pediatric Emergency Medicine, the Victorian Government’s Operational Infrastructure Support Program, Cure Kids New Zealand, the Royal Children’s Hospital Foundation, and the Starship Foundation. Dr. Lee and Dr. Dunn had no competing interests to disclose with regard to their comments.

A common cause of infant morbidity and hospitalization in developed countries, infant viral bronchiolitis, has long been bedeviled by treatment uncertainty beyond supportive care.

Rationales for most pharmacologic treatments continue to be debated, and clinical practice guidelines generally advise respiratory and hydration support, discouraging the use of chest radiography, albuterol, glucocorticoids, antibiotics, and epinephrine.

Despite evidence that the latter interventions are ineffective, they are still too often applied, according to two recent studies, one in Pediatrics, the other in JAMA Pediatrics.

“The pull of the therapeutic vacuum surrounding this disease has been noted in the pages of this journal for at least 50 years, with Wright and Beem writing in 1965 that ‘energies should not be frittered away by the annoyance of unnecessary or futile medications and procedures’ for the child with bronchiolitis,” said emergency physicians Matthew J. Lipshaw, MD, MS, of the Cincinnati Children’s Hospital Medical Center, and Todd A. Florin, MD, MSCE, of Ann and Robert H. Lurie Children’s Hospital of Chicago.

These remarks came in their editorial in Pediatrics wryly titled: “Don’t Just Do Something, Stand There” and published online to accompany a recent study of three network meta-analyses.

Led by Sarah A. Elliott, PhD, of the Alberta Research Centre for Health Evidence at the University of Alberta in Edmonton, this analysis amalgamated 150 randomized, controlled trials comparing a placebo or active comparator with any bronchodilator, glucocorticoid steroid, hypertonic saline solution, antibiotic, helium-oxygen therapy, or high-flow oxygen therapy. It then looked at the following outcomes in children aged 2 years and younger: hospital admission rate on day 1, hospital admission rate within 7 days, and total hospital length of stay.

Few treatments seemed more effective than nebulized placebo (0.9% saline) for short-term outcomes, the authors found. While nebulized epinephrine and nebulized hypertonic saline plus salbutamol appeared to reduce admission rates during the index ED presentation, and hypertonic saline, alone or in combination with epinephrine, seemed to reduce hospital stays, such treatment had no effect on admissions within 7 days of initial presentation. Furthermore, most benefits disappeared in higher-quality studies.

Concluding, albeit with weak evidence and low confidence, that some benefit might accrue with hypertonic saline with salbutamol to reduce admission rates on initial presentation to the ED, the authors called for well-designed studies on treatments in inpatients and outpatients.

According to Dr. Lipshaw, assistant professor of clinical pediatrics, the lack of benefit observed in superior studies limits the applicability of Dr. Elliott and colleagues’ results to immediate clinical practice. “These findings could be used, however, to target future high-quality studies toward the medications that they found might be useful,” he said in an interview.

For the present, other recent research augurs well for strategically reducing unnecessary care. In a paper published online in JAMA Pediatrics, Libby Haskell, MN, of the ED at Starship Children’s Hospital in Auckland, New Zealand, and associates reported on a cluster-randomized, controlled trial of targeted interventions.

Conducted in 2017 at 26 hospitals and with 3,727 babies in New Zealand and Australia, the study addressed drivers of non–evidence-based approaches with behavior-modifying approaches such as on-site clinical leads, stakeholder meetings, a train-the-trainer workshop, education, and audit and feedback.

The authors reported a 14.1% difference in rates of compliance during the first 24 hours of hospitalization favoring the intervention group for all five bronchiolitis guideline recommendations. The greatest change was seen in albuterol and chest radiography use, with other improvements in ED visits, inpatient consultations, and throughout hospitalization.

“These results provide clinicians and hospitals with clear implementation strategies to address unnecessary treatment of infants with bronchiolitis,” Dr. Haskell’s group wrote. Dr. Lipshaw agreed that multifaceted deimplementation packages including clinician and family education, audit and feedback, and clinical decision support have been successful. “Haskell et al. demonstrated that it is possible to successfully deimplement non–evidence-based practices for bronchiolitis with targeted inventions,” he said. “It would be wonderful to see their success replicated in the U.S.”


 

Why the slow adoption of guidelines?

The American Academy of Pediatrics issued bronchiolitis guidelines for babies to 23 months in 2014 and updated them in 2018. Why, then, has care in some centers been seemingly all over the map and counter to guidelines? “Both parents and clinicians are acting in what they believe to be the best interests of the child, and in the absence of high-value interventions, can feel the need to do something, even if that something is not supported by evidence,” Dr. Lipshaw said. 

Furthermore, with children in obvious distress, breathing fast and with difficulty, and sometimes unable to eat or drink, “we feel like we should have some way to make them feel better quicker. Unfortunately, none of the medications we have tried seem to be useful for most children, and we are left with supportive care measures such as suctioning their noses, giving them oxygen if their oxygen is low, and giving them fluids if they are dehydrated.”

Other physicians agree that taking a less-is-more approach can be challenging and even counterintuitive. “To families, seeing their child’s doctor ‘doing less’ can be frustrating,” admitted Diana S. Lee, MD, assistant professor of pediatrics at Icahn School of Medicine at Mount Sinai, New York.

Beyond that, altering practice behavior will need more than guidelines, Dr. Lee said in an interview. “Haskell et al. showed targeted behavior-change interventions improved compliance with bronchiolitis guidelines, but such change requires motivation and resources, and the sustainability of this effect over time remains to be seen.”

At Dr. Lipshaw’s institution, treatment depends on the attending physician, “but we have an emergency department care algorithm, which does not recommend any inhaled medications or steroids in accordance with the 2014 AAP guidelines,” he said.

Similarly at Mount Sinai, practitioners strive to follow the AAP guidelines, although their implementation has not been immediate, Dr. Lee said. “This is a situation where we must make the effort to choose not to do more, given current evidence.”

But Michelle Dunn, MD, an attending physician in the division of general pediatrics at the Children’s Hospital of Philadelphia, said the American practice norm already tends more to the observance than the breach of the guidelines, noting that since 2014 quality improvement efforts have been made throughout the country. “At our institution, we have effectively reduced the use of albuterol in patients with bronchiolitis and we use evidence-based therapy as much as possible, which in the case of bronchiolitis generally involves supportive management alone,” she said in an interview.

Still, Dr. Dunn added, many patients receive unnecessary diagnostic testing and ineffective therapies, with some providers facing psychological barriers to doing less. “However, with more and more evidence to support this, hopefully, physicians will become more comfortable with this.”

To that end, Dr. Lipshaw’s editorial urges physicians to “curb the rampant use of therapies repeatedly revealed to be ineffective,” citing team engagement, clear practice guidelines, and information technology as key factors in deimplementation. In the meantime, his mantra remains: “Don’t just do something, stand there.”

The study by Dr. Elliot and colleagues was supported by the Canadian Institutes of Health Research Knowledge Synthesis grant program. One coauthor is supported by a University of Ottawa Tier I Research Chair in Pediatric Emergency Medicine. Another is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation and the Stollery Science Laboratory. Dr. Lipshaw and Dr. Florin disclosed no financial relationships relevant to their commentary. Dr. Haskell and colleagues were supported, variously, by the National Health and Medical Research Council of New Zealand, the Center of Research Excellence for Pediatric Emergency Medicine, the Victorian Government’s Operational Infrastructure Support Program, Cure Kids New Zealand, the Royal Children’s Hospital Foundation, and the Starship Foundation. Dr. Lee and Dr. Dunn had no competing interests to disclose with regard to their comments.

A common cause of infant morbidity and hospitalization in developed countries, infant viral bronchiolitis, has long been bedeviled by treatment uncertainty beyond supportive care.

Rationales for most pharmacologic treatments continue to be debated, and clinical practice guidelines generally advise respiratory and hydration support, discouraging the use of chest radiography, albuterol, glucocorticoids, antibiotics, and epinephrine.

Despite evidence that the latter interventions are ineffective, they are still too often applied, according to two recent studies, one in Pediatrics, the other in JAMA Pediatrics.

“The pull of the therapeutic vacuum surrounding this disease has been noted in the pages of this journal for at least 50 years, with Wright and Beem writing in 1965 that ‘energies should not be frittered away by the annoyance of unnecessary or futile medications and procedures’ for the child with bronchiolitis,” said emergency physicians Matthew J. Lipshaw, MD, MS, of the Cincinnati Children’s Hospital Medical Center, and Todd A. Florin, MD, MSCE, of Ann and Robert H. Lurie Children’s Hospital of Chicago.

These remarks came in their editorial in Pediatrics wryly titled: “Don’t Just Do Something, Stand There” and published online to accompany a recent study of three network meta-analyses.

Led by Sarah A. Elliott, PhD, of the Alberta Research Centre for Health Evidence at the University of Alberta in Edmonton, this analysis amalgamated 150 randomized, controlled trials comparing a placebo or active comparator with any bronchodilator, glucocorticoid steroid, hypertonic saline solution, antibiotic, helium-oxygen therapy, or high-flow oxygen therapy. It then looked at the following outcomes in children aged 2 years and younger: hospital admission rate on day 1, hospital admission rate within 7 days, and total hospital length of stay.

Few treatments seemed more effective than nebulized placebo (0.9% saline) for short-term outcomes, the authors found. While nebulized epinephrine and nebulized hypertonic saline plus salbutamol appeared to reduce admission rates during the index ED presentation, and hypertonic saline, alone or in combination with epinephrine, seemed to reduce hospital stays, such treatment had no effect on admissions within 7 days of initial presentation. Furthermore, most benefits disappeared in higher-quality studies.

Concluding, albeit with weak evidence and low confidence, that some benefit might accrue with hypertonic saline with salbutamol to reduce admission rates on initial presentation to the ED, the authors called for well-designed studies on treatments in inpatients and outpatients.

According to Dr. Lipshaw, assistant professor of clinical pediatrics, the lack of benefit observed in superior studies limits the applicability of Dr. Elliott and colleagues’ results to immediate clinical practice. “These findings could be used, however, to target future high-quality studies toward the medications that they found might be useful,” he said in an interview.

For the present, other recent research augurs well for strategically reducing unnecessary care. In a paper published online in JAMA Pediatrics, Libby Haskell, MN, of the ED at Starship Children’s Hospital in Auckland, New Zealand, and associates reported on a cluster-randomized, controlled trial of targeted interventions.

Conducted in 2017 at 26 hospitals and with 3,727 babies in New Zealand and Australia, the study addressed drivers of non–evidence-based approaches with behavior-modifying approaches such as on-site clinical leads, stakeholder meetings, a train-the-trainer workshop, education, and audit and feedback.

The authors reported a 14.1% difference in rates of compliance during the first 24 hours of hospitalization favoring the intervention group for all five bronchiolitis guideline recommendations. The greatest change was seen in albuterol and chest radiography use, with other improvements in ED visits, inpatient consultations, and throughout hospitalization.

“These results provide clinicians and hospitals with clear implementation strategies to address unnecessary treatment of infants with bronchiolitis,” Dr. Haskell’s group wrote. Dr. Lipshaw agreed that multifaceted deimplementation packages including clinician and family education, audit and feedback, and clinical decision support have been successful. “Haskell et al. demonstrated that it is possible to successfully deimplement non–evidence-based practices for bronchiolitis with targeted inventions,” he said. “It would be wonderful to see their success replicated in the U.S.”


 

Why the slow adoption of guidelines?

The American Academy of Pediatrics issued bronchiolitis guidelines for babies to 23 months in 2014 and updated them in 2018. Why, then, has care in some centers been seemingly all over the map and counter to guidelines? “Both parents and clinicians are acting in what they believe to be the best interests of the child, and in the absence of high-value interventions, can feel the need to do something, even if that something is not supported by evidence,” Dr. Lipshaw said. 

Furthermore, with children in obvious distress, breathing fast and with difficulty, and sometimes unable to eat or drink, “we feel like we should have some way to make them feel better quicker. Unfortunately, none of the medications we have tried seem to be useful for most children, and we are left with supportive care measures such as suctioning their noses, giving them oxygen if their oxygen is low, and giving them fluids if they are dehydrated.”

Other physicians agree that taking a less-is-more approach can be challenging and even counterintuitive. “To families, seeing their child’s doctor ‘doing less’ can be frustrating,” admitted Diana S. Lee, MD, assistant professor of pediatrics at Icahn School of Medicine at Mount Sinai, New York.

Beyond that, altering practice behavior will need more than guidelines, Dr. Lee said in an interview. “Haskell et al. showed targeted behavior-change interventions improved compliance with bronchiolitis guidelines, but such change requires motivation and resources, and the sustainability of this effect over time remains to be seen.”

At Dr. Lipshaw’s institution, treatment depends on the attending physician, “but we have an emergency department care algorithm, which does not recommend any inhaled medications or steroids in accordance with the 2014 AAP guidelines,” he said.

Similarly at Mount Sinai, practitioners strive to follow the AAP guidelines, although their implementation has not been immediate, Dr. Lee said. “This is a situation where we must make the effort to choose not to do more, given current evidence.”

But Michelle Dunn, MD, an attending physician in the division of general pediatrics at the Children’s Hospital of Philadelphia, said the American practice norm already tends more to the observance than the breach of the guidelines, noting that since 2014 quality improvement efforts have been made throughout the country. “At our institution, we have effectively reduced the use of albuterol in patients with bronchiolitis and we use evidence-based therapy as much as possible, which in the case of bronchiolitis generally involves supportive management alone,” she said in an interview.

Still, Dr. Dunn added, many patients receive unnecessary diagnostic testing and ineffective therapies, with some providers facing psychological barriers to doing less. “However, with more and more evidence to support this, hopefully, physicians will become more comfortable with this.”

To that end, Dr. Lipshaw’s editorial urges physicians to “curb the rampant use of therapies repeatedly revealed to be ineffective,” citing team engagement, clear practice guidelines, and information technology as key factors in deimplementation. In the meantime, his mantra remains: “Don’t just do something, stand there.”

The study by Dr. Elliot and colleagues was supported by the Canadian Institutes of Health Research Knowledge Synthesis grant program. One coauthor is supported by a University of Ottawa Tier I Research Chair in Pediatric Emergency Medicine. Another is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation and the Stollery Science Laboratory. Dr. Lipshaw and Dr. Florin disclosed no financial relationships relevant to their commentary. Dr. Haskell and colleagues were supported, variously, by the National Health and Medical Research Council of New Zealand, the Center of Research Excellence for Pediatric Emergency Medicine, the Victorian Government’s Operational Infrastructure Support Program, Cure Kids New Zealand, the Royal Children’s Hospital Foundation, and the Starship Foundation. Dr. Lee and Dr. Dunn had no competing interests to disclose with regard to their comments.