Conference Coverage

For patients with refractory acute respiratory distress syndrome (ARDS) caused by COVID-19 infections, extracorporeal membrane oxygenation (ECMO) may be the treatment of last resort.

But for reasons that aren’t clear, in the second wave of the COVID-19 pandemic at a major teaching hospital, the mortality rate of patients on ECMO for COVID-induced ARDS was significantly higher than it was during the first wave, despite changes in drug therapy and clinical management, reported Rohit Reddy, BS, a second-year medical student, and colleagues at Thomas Jefferson University Hospital in Philadelphia.

During the first wave, from April to September 2020, the survival rate of patients while on ECMO in their ICUs was 67%. In contrast, for patients treated during the second wave, from November 2020 to March 2021, the ECMO survival rate was 31% (P = .003).

The 30-day survival rates were also higher in the first wave compared with the second, at 54% versus 31%, but this difference was not statistically significant.

“More research is required to develop stricter inclusion/exclusion criteria and to improve pre-ECMO management in order to improve outcomes,” Mr. Reddy said in a narrated poster presented at the annual meeting of the American College of Chest Physicians, held virtually this year.
 

ARDS severity higher

ARDS is a major complication of COVID-19 infections, and there is evidence to suggest that COVID-associated ARDS is more severe than ARDS caused by other causes, the investigators noted.

“ECMO, which has been used as a rescue therapy in prior viral outbreaks, has been used to support certain patients with refractory ARDS due to COVID-19, but evidence for its efficacy is limited. Respiratory failure remained a highly concerning complication in the second wave of the COVID-19 pandemic, but it is unclear how the evolution of the disease and pharmacologic utility has affected the clinical utility of ECMO,” Mr. Reddy said.

To see whether changes in disease course or in treatment could explain changes in outcomes for patients with COVID-related ARDS, the investigators compared characteristics and outcomes for patients treated in the first versus second waves of the pandemic. Their study did not include data from patients infected with the Delta variant of the SARS-CoV-2 virus, which became the predominant viral strain later in 2021.

The study included data on 28 patients treated during the first wave, and 13 during the second. The sample included 28 men and 13 women with a mean age of 51 years.

All patients had venovenous ECMO, with cannulation in the femoral or internal jugular veins; some patients received ECMO via a single double-lumen cannula.

There were no significant differences between the two time periods in patient comorbidities prior to initiation of ECMO.

Patients in the second wave were significantly more likely to receive steroids (54% vs. 100%; P = .003) and remdesivir (39% vs. 85%; P = .007). Prone positioning before ECMO was also significantly more frequent in the second wave (11% vs. 85%; P < .001).

Patients in the second wave stayed on ECMO longer – median 20 days versus 14 days for first-wave patients – but as noted before, ECMO mortality rates were significantly higher during the second wave. During the first wave, 33% of patients died while on ECMO, compared with 69% in the second wave (P = .03). Respective 30-day mortality rates were 46% versus 69% (ns).

Rates of complications during ECMO were generally comparable between the groups, including acute renal failure (39% in the first wave vs 38% in the second), sepsis (32% vs. 23%), bacterial pneumonia (11% vs. 8%), and gastrointestinal bleeding (21% vs. 15%). However, significantly more patients in the second wave had cerebral vascular accidents (4% vs. 23%; P = .050).

Senior author Hitoshi Hirose, MD, PhD, professor of surgery at Thomas Jefferson University, said in an interview that the difference in outcomes was likely caused by changes in pre-ECMO therapy between the first and second waves.

“Our study showed the incidence of sepsis had a large impact on the patient outcomes,” he wrote. “We speculate that sepsis was attributed to use of immune modulation therapy. The prevention of the sepsis would be key to improve survival of ECMO for COVID 19.”

“It’s possible that the explanation for this is that patients in the second wave were sicker in a way that wasn’t adequately measured in the first wave,” CHEST 2021 program cochair Christopher Carroll, MD, FCCP, from Connecticut Children’s Medical Center in Hartford, said in an interview.

The differences may also have been attributable to changes in virulence, or to clinical decisions to put sicker patients on ECMO, he said.

Casey Cable, MD, MSc, a pulmonary disease and critical care specialist at Virginia Commonwealth Medical Center in Richmond, also speculated in an interview that second-wave patients may have been sicker.

“One interesting piece of this story is that we now know a lot more – we know about the use of steroids plus or minus remdesivir and proning, and patients received a large majority of those treatments but still got put on ECMO,” she said. “I wonder if there is a subset of really sick patients, and no matter what we treat with – steroids, proning – whatever we do they’re just not going to do well.”

Both Dr. Carroll and Dr. Cable emphasized the importance of ECMO as a rescue therapy for patients with severe, refractory ARDS associated with COVID-19 or other diseases.

Neither Dr. Carroll nor Dr. Cable were involved in the study.

No study funding was reported. Mr. Reddy, Dr. Hirose, Dr. Carroll, and Dr. Cable disclosed no relevant financial relationships.

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

For patients with refractory acute respiratory distress syndrome (ARDS) caused by COVID-19 infections, extracorporeal membrane oxygenation (ECMO) may be the treatment of last resort.

But for reasons that aren’t clear, in the second wave of the COVID-19 pandemic at a major teaching hospital, the mortality rate of patients on ECMO for COVID-induced ARDS was significantly higher than it was during the first wave, despite changes in drug therapy and clinical management, reported Rohit Reddy, BS, a second-year medical student, and colleagues at Thomas Jefferson University Hospital in Philadelphia.

During the first wave, from April to September 2020, the survival rate of patients while on ECMO in their ICUs was 67%. In contrast, for patients treated during the second wave, from November 2020 to March 2021, the ECMO survival rate was 31% (P = .003).

The 30-day survival rates were also higher in the first wave compared with the second, at 54% versus 31%, but this difference was not statistically significant.

“More research is required to develop stricter inclusion/exclusion criteria and to improve pre-ECMO management in order to improve outcomes,” Mr. Reddy said in a narrated poster presented at the annual meeting of the American College of Chest Physicians, held virtually this year.
 

ARDS severity higher

ARDS is a major complication of COVID-19 infections, and there is evidence to suggest that COVID-associated ARDS is more severe than ARDS caused by other causes, the investigators noted.

“ECMO, which has been used as a rescue therapy in prior viral outbreaks, has been used to support certain patients with refractory ARDS due to COVID-19, but evidence for its efficacy is limited. Respiratory failure remained a highly concerning complication in the second wave of the COVID-19 pandemic, but it is unclear how the evolution of the disease and pharmacologic utility has affected the clinical utility of ECMO,” Mr. Reddy said.

To see whether changes in disease course or in treatment could explain changes in outcomes for patients with COVID-related ARDS, the investigators compared characteristics and outcomes for patients treated in the first versus second waves of the pandemic. Their study did not include data from patients infected with the Delta variant of the SARS-CoV-2 virus, which became the predominant viral strain later in 2021.

The study included data on 28 patients treated during the first wave, and 13 during the second. The sample included 28 men and 13 women with a mean age of 51 years.

All patients had venovenous ECMO, with cannulation in the femoral or internal jugular veins; some patients received ECMO via a single double-lumen cannula.

There were no significant differences between the two time periods in patient comorbidities prior to initiation of ECMO.

Patients in the second wave were significantly more likely to receive steroids (54% vs. 100%; P = .003) and remdesivir (39% vs. 85%; P = .007). Prone positioning before ECMO was also significantly more frequent in the second wave (11% vs. 85%; P < .001).

Patients in the second wave stayed on ECMO longer – median 20 days versus 14 days for first-wave patients – but as noted before, ECMO mortality rates were significantly higher during the second wave. During the first wave, 33% of patients died while on ECMO, compared with 69% in the second wave (P = .03). Respective 30-day mortality rates were 46% versus 69% (ns).

Rates of complications during ECMO were generally comparable between the groups, including acute renal failure (39% in the first wave vs 38% in the second), sepsis (32% vs. 23%), bacterial pneumonia (11% vs. 8%), and gastrointestinal bleeding (21% vs. 15%). However, significantly more patients in the second wave had cerebral vascular accidents (4% vs. 23%; P = .050).

Senior author Hitoshi Hirose, MD, PhD, professor of surgery at Thomas Jefferson University, said in an interview that the difference in outcomes was likely caused by changes in pre-ECMO therapy between the first and second waves.

“Our study showed the incidence of sepsis had a large impact on the patient outcomes,” he wrote. “We speculate that sepsis was attributed to use of immune modulation therapy. The prevention of the sepsis would be key to improve survival of ECMO for COVID 19.”

“It’s possible that the explanation for this is that patients in the second wave were sicker in a way that wasn’t adequately measured in the first wave,” CHEST 2021 program cochair Christopher Carroll, MD, FCCP, from Connecticut Children’s Medical Center in Hartford, said in an interview.

The differences may also have been attributable to changes in virulence, or to clinical decisions to put sicker patients on ECMO, he said.

Casey Cable, MD, MSc, a pulmonary disease and critical care specialist at Virginia Commonwealth Medical Center in Richmond, also speculated in an interview that second-wave patients may have been sicker.

“One interesting piece of this story is that we now know a lot more – we know about the use of steroids plus or minus remdesivir and proning, and patients received a large majority of those treatments but still got put on ECMO,” she said. “I wonder if there is a subset of really sick patients, and no matter what we treat with – steroids, proning – whatever we do they’re just not going to do well.”

Both Dr. Carroll and Dr. Cable emphasized the importance of ECMO as a rescue therapy for patients with severe, refractory ARDS associated with COVID-19 or other diseases.

Neither Dr. Carroll nor Dr. Cable were involved in the study.

No study funding was reported. Mr. Reddy, Dr. Hirose, Dr. Carroll, and Dr. Cable disclosed no relevant financial relationships.

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

For patients with refractory acute respiratory distress syndrome (ARDS) caused by COVID-19 infections, extracorporeal membrane oxygenation (ECMO) may be the treatment of last resort.

But for reasons that aren’t clear, in the second wave of the COVID-19 pandemic at a major teaching hospital, the mortality rate of patients on ECMO for COVID-induced ARDS was significantly higher than it was during the first wave, despite changes in drug therapy and clinical management, reported Rohit Reddy, BS, a second-year medical student, and colleagues at Thomas Jefferson University Hospital in Philadelphia.

During the first wave, from April to September 2020, the survival rate of patients while on ECMO in their ICUs was 67%. In contrast, for patients treated during the second wave, from November 2020 to March 2021, the ECMO survival rate was 31% (P = .003).

The 30-day survival rates were also higher in the first wave compared with the second, at 54% versus 31%, but this difference was not statistically significant.

“More research is required to develop stricter inclusion/exclusion criteria and to improve pre-ECMO management in order to improve outcomes,” Mr. Reddy said in a narrated poster presented at the annual meeting of the American College of Chest Physicians, held virtually this year.
 

ARDS severity higher

ARDS is a major complication of COVID-19 infections, and there is evidence to suggest that COVID-associated ARDS is more severe than ARDS caused by other causes, the investigators noted.

“ECMO, which has been used as a rescue therapy in prior viral outbreaks, has been used to support certain patients with refractory ARDS due to COVID-19, but evidence for its efficacy is limited. Respiratory failure remained a highly concerning complication in the second wave of the COVID-19 pandemic, but it is unclear how the evolution of the disease and pharmacologic utility has affected the clinical utility of ECMO,” Mr. Reddy said.

To see whether changes in disease course or in treatment could explain changes in outcomes for patients with COVID-related ARDS, the investigators compared characteristics and outcomes for patients treated in the first versus second waves of the pandemic. Their study did not include data from patients infected with the Delta variant of the SARS-CoV-2 virus, which became the predominant viral strain later in 2021.

The study included data on 28 patients treated during the first wave, and 13 during the second. The sample included 28 men and 13 women with a mean age of 51 years.

All patients had venovenous ECMO, with cannulation in the femoral or internal jugular veins; some patients received ECMO via a single double-lumen cannula.

There were no significant differences between the two time periods in patient comorbidities prior to initiation of ECMO.

Patients in the second wave were significantly more likely to receive steroids (54% vs. 100%; P = .003) and remdesivir (39% vs. 85%; P = .007). Prone positioning before ECMO was also significantly more frequent in the second wave (11% vs. 85%; P < .001).

Patients in the second wave stayed on ECMO longer – median 20 days versus 14 days for first-wave patients – but as noted before, ECMO mortality rates were significantly higher during the second wave. During the first wave, 33% of patients died while on ECMO, compared with 69% in the second wave (P = .03). Respective 30-day mortality rates were 46% versus 69% (ns).

Rates of complications during ECMO were generally comparable between the groups, including acute renal failure (39% in the first wave vs 38% in the second), sepsis (32% vs. 23%), bacterial pneumonia (11% vs. 8%), and gastrointestinal bleeding (21% vs. 15%). However, significantly more patients in the second wave had cerebral vascular accidents (4% vs. 23%; P = .050).

Senior author Hitoshi Hirose, MD, PhD, professor of surgery at Thomas Jefferson University, said in an interview that the difference in outcomes was likely caused by changes in pre-ECMO therapy between the first and second waves.

“Our study showed the incidence of sepsis had a large impact on the patient outcomes,” he wrote. “We speculate that sepsis was attributed to use of immune modulation therapy. The prevention of the sepsis would be key to improve survival of ECMO for COVID 19.”

“It’s possible that the explanation for this is that patients in the second wave were sicker in a way that wasn’t adequately measured in the first wave,” CHEST 2021 program cochair Christopher Carroll, MD, FCCP, from Connecticut Children’s Medical Center in Hartford, said in an interview.

The differences may also have been attributable to changes in virulence, or to clinical decisions to put sicker patients on ECMO, he said.

Casey Cable, MD, MSc, a pulmonary disease and critical care specialist at Virginia Commonwealth Medical Center in Richmond, also speculated in an interview that second-wave patients may have been sicker.

“One interesting piece of this story is that we now know a lot more – we know about the use of steroids plus or minus remdesivir and proning, and patients received a large majority of those treatments but still got put on ECMO,” she said. “I wonder if there is a subset of really sick patients, and no matter what we treat with – steroids, proning – whatever we do they’re just not going to do well.”

Both Dr. Carroll and Dr. Cable emphasized the importance of ECMO as a rescue therapy for patients with severe, refractory ARDS associated with COVID-19 or other diseases.

Neither Dr. Carroll nor Dr. Cable were involved in the study.

No study funding was reported. Mr. Reddy, Dr. Hirose, Dr. Carroll, and Dr. Cable disclosed no relevant financial relationships.

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

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

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

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

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

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

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

Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.

TimothyOLeary/Thinkstock

Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.

Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.

“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.

Crucially, the positive effects “persisted throughout the observation period,” she added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

A promising approach

Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”

“We hope this approach is very promising and would be widely adopted.”

She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”

This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”

The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.

They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.

To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.

Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
 

Multiple benefits

Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.

Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.

Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.

Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.

The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.

Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).

The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.

Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.

Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
 

Many benefits, no side effects

Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”

She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”

“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”

Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”

Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”

Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.

“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”

No funding was declared. The authors have disclosed no relevant financial relationships.

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

Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.

TimothyOLeary/Thinkstock

Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.

Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.

“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.

Crucially, the positive effects “persisted throughout the observation period,” she added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

A promising approach

Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”

“We hope this approach is very promising and would be widely adopted.”

She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”

This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”

The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.

They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.

To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.

Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
 

Multiple benefits

Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.

Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.

Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.

Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.

The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.

Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).

The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.

Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.

Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
 

Many benefits, no side effects

Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”

She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”

“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”

Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”

Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”

Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.

“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”

No funding was declared. The authors have disclosed no relevant financial relationships.

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

Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.

TimothyOLeary/Thinkstock

Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.

Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.

“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.

Crucially, the positive effects “persisted throughout the observation period,” she added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

A promising approach

Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”

“We hope this approach is very promising and would be widely adopted.”

She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”

This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”

The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.

They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.

To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.

Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
 

Multiple benefits

Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.

Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.

Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.

Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.

The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.

Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).

The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.

Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.

Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
 

Many benefits, no side effects

Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”

She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”

“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”

Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”

Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”

Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.

“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”

No funding was declared. The authors have disclosed no relevant financial relationships.

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

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have produced a joint position statement on COVID-19 vaccination for patients with multiple sclerosis (MS).

The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.

This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.

Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”

“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
 

Risk for COVID-19 among patients with MS

On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.

The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.

As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.

However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
 

COVID-19 vaccine safety

Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.

All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.

In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.

Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.

“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
 

Are there different recommendations for different MS therapies?

On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.

Patients taking natalizumab will also likely be protected with COVID vaccination.

It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.

In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
 

Low antibody level with fingolimod

The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.

Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.

Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
 

Anti-CD20 antibody drugs

Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.

A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
 

Booster doses/antibody tests

The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.

Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.


Vaccination strategy after COVID

People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.

Pregnancy/children

Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.

Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.

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

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have produced a joint position statement on COVID-19 vaccination for patients with multiple sclerosis (MS).

The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.

This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.

Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”

“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
 

Risk for COVID-19 among patients with MS

On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.

The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.

As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.

However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
 

COVID-19 vaccine safety

Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.

All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.

In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.

Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.

“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
 

Are there different recommendations for different MS therapies?

On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.

Patients taking natalizumab will also likely be protected with COVID vaccination.

It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.

In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
 

Low antibody level with fingolimod

The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.

Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.

Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
 

Anti-CD20 antibody drugs

Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.

A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
 

Booster doses/antibody tests

The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.

Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.


Vaccination strategy after COVID

People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.

Pregnancy/children

Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.

Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.

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

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have produced a joint position statement on COVID-19 vaccination for patients with multiple sclerosis (MS).

The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.

This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.

Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”

“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
 

Risk for COVID-19 among patients with MS

On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.

The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.

As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.

However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
 

COVID-19 vaccine safety

Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.

All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.

In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.

Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.

“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
 

Are there different recommendations for different MS therapies?

On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.

Patients taking natalizumab will also likely be protected with COVID vaccination.

It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.

In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
 

Low antibody level with fingolimod

The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.

Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.

Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
 

Anti-CD20 antibody drugs

Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.

A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
 

Booster doses/antibody tests

The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.

Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.


Vaccination strategy after COVID

People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.

Pregnancy/children

Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.

Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.

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

You have probably heard that determining the A(ntecedent)s, B(ehavior)s, and C(onsequence)s of a behavior is basic to counseling about oppositionality or aggression. But sorting out the As is especially important to going beyond disciplining a misbehavior to building insight for both parents and children.

Antecedents are of two types: triggers such as actions, words, or feelings that happen just before the behavior, and “setting events” that can occur intermittently hours or even days beforehand and lower the threshold for a trigger to cause a child to act out. Lack of sleep, hunger, or fatigue are common setting events that parents recognize and take into account as in “Oh, he missed his nap” to excuse a tantrum in younger children, but is less often considered or excused in older children in whom self-regulation is expected. Often, behavioral specialists in schools are asked to observe a child to identify the triggers and create a “functional behavioral assessment” based on what is observed.

While a functional behavioral assessment requires observations, invisible antecedents to consider include internal thoughts and feelings (meaning). A child feeling shame from a failed math test the day before may be on edge, then, when called on, may uncharacteristically talk back. The child may regard punishment for this “justified” response as unfair, accelerating anger. Feelings of shame or humiliation for failing one’s own standards (or perceived expectations of others the child cares about) are major setups for eliciting defiance.

Even more subtle are meanings the child creates for situations and people, whether real or imagined. A child’s behavior has meaning for the child and the family and can be initiated or maintained by that meaning. For example, a child may “live down” to what the family thinks of him/her; if you think I am bad, I will act badly.

Children may feel guilty about some real or imagined offense, such as divorce or death they think may be their fault, and act up with the family to elicit punishment as payment. When children feel conflicted in a relationship, such as a late adolescent feeling dependent on their mother when their age expectation is independence, they may act up expecting to be ejected from home when they are unable to gather the courage to voluntarily leave. This acting out may also occur with nonconflicted adults, who are actually safer targets. For example, school is often a safer place to express anger through aggression or bullying than home, the real source of the feelings, because family is the “lifeboat” of food and shelter they dare not upset.

Conflicted relationships may be present in blended families, especially if the ex speaks negatively about the other parent. The child of divorce, feeling himself composed of parts of each parent, has diminished self-esteem and anger on behalf of that side being put down. Marital conflict may set children up to feel they have to take sides to angrily defend the parent of like-gender by being oppositional to the other.

Just as we ponder whether the color blue looks the same to someone else, neurologically based differences in perception may make a child misinterpret or act inflexibly or explode in situations that seem normal to adults. While people joke about “being a little OCD,” for some children the distress caused by a change in routine, a messy room, a delayed bus, or loud music is enough to disrupt their functioning and coping enough to explode. Such hypersensitivity can be part of autism or obsessive compulsive disorder or a subthreshold variant. Children vary by age and individually in their ability to understand language, especially sarcastic humor, and often misinterpret it as insulting, threatening, or scary and act accordingly. While most common in children with autism, those with a language learning disability, intellectual disability, or who have English as a second language, or are anxious or vigilant may also take sarcasm the wrong way. Anxious children also may react aggressively from a “hostile bias attribution” of expecting the worst from others.

Another possible meaning of a behavior is that it is being used by the child to manage their feelings. I have found it useful to remind depressed children and parents that it “feels better to be mad than sad” as a reason for irritability. Anger can also push away a person whose otherwise sympathetic approach might release a collapse into tears the child can’t tolerate or would find embarrassing.

The meaning of a child’s misbehavior also resides in the minds of the adults. In addition to all the categories of meaning just described, a parent may be reminded by the child of someone else for whom the adult has strong or conflicted feelings (“projection”) such as a now-hated ex, a sibling of whom the adult is jealous, or a bully from childhood, thus eliciting a reaction falsely triggered by that connection rather than the actual child. Asking parents whom the child “takes after” may elicit such parental projections based on appearance, behavior, or temperament. Helping them pick a feature of the child to focus on to differentiate him/her can serve as an anchor to remind them to control these reactions. Other useful questions to detect meanings of behavior might include asking the child “What’s up with that?” or “What did that make you think/feel?” We can ask parents “How is that for you?” or “What do you think things will be like in 10 years?” to determine despair, mood disorders, or family discord contributing to maladaptive responses possibly maintaining unwanted behaviors.

Throughout life, putting feelings into words is the main way meanings that are contributing to misbehaviors or parenting dysfunction can be uncovered and shifted. For this, the child or adult must feel emotionally safe to talk with a person who conveys curiosity rather than judgment. Helping families explain that divorce is not the child’s fault; admit they also make mistakes; rebuild conflicted relationships through play or talking; identify hypersensitivities or triggers to avoid; and express confidence that the child is a good person, still young, and sure to do better over time, are all things we pediatricians can do to help sort out the meanings of behaviors.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

You have probably heard that determining the A(ntecedent)s, B(ehavior)s, and C(onsequence)s of a behavior is basic to counseling about oppositionality or aggression. But sorting out the As is especially important to going beyond disciplining a misbehavior to building insight for both parents and children.

Antecedents are of two types: triggers such as actions, words, or feelings that happen just before the behavior, and “setting events” that can occur intermittently hours or even days beforehand and lower the threshold for a trigger to cause a child to act out. Lack of sleep, hunger, or fatigue are common setting events that parents recognize and take into account as in “Oh, he missed his nap” to excuse a tantrum in younger children, but is less often considered or excused in older children in whom self-regulation is expected. Often, behavioral specialists in schools are asked to observe a child to identify the triggers and create a “functional behavioral assessment” based on what is observed.

While a functional behavioral assessment requires observations, invisible antecedents to consider include internal thoughts and feelings (meaning). A child feeling shame from a failed math test the day before may be on edge, then, when called on, may uncharacteristically talk back. The child may regard punishment for this “justified” response as unfair, accelerating anger. Feelings of shame or humiliation for failing one’s own standards (or perceived expectations of others the child cares about) are major setups for eliciting defiance.

Even more subtle are meanings the child creates for situations and people, whether real or imagined. A child’s behavior has meaning for the child and the family and can be initiated or maintained by that meaning. For example, a child may “live down” to what the family thinks of him/her; if you think I am bad, I will act badly.

Children may feel guilty about some real or imagined offense, such as divorce or death they think may be their fault, and act up with the family to elicit punishment as payment. When children feel conflicted in a relationship, such as a late adolescent feeling dependent on their mother when their age expectation is independence, they may act up expecting to be ejected from home when they are unable to gather the courage to voluntarily leave. This acting out may also occur with nonconflicted adults, who are actually safer targets. For example, school is often a safer place to express anger through aggression or bullying than home, the real source of the feelings, because family is the “lifeboat” of food and shelter they dare not upset.

Conflicted relationships may be present in blended families, especially if the ex speaks negatively about the other parent. The child of divorce, feeling himself composed of parts of each parent, has diminished self-esteem and anger on behalf of that side being put down. Marital conflict may set children up to feel they have to take sides to angrily defend the parent of like-gender by being oppositional to the other.

Just as we ponder whether the color blue looks the same to someone else, neurologically based differences in perception may make a child misinterpret or act inflexibly or explode in situations that seem normal to adults. While people joke about “being a little OCD,” for some children the distress caused by a change in routine, a messy room, a delayed bus, or loud music is enough to disrupt their functioning and coping enough to explode. Such hypersensitivity can be part of autism or obsessive compulsive disorder or a subthreshold variant. Children vary by age and individually in their ability to understand language, especially sarcastic humor, and often misinterpret it as insulting, threatening, or scary and act accordingly. While most common in children with autism, those with a language learning disability, intellectual disability, or who have English as a second language, or are anxious or vigilant may also take sarcasm the wrong way. Anxious children also may react aggressively from a “hostile bias attribution” of expecting the worst from others.

Another possible meaning of a behavior is that it is being used by the child to manage their feelings. I have found it useful to remind depressed children and parents that it “feels better to be mad than sad” as a reason for irritability. Anger can also push away a person whose otherwise sympathetic approach might release a collapse into tears the child can’t tolerate or would find embarrassing.

The meaning of a child’s misbehavior also resides in the minds of the adults. In addition to all the categories of meaning just described, a parent may be reminded by the child of someone else for whom the adult has strong or conflicted feelings (“projection”) such as a now-hated ex, a sibling of whom the adult is jealous, or a bully from childhood, thus eliciting a reaction falsely triggered by that connection rather than the actual child. Asking parents whom the child “takes after” may elicit such parental projections based on appearance, behavior, or temperament. Helping them pick a feature of the child to focus on to differentiate him/her can serve as an anchor to remind them to control these reactions. Other useful questions to detect meanings of behavior might include asking the child “What’s up with that?” or “What did that make you think/feel?” We can ask parents “How is that for you?” or “What do you think things will be like in 10 years?” to determine despair, mood disorders, or family discord contributing to maladaptive responses possibly maintaining unwanted behaviors.

Throughout life, putting feelings into words is the main way meanings that are contributing to misbehaviors or parenting dysfunction can be uncovered and shifted. For this, the child or adult must feel emotionally safe to talk with a person who conveys curiosity rather than judgment. Helping families explain that divorce is not the child’s fault; admit they also make mistakes; rebuild conflicted relationships through play or talking; identify hypersensitivities or triggers to avoid; and express confidence that the child is a good person, still young, and sure to do better over time, are all things we pediatricians can do to help sort out the meanings of behaviors.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

You have probably heard that determining the A(ntecedent)s, B(ehavior)s, and C(onsequence)s of a behavior is basic to counseling about oppositionality or aggression. But sorting out the As is especially important to going beyond disciplining a misbehavior to building insight for both parents and children.

Antecedents are of two types: triggers such as actions, words, or feelings that happen just before the behavior, and “setting events” that can occur intermittently hours or even days beforehand and lower the threshold for a trigger to cause a child to act out. Lack of sleep, hunger, or fatigue are common setting events that parents recognize and take into account as in “Oh, he missed his nap” to excuse a tantrum in younger children, but is less often considered or excused in older children in whom self-regulation is expected. Often, behavioral specialists in schools are asked to observe a child to identify the triggers and create a “functional behavioral assessment” based on what is observed.

While a functional behavioral assessment requires observations, invisible antecedents to consider include internal thoughts and feelings (meaning). A child feeling shame from a failed math test the day before may be on edge, then, when called on, may uncharacteristically talk back. The child may regard punishment for this “justified” response as unfair, accelerating anger. Feelings of shame or humiliation for failing one’s own standards (or perceived expectations of others the child cares about) are major setups for eliciting defiance.

Even more subtle are meanings the child creates for situations and people, whether real or imagined. A child’s behavior has meaning for the child and the family and can be initiated or maintained by that meaning. For example, a child may “live down” to what the family thinks of him/her; if you think I am bad, I will act badly.

Children may feel guilty about some real or imagined offense, such as divorce or death they think may be their fault, and act up with the family to elicit punishment as payment. When children feel conflicted in a relationship, such as a late adolescent feeling dependent on their mother when their age expectation is independence, they may act up expecting to be ejected from home when they are unable to gather the courage to voluntarily leave. This acting out may also occur with nonconflicted adults, who are actually safer targets. For example, school is often a safer place to express anger through aggression or bullying than home, the real source of the feelings, because family is the “lifeboat” of food and shelter they dare not upset.

Conflicted relationships may be present in blended families, especially if the ex speaks negatively about the other parent. The child of divorce, feeling himself composed of parts of each parent, has diminished self-esteem and anger on behalf of that side being put down. Marital conflict may set children up to feel they have to take sides to angrily defend the parent of like-gender by being oppositional to the other.

Just as we ponder whether the color blue looks the same to someone else, neurologically based differences in perception may make a child misinterpret or act inflexibly or explode in situations that seem normal to adults. While people joke about “being a little OCD,” for some children the distress caused by a change in routine, a messy room, a delayed bus, or loud music is enough to disrupt their functioning and coping enough to explode. Such hypersensitivity can be part of autism or obsessive compulsive disorder or a subthreshold variant. Children vary by age and individually in their ability to understand language, especially sarcastic humor, and often misinterpret it as insulting, threatening, or scary and act accordingly. While most common in children with autism, those with a language learning disability, intellectual disability, or who have English as a second language, or are anxious or vigilant may also take sarcasm the wrong way. Anxious children also may react aggressively from a “hostile bias attribution” of expecting the worst from others.

Another possible meaning of a behavior is that it is being used by the child to manage their feelings. I have found it useful to remind depressed children and parents that it “feels better to be mad than sad” as a reason for irritability. Anger can also push away a person whose otherwise sympathetic approach might release a collapse into tears the child can’t tolerate or would find embarrassing.

The meaning of a child’s misbehavior also resides in the minds of the adults. In addition to all the categories of meaning just described, a parent may be reminded by the child of someone else for whom the adult has strong or conflicted feelings (“projection”) such as a now-hated ex, a sibling of whom the adult is jealous, or a bully from childhood, thus eliciting a reaction falsely triggered by that connection rather than the actual child. Asking parents whom the child “takes after” may elicit such parental projections based on appearance, behavior, or temperament. Helping them pick a feature of the child to focus on to differentiate him/her can serve as an anchor to remind them to control these reactions. Other useful questions to detect meanings of behavior might include asking the child “What’s up with that?” or “What did that make you think/feel?” We can ask parents “How is that for you?” or “What do you think things will be like in 10 years?” to determine despair, mood disorders, or family discord contributing to maladaptive responses possibly maintaining unwanted behaviors.

Throughout life, putting feelings into words is the main way meanings that are contributing to misbehaviors or parenting dysfunction can be uncovered and shifted. For this, the child or adult must feel emotionally safe to talk with a person who conveys curiosity rather than judgment. Helping families explain that divorce is not the child’s fault; admit they also make mistakes; rebuild conflicted relationships through play or talking; identify hypersensitivities or triggers to avoid; and express confidence that the child is a good person, still young, and sure to do better over time, are all things we pediatricians can do to help sort out the meanings of behaviors.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

Nearly 2 years into the pandemic, all things COVID-19 will of course be a major focus at the annual meeting of the American College of Chest Physicians, held virtually this year.

“During the pandemic, critical care has been at the forefront of what people are interested in,” said CHEST 2021 program cochair Christopher Carroll, MD, FCCP, from Connecticut Children’s Medical Center, Hartford.

“There is so much volume in critical care units that people have interest in anything related to critical care, including infectious diseases and disaster management in critical care,” he said in an interview.

Sessions at this year’s meeting that have a COVID-19 theme will focus on care of both patients and caregivers. Multiple symposiums, oral abstracts, scientific posters, and case reports will focus on clinical aspects of SARS-CoV-2 infections and COVID-19, including complications such as ventilator-associated and hospital-acquired pneumonia, a session called “Viruses, Variants, Vaccines, and Virulence: The Present and Future of COVID-19,” and support of patients and families.

Other presentations will focus on how COVID-19 has affected lung cancer screening, outpatient practices, pulmonary care, and sleep medicine.

Importantly, the meeting will include sessions focusing on the mental, physical, and social health of clinicians, especially those on the front lines in critical care and intensive care units. There will be sessions on how to recognize and avoid burnout, practice mental health awareness, and take time for self-care.

Presidential Honor Lecturer Curtis N. Sessler, MD, Master FCCP, FCCM, of Virginia Commonwealth University, Richmond, with give a talk titled, “Navigating the Road to Well-Being in the ICU.”
 

Empathy and diversity

Program cochair David Zielinski, MD, FCCP, of Montreal Children’s Hospital, Quebec, told this news organization that the COVID-19 pandemic has brought into even starker contrast inequities in patient care and in the health care system at large.

“This is a subject people are very keen about right now, whether it’s about how providers are treated, opportunities for improvement, or correcting inequities in outcomes for patients,” he said in an interview.

The program doesn’t shy away from the controversy, either, with a session provocatively titled, “Racism in Health Care: The Fuel That Lit the COVID-19 Fire.”

Keynote speaker Demondes Haynes, MD, FCCP, professor of medicine and associate dean of admissions at the University of Mississippi, Jackson, will speak on the importance of empathy in physician-patient communications and on ways to create a more diverse and inclusive workforce in medicine.
 

Beyond COVID-19

CHEST 2021 will include important information for sleep medicine physicians, including the latest news regarding an equipment recall affecting one of the two major manufacturers of continuous positive airway pressure devices.

“This has caused a lot of angst among sleep physicians and patients, and there are not enough devices to replace them,” Dr. Zielinski said.

“People who are on home ventilators are also affected by this recall,” Dr. Carroll added. “The population of patients who have sleep apnea is much greater than the population who are on home ventilators, but patients who are on home ventilators need it to save their lives.”

The meeting will include informative sessions summarizing U.S. and European asthma guidelines published over the past 2 years, as well as pending guidelines from the American College of Chest Physicians on venous thromboembolism and lung cancer screening.

Additional topics of importance include chronic obstructive pulmonary disease, interstitial lung disease, asthma management, acute respiratory failure in special populations, new therapies and strategies for treating tuberculosis, and many others.

There will be skill-polishing simulation sessions designed to help clinicians connect with experts in the field, update their knowledge, and sharpen their technique.
 

Fun and games

In addition to the serious subjects, CHEST 2021 attendees will have the chance to network with colleagues and friends and enjoy online games, including the 20th annual CHEST Challenge, which will pit teams of fellows-in-training from the Interfaith Medical Center, in Brooklyn, New York; the State University of New York, in Buffalo; and the Ohio State University Medical Center, in Columbus, in a Jeopardy!-style battle of wits and medical knowledge.

Close to 7,000 registrants from around the world took part in last year’s CHEST annual meeting, and a similar number is expected for this year’s edition, Dr. Carroll and Dr. Zielinski said.
 

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

Nearly 2 years into the pandemic, all things COVID-19 will of course be a major focus at the annual meeting of the American College of Chest Physicians, held virtually this year.

“During the pandemic, critical care has been at the forefront of what people are interested in,” said CHEST 2021 program cochair Christopher Carroll, MD, FCCP, from Connecticut Children’s Medical Center, Hartford.

“There is so much volume in critical care units that people have interest in anything related to critical care, including infectious diseases and disaster management in critical care,” he said in an interview.

Sessions at this year’s meeting that have a COVID-19 theme will focus on care of both patients and caregivers. Multiple symposiums, oral abstracts, scientific posters, and case reports will focus on clinical aspects of SARS-CoV-2 infections and COVID-19, including complications such as ventilator-associated and hospital-acquired pneumonia, a session called “Viruses, Variants, Vaccines, and Virulence: The Present and Future of COVID-19,” and support of patients and families.

Other presentations will focus on how COVID-19 has affected lung cancer screening, outpatient practices, pulmonary care, and sleep medicine.

Importantly, the meeting will include sessions focusing on the mental, physical, and social health of clinicians, especially those on the front lines in critical care and intensive care units. There will be sessions on how to recognize and avoid burnout, practice mental health awareness, and take time for self-care.

Presidential Honor Lecturer Curtis N. Sessler, MD, Master FCCP, FCCM, of Virginia Commonwealth University, Richmond, with give a talk titled, “Navigating the Road to Well-Being in the ICU.”
 

Empathy and diversity

Program cochair David Zielinski, MD, FCCP, of Montreal Children’s Hospital, Quebec, told this news organization that the COVID-19 pandemic has brought into even starker contrast inequities in patient care and in the health care system at large.

“This is a subject people are very keen about right now, whether it’s about how providers are treated, opportunities for improvement, or correcting inequities in outcomes for patients,” he said in an interview.

The program doesn’t shy away from the controversy, either, with a session provocatively titled, “Racism in Health Care: The Fuel That Lit the COVID-19 Fire.”

Keynote speaker Demondes Haynes, MD, FCCP, professor of medicine and associate dean of admissions at the University of Mississippi, Jackson, will speak on the importance of empathy in physician-patient communications and on ways to create a more diverse and inclusive workforce in medicine.
 

Beyond COVID-19

CHEST 2021 will include important information for sleep medicine physicians, including the latest news regarding an equipment recall affecting one of the two major manufacturers of continuous positive airway pressure devices.

“This has caused a lot of angst among sleep physicians and patients, and there are not enough devices to replace them,” Dr. Zielinski said.

“People who are on home ventilators are also affected by this recall,” Dr. Carroll added. “The population of patients who have sleep apnea is much greater than the population who are on home ventilators, but patients who are on home ventilators need it to save their lives.”

The meeting will include informative sessions summarizing U.S. and European asthma guidelines published over the past 2 years, as well as pending guidelines from the American College of Chest Physicians on venous thromboembolism and lung cancer screening.

Additional topics of importance include chronic obstructive pulmonary disease, interstitial lung disease, asthma management, acute respiratory failure in special populations, new therapies and strategies for treating tuberculosis, and many others.

There will be skill-polishing simulation sessions designed to help clinicians connect with experts in the field, update their knowledge, and sharpen their technique.
 

Fun and games

In addition to the serious subjects, CHEST 2021 attendees will have the chance to network with colleagues and friends and enjoy online games, including the 20th annual CHEST Challenge, which will pit teams of fellows-in-training from the Interfaith Medical Center, in Brooklyn, New York; the State University of New York, in Buffalo; and the Ohio State University Medical Center, in Columbus, in a Jeopardy!-style battle of wits and medical knowledge.

Close to 7,000 registrants from around the world took part in last year’s CHEST annual meeting, and a similar number is expected for this year’s edition, Dr. Carroll and Dr. Zielinski said.
 

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

Nearly 2 years into the pandemic, all things COVID-19 will of course be a major focus at the annual meeting of the American College of Chest Physicians, held virtually this year.

“During the pandemic, critical care has been at the forefront of what people are interested in,” said CHEST 2021 program cochair Christopher Carroll, MD, FCCP, from Connecticut Children’s Medical Center, Hartford.

“There is so much volume in critical care units that people have interest in anything related to critical care, including infectious diseases and disaster management in critical care,” he said in an interview.

Sessions at this year’s meeting that have a COVID-19 theme will focus on care of both patients and caregivers. Multiple symposiums, oral abstracts, scientific posters, and case reports will focus on clinical aspects of SARS-CoV-2 infections and COVID-19, including complications such as ventilator-associated and hospital-acquired pneumonia, a session called “Viruses, Variants, Vaccines, and Virulence: The Present and Future of COVID-19,” and support of patients and families.

Other presentations will focus on how COVID-19 has affected lung cancer screening, outpatient practices, pulmonary care, and sleep medicine.

Importantly, the meeting will include sessions focusing on the mental, physical, and social health of clinicians, especially those on the front lines in critical care and intensive care units. There will be sessions on how to recognize and avoid burnout, practice mental health awareness, and take time for self-care.

Presidential Honor Lecturer Curtis N. Sessler, MD, Master FCCP, FCCM, of Virginia Commonwealth University, Richmond, with give a talk titled, “Navigating the Road to Well-Being in the ICU.”
 

Empathy and diversity

Program cochair David Zielinski, MD, FCCP, of Montreal Children’s Hospital, Quebec, told this news organization that the COVID-19 pandemic has brought into even starker contrast inequities in patient care and in the health care system at large.

“This is a subject people are very keen about right now, whether it’s about how providers are treated, opportunities for improvement, or correcting inequities in outcomes for patients,” he said in an interview.

The program doesn’t shy away from the controversy, either, with a session provocatively titled, “Racism in Health Care: The Fuel That Lit the COVID-19 Fire.”

Keynote speaker Demondes Haynes, MD, FCCP, professor of medicine and associate dean of admissions at the University of Mississippi, Jackson, will speak on the importance of empathy in physician-patient communications and on ways to create a more diverse and inclusive workforce in medicine.
 

Beyond COVID-19

CHEST 2021 will include important information for sleep medicine physicians, including the latest news regarding an equipment recall affecting one of the two major manufacturers of continuous positive airway pressure devices.

“This has caused a lot of angst among sleep physicians and patients, and there are not enough devices to replace them,” Dr. Zielinski said.

“People who are on home ventilators are also affected by this recall,” Dr. Carroll added. “The population of patients who have sleep apnea is much greater than the population who are on home ventilators, but patients who are on home ventilators need it to save their lives.”

The meeting will include informative sessions summarizing U.S. and European asthma guidelines published over the past 2 years, as well as pending guidelines from the American College of Chest Physicians on venous thromboembolism and lung cancer screening.

Additional topics of importance include chronic obstructive pulmonary disease, interstitial lung disease, asthma management, acute respiratory failure in special populations, new therapies and strategies for treating tuberculosis, and many others.

There will be skill-polishing simulation sessions designed to help clinicians connect with experts in the field, update their knowledge, and sharpen their technique.
 

Fun and games

In addition to the serious subjects, CHEST 2021 attendees will have the chance to network with colleagues and friends and enjoy online games, including the 20th annual CHEST Challenge, which will pit teams of fellows-in-training from the Interfaith Medical Center, in Brooklyn, New York; the State University of New York, in Buffalo; and the Ohio State University Medical Center, in Columbus, in a Jeopardy!-style battle of wits and medical knowledge.

Close to 7,000 registrants from around the world took part in last year’s CHEST annual meeting, and a similar number is expected for this year’s edition, Dr. Carroll and Dr. Zielinski said.
 

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

The Barcelona baseline risk score predicted progression of multiple sclerosis (MS) in patients by assigning them to low-, medium-, and high-risk groups. The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.

The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.

“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.

She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
 

Proof of concept

The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.

The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.

The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”

Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
 

Predicting time to EDSS 3.0

The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.

In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).

At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).

At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).

Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.

Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.

The Barcelona baseline risk score predicted progression of multiple sclerosis (MS) in patients by assigning them to low-, medium-, and high-risk groups. The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.

The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.

“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.

She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
 

Proof of concept

The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.

The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.

The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”

Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
 

Predicting time to EDSS 3.0

The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.

In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).

At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).

At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).

Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.

Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.

The Barcelona baseline risk score predicted progression of multiple sclerosis (MS) in patients by assigning them to low-, medium-, and high-risk groups. The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.

The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.

“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.

She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
 

Proof of concept

The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.

The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.

The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”

Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
 

Predicting time to EDSS 3.0

The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.

In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).

At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).

At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).

Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.

Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.

Add-on treatment with dupilumab may improve lung function in children aged 6-11 years with uncontrolled moderate to severe type 2 inflammatory asthma, results from a randomized, placebo-controlled, phase 3 study show.

Improvements in lung function parameters were observed as early as 2 weeks and persisted over the 52-week treatment period among children in the LIBERTY ASTHMA VOYAGE study, according to investigator Leonard B. Bacharier, MD, of Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center, Nashville, Tenn.

“Dupilumab led to clinically meaningful rapid and sustained improvements in lung function parameters,” Dr. Bacharier said in an online poster presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

The improvements in forced expiratory volume in 1 second (FEV₁) and other measures reported for children with moderate to severe asthma who have the type 2 phenotype, which is the most common driver of pediatric asthma, according to Dr. Bacharier.

“Many children with moderate to severe asthma have abnormal lung function, and this can be a risk factor for future lung disease in adulthood,” Dr. Bacharier said in his presentation.
 

The VOYAGE continues

The findings presented at the meeting build on another report earlier this year from the LIBERTY ASTHMA VOYAGE study demonstrating that add-on dupilumab treatment led to a significant improvement versus placebo in FEV₁ up to 12 weeks.

“We now have a long term data on this drug as well, showing its efficacy over a period of time,” said Muhammad Adrish, MD, MBA, FCCP, associate professor of pulmonary, critical care and sleep medicine at Baylor College of Medicine, Houston.

“I think that’s pretty exciting, and that’s another step towards precision medicine in treatment of asthma,” Dr. Adrish, who is Vice-Chair of CHEST’s Airways Disorders NetWork Steering Committee and was not involved in the study.

Dupilumab received Food and Drug Administration approval in 2018 as add-on maintenance therapy for the treatment of patients aged 12 years or older with moderate to severe asthma that has an eosinophilic phenotype or that is dependent on oral corticosteroid treatment.

In March 2021, Sanofi and Regeneron announced that the FDA had accepted for review a supplemental Biologics License Application for dupilumab as an add-on treatment in children aged 6-11 years with uncontrolled moderate to severe asthma.

That sBLA is supported by data from the LIBERTY ASTHMA VOYAGE study, Sanofi and Regeneron said.

In results of the phase 3 study that Dr. Bacharier presented in May at the American Thoracic Society International Conference, add-on dupilumab dosed every 2 weeks significant improved percent predicted prebronchodilator FEV₁ by an additional 5.21 percentage points versus placebo at week 12.
 

Dupilumab and the type 2 phenotype

The new data reported at the CHEST meeting come from a prespecified analysis evaluating the impact of dupilumab on lung function over a 52-week treatment period in patients with a T2 inflammatory asthma phenotype.

“Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and -13, key and central drivers of T2 inflammation in multiple diseases,” Dr. Bacharier and coinvestigators reported in their study abstract.

Of 408 patients in the study, 350 met the T2 phenotype criteria, including 236 in the dupilumab arm and 114 in the placebo arm.

Patients met T2 phenotype criteria if they had blood eosinophils of at least 150 cells/mcL or fractional exhaled nitric oxide FeNO of at least 20 parts per billion at baseline, investigators said.

Dr. Bacharier and coinvestigators reported on several different endpoints, including absolute and percent predicted prebronchodilator FEV₁, percent predicted postbronchodilator FEV₁, prebronchodilator forced expiratory flow at 25%-75% of pulmonary volume (FEF_25%-75%), and forced vital capacity (FVC).

Dupilumab, when compared with placebo, significantly improved prebronchodilator FEV₁ in pediatric patients with uncontrolled moderate to severe type 2 asthma, according to Dr. Bacharier.

“Patients receiving dupilumab experienced rapid improvements by week 2, and this was sustained for up to 52 weeks,” he said.

The prebronchodilator FEV₁ improved from baseline for dupilumab versus placebo, with a least squares mean difference of 0.06 L at week 2, which reached 0.17 L by week 52, according to their data. Similarly, postbronchodilator FEV₁ improved from baseline for dupilumab, with a least square mean difference versus placebo of 0.09 L at week 52.

Dupilumab compared to placebo also significantly improved percent predicted FEF_25%-75%, and percent predicted FVC over the 52-week treatment period, according to Dr. Bacharier.

“Dupilumab led to significant, rapid, and sustained improvements in multiple aspects of lung function in children aged 6-11 years,” Dr. Bacharier added in a CHEST press release that described the findings.

The LIBERTY ASTHMA VOYAGE study was sponsored by Sanofi and Regeneron Pharmaceuticals. Dr. Bacharier provided disclosures related to AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals, Sanofi, CF Foundation, DBV Technologies, NIH, and Vectura.

Add-on treatment with dupilumab may improve lung function in children aged 6-11 years with uncontrolled moderate to severe type 2 inflammatory asthma, results from a randomized, placebo-controlled, phase 3 study show.

Improvements in lung function parameters were observed as early as 2 weeks and persisted over the 52-week treatment period among children in the LIBERTY ASTHMA VOYAGE study, according to investigator Leonard B. Bacharier, MD, of Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center, Nashville, Tenn.

“Dupilumab led to clinically meaningful rapid and sustained improvements in lung function parameters,” Dr. Bacharier said in an online poster presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

The improvements in forced expiratory volume in 1 second (FEV₁) and other measures reported for children with moderate to severe asthma who have the type 2 phenotype, which is the most common driver of pediatric asthma, according to Dr. Bacharier.

“Many children with moderate to severe asthma have abnormal lung function, and this can be a risk factor for future lung disease in adulthood,” Dr. Bacharier said in his presentation.
 

The VOYAGE continues

The findings presented at the meeting build on another report earlier this year from the LIBERTY ASTHMA VOYAGE study demonstrating that add-on dupilumab treatment led to a significant improvement versus placebo in FEV₁ up to 12 weeks.

“We now have a long term data on this drug as well, showing its efficacy over a period of time,” said Muhammad Adrish, MD, MBA, FCCP, associate professor of pulmonary, critical care and sleep medicine at Baylor College of Medicine, Houston.

“I think that’s pretty exciting, and that’s another step towards precision medicine in treatment of asthma,” Dr. Adrish, who is Vice-Chair of CHEST’s Airways Disorders NetWork Steering Committee and was not involved in the study.

Dupilumab received Food and Drug Administration approval in 2018 as add-on maintenance therapy for the treatment of patients aged 12 years or older with moderate to severe asthma that has an eosinophilic phenotype or that is dependent on oral corticosteroid treatment.

In March 2021, Sanofi and Regeneron announced that the FDA had accepted for review a supplemental Biologics License Application for dupilumab as an add-on treatment in children aged 6-11 years with uncontrolled moderate to severe asthma.

That sBLA is supported by data from the LIBERTY ASTHMA VOYAGE study, Sanofi and Regeneron said.

In results of the phase 3 study that Dr. Bacharier presented in May at the American Thoracic Society International Conference, add-on dupilumab dosed every 2 weeks significant improved percent predicted prebronchodilator FEV₁ by an additional 5.21 percentage points versus placebo at week 12.
 

Dupilumab and the type 2 phenotype

The new data reported at the CHEST meeting come from a prespecified analysis evaluating the impact of dupilumab on lung function over a 52-week treatment period in patients with a T2 inflammatory asthma phenotype.

“Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and -13, key and central drivers of T2 inflammation in multiple diseases,” Dr. Bacharier and coinvestigators reported in their study abstract.

Of 408 patients in the study, 350 met the T2 phenotype criteria, including 236 in the dupilumab arm and 114 in the placebo arm.

Patients met T2 phenotype criteria if they had blood eosinophils of at least 150 cells/mcL or fractional exhaled nitric oxide FeNO of at least 20 parts per billion at baseline, investigators said.

Dr. Bacharier and coinvestigators reported on several different endpoints, including absolute and percent predicted prebronchodilator FEV₁, percent predicted postbronchodilator FEV₁, prebronchodilator forced expiratory flow at 25%-75% of pulmonary volume (FEF_25%-75%), and forced vital capacity (FVC).

Dupilumab, when compared with placebo, significantly improved prebronchodilator FEV₁ in pediatric patients with uncontrolled moderate to severe type 2 asthma, according to Dr. Bacharier.

“Patients receiving dupilumab experienced rapid improvements by week 2, and this was sustained for up to 52 weeks,” he said.

The prebronchodilator FEV₁ improved from baseline for dupilumab versus placebo, with a least squares mean difference of 0.06 L at week 2, which reached 0.17 L by week 52, according to their data. Similarly, postbronchodilator FEV₁ improved from baseline for dupilumab, with a least square mean difference versus placebo of 0.09 L at week 52.

Dupilumab compared to placebo also significantly improved percent predicted FEF_25%-75%, and percent predicted FVC over the 52-week treatment period, according to Dr. Bacharier.

“Dupilumab led to significant, rapid, and sustained improvements in multiple aspects of lung function in children aged 6-11 years,” Dr. Bacharier added in a CHEST press release that described the findings.

The LIBERTY ASTHMA VOYAGE study was sponsored by Sanofi and Regeneron Pharmaceuticals. Dr. Bacharier provided disclosures related to AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals, Sanofi, CF Foundation, DBV Technologies, NIH, and Vectura.

Add-on treatment with dupilumab may improve lung function in children aged 6-11 years with uncontrolled moderate to severe type 2 inflammatory asthma, results from a randomized, placebo-controlled, phase 3 study show.

Improvements in lung function parameters were observed as early as 2 weeks and persisted over the 52-week treatment period among children in the LIBERTY ASTHMA VOYAGE study, according to investigator Leonard B. Bacharier, MD, of Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center, Nashville, Tenn.

“Dupilumab led to clinically meaningful rapid and sustained improvements in lung function parameters,” Dr. Bacharier said in an online poster presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

The improvements in forced expiratory volume in 1 second (FEV₁) and other measures reported for children with moderate to severe asthma who have the type 2 phenotype, which is the most common driver of pediatric asthma, according to Dr. Bacharier.

“Many children with moderate to severe asthma have abnormal lung function, and this can be a risk factor for future lung disease in adulthood,” Dr. Bacharier said in his presentation.
 

The VOYAGE continues

The findings presented at the meeting build on another report earlier this year from the LIBERTY ASTHMA VOYAGE study demonstrating that add-on dupilumab treatment led to a significant improvement versus placebo in FEV₁ up to 12 weeks.

“We now have a long term data on this drug as well, showing its efficacy over a period of time,” said Muhammad Adrish, MD, MBA, FCCP, associate professor of pulmonary, critical care and sleep medicine at Baylor College of Medicine, Houston.

“I think that’s pretty exciting, and that’s another step towards precision medicine in treatment of asthma,” Dr. Adrish, who is Vice-Chair of CHEST’s Airways Disorders NetWork Steering Committee and was not involved in the study.

Dupilumab received Food and Drug Administration approval in 2018 as add-on maintenance therapy for the treatment of patients aged 12 years or older with moderate to severe asthma that has an eosinophilic phenotype or that is dependent on oral corticosteroid treatment.

In March 2021, Sanofi and Regeneron announced that the FDA had accepted for review a supplemental Biologics License Application for dupilumab as an add-on treatment in children aged 6-11 years with uncontrolled moderate to severe asthma.

That sBLA is supported by data from the LIBERTY ASTHMA VOYAGE study, Sanofi and Regeneron said.

In results of the phase 3 study that Dr. Bacharier presented in May at the American Thoracic Society International Conference, add-on dupilumab dosed every 2 weeks significant improved percent predicted prebronchodilator FEV₁ by an additional 5.21 percentage points versus placebo at week 12.
 

Dupilumab and the type 2 phenotype

The new data reported at the CHEST meeting come from a prespecified analysis evaluating the impact of dupilumab on lung function over a 52-week treatment period in patients with a T2 inflammatory asthma phenotype.

“Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and -13, key and central drivers of T2 inflammation in multiple diseases,” Dr. Bacharier and coinvestigators reported in their study abstract.

Of 408 patients in the study, 350 met the T2 phenotype criteria, including 236 in the dupilumab arm and 114 in the placebo arm.

Patients met T2 phenotype criteria if they had blood eosinophils of at least 150 cells/mcL or fractional exhaled nitric oxide FeNO of at least 20 parts per billion at baseline, investigators said.

Dr. Bacharier and coinvestigators reported on several different endpoints, including absolute and percent predicted prebronchodilator FEV₁, percent predicted postbronchodilator FEV₁, prebronchodilator forced expiratory flow at 25%-75% of pulmonary volume (FEF_25%-75%), and forced vital capacity (FVC).

Dupilumab, when compared with placebo, significantly improved prebronchodilator FEV₁ in pediatric patients with uncontrolled moderate to severe type 2 asthma, according to Dr. Bacharier.

“Patients receiving dupilumab experienced rapid improvements by week 2, and this was sustained for up to 52 weeks,” he said.

The prebronchodilator FEV₁ improved from baseline for dupilumab versus placebo, with a least squares mean difference of 0.06 L at week 2, which reached 0.17 L by week 52, according to their data. Similarly, postbronchodilator FEV₁ improved from baseline for dupilumab, with a least square mean difference versus placebo of 0.09 L at week 52.

Dupilumab compared to placebo also significantly improved percent predicted FEF_25%-75%, and percent predicted FVC over the 52-week treatment period, according to Dr. Bacharier.

“Dupilumab led to significant, rapid, and sustained improvements in multiple aspects of lung function in children aged 6-11 years,” Dr. Bacharier added in a CHEST press release that described the findings.

The LIBERTY ASTHMA VOYAGE study was sponsored by Sanofi and Regeneron Pharmaceuticals. Dr. Bacharier provided disclosures related to AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals, Sanofi, CF Foundation, DBV Technologies, NIH, and Vectura.

Two biomarkers could potentially indicate which children with SARS-CoV-2 infection will develop severe disease, according to research presented at the American Academy of Pediatrics 2021 National Conference.

“Most children with COVID-19 present with common symptoms, such as fever, vomiting, and abdominal pain, which are very similar to other common viruses,” said senior researcher Usha Sethuraman, MD, professor of pediatric emergency medicine at Central Michigan University in Detroit.

“It is impossible, in many instances, to predict which child, even after identification of SARS-CoV-2 infection, is going to develop severe consequences, such as multisystem inflammatory syndrome [MIS-C] or severe pneumonia,” she said in an interview.

“In fact, many of these kids have been sent home the first time around as they appeared clinically well, only to return a couple of days later in cardiogenic shock and requiring invasive interventions,” she added. “It would be invaluable to have the ability to know which child is likely to develop severe infection so appropriate disposition can be made and treatment initiated.”

In their prospective observational cohort study, Dr. Sethuraman and her colleagues collected saliva samples from children and adolescents when they were diagnosed with SARS-CoV-2 infection. They assessed the saliva for micro (mi)RNAs, which are small noncoding RNAs that help regulate gene expression and are “thought to play a role in the regulation of inflammation following an infection,” the researchers write in their poster.

Of the 129 young people assessed, 32 (25%) developed severe infection and 97 (75%) did not. The researchers defined severe infection as an MIS-C diagnosis, death in the 30 days after diagnosis, or the need for at least 2 L of oxygen, inotropes, mechanical ventilation, or extracorporeal membrane oxygenation.

The expression of 63 miRNAs was significantly different between young people who developed severe infection and those who did not (P < .05). In cases of severe disease, expression was downregulated for 38 of the 63 miRNAs (60%).

“A model of six miRNAs was able to discriminate between severe and nonsevere infections with high sensitivity and accuracy in a preliminary analysis,” Dr. Sethuraman reported. “While salivary miRNA has been shown in other studies to help differentiate persistent concussion in children, we did not expect them to be downregulated in children with severe COVID-19.”

The significant differences in miRNA expression in those with and without severe disease is “striking,” despite this being an interim analysis in a fairly small sample size, said Sindhu Mohandas, MD, a pediatric infectious disease specialist at Children’s Hospital Los Angeles.

“It will be interesting to see if these findings persist when larger numbers are analyzed,” she told this news organization. “Biomarkers that can predict potential severity can be very useful in making risk and management determinations. A child who has the biomarkers that indicate increased severity can be monitored more closely and complications can be preempted and prevented.”

The largest difference between severe and nonsevere cases was in the expression of miRNA 4495. In addition, miRNA 6125 appears to have prognostic potential, the researchers conclude. And three cytokines from saliva samples were elevated in cases of severe infection, but cytokine levels could not distinguish between severe and nonsevere infections, Dr. Sethuraman said.

If further research confirms these findings and determines that these miRNAs truly can provide insight into the likely course of an infection, it “would be a game changer, clinically,” she added, particularly because saliva samples are less invasive and less painful than blood draws.

The potential applications of these biomarkers could extend beyond children admitted to the hospital, Dr. Mohandas noted.

“For example, it would be a noninvasive and easy method to predict potential severity in a child seen in the emergency room and could help with deciding between observation, admission to the general floor, or admission to the ICU,” she told this news organization. “However, this test is not easily or routinely available at present, and cost and accessibility will be the main factors that will have to be overcome before it can be used for this purpose.”

These findings are preliminary, from a small sample, and require confirmation and validation, Dr. Sethuraman cautioned. And the team only analyzed saliva collected at diagnosis, so they have no data on potential changes in cytokines or miRNAs that occur as the disease progresses.

The next step is to “better characterize what happens with time to these profiles,” she explained. “The role of age, race, and gender differences in saliva biomarker profiles needs additional investigation as well.”

It would also be interesting to see whether varied expression of miRNAs “can help differentiate the various complications after COVID-19, like acute respiratory failure, MIS-C, and long COVID,” said Dr. Mohandas. “That would mean it could be used not only to potentially predict severity, but also to predict longer-term outcomes.”

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the National Institutes of Health’s Rapid Acceleration of Diagnostics (RADx) program. Coauthor Steven D. Hicks, MD, PhD, reports being a paid consultant for Quadrant Biosciences.

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

Two biomarkers could potentially indicate which children with SARS-CoV-2 infection will develop severe disease, according to research presented at the American Academy of Pediatrics 2021 National Conference.

“Most children with COVID-19 present with common symptoms, such as fever, vomiting, and abdominal pain, which are very similar to other common viruses,” said senior researcher Usha Sethuraman, MD, professor of pediatric emergency medicine at Central Michigan University in Detroit.

“It is impossible, in many instances, to predict which child, even after identification of SARS-CoV-2 infection, is going to develop severe consequences, such as multisystem inflammatory syndrome [MIS-C] or severe pneumonia,” she said in an interview.

“In fact, many of these kids have been sent home the first time around as they appeared clinically well, only to return a couple of days later in cardiogenic shock and requiring invasive interventions,” she added. “It would be invaluable to have the ability to know which child is likely to develop severe infection so appropriate disposition can be made and treatment initiated.”

In their prospective observational cohort study, Dr. Sethuraman and her colleagues collected saliva samples from children and adolescents when they were diagnosed with SARS-CoV-2 infection. They assessed the saliva for micro (mi)RNAs, which are small noncoding RNAs that help regulate gene expression and are “thought to play a role in the regulation of inflammation following an infection,” the researchers write in their poster.

Of the 129 young people assessed, 32 (25%) developed severe infection and 97 (75%) did not. The researchers defined severe infection as an MIS-C diagnosis, death in the 30 days after diagnosis, or the need for at least 2 L of oxygen, inotropes, mechanical ventilation, or extracorporeal membrane oxygenation.

The expression of 63 miRNAs was significantly different between young people who developed severe infection and those who did not (P < .05). In cases of severe disease, expression was downregulated for 38 of the 63 miRNAs (60%).

“A model of six miRNAs was able to discriminate between severe and nonsevere infections with high sensitivity and accuracy in a preliminary analysis,” Dr. Sethuraman reported. “While salivary miRNA has been shown in other studies to help differentiate persistent concussion in children, we did not expect them to be downregulated in children with severe COVID-19.”

The significant differences in miRNA expression in those with and without severe disease is “striking,” despite this being an interim analysis in a fairly small sample size, said Sindhu Mohandas, MD, a pediatric infectious disease specialist at Children’s Hospital Los Angeles.

“It will be interesting to see if these findings persist when larger numbers are analyzed,” she told this news organization. “Biomarkers that can predict potential severity can be very useful in making risk and management determinations. A child who has the biomarkers that indicate increased severity can be monitored more closely and complications can be preempted and prevented.”

The largest difference between severe and nonsevere cases was in the expression of miRNA 4495. In addition, miRNA 6125 appears to have prognostic potential, the researchers conclude. And three cytokines from saliva samples were elevated in cases of severe infection, but cytokine levels could not distinguish between severe and nonsevere infections, Dr. Sethuraman said.

If further research confirms these findings and determines that these miRNAs truly can provide insight into the likely course of an infection, it “would be a game changer, clinically,” she added, particularly because saliva samples are less invasive and less painful than blood draws.

The potential applications of these biomarkers could extend beyond children admitted to the hospital, Dr. Mohandas noted.

“For example, it would be a noninvasive and easy method to predict potential severity in a child seen in the emergency room and could help with deciding between observation, admission to the general floor, or admission to the ICU,” she told this news organization. “However, this test is not easily or routinely available at present, and cost and accessibility will be the main factors that will have to be overcome before it can be used for this purpose.”

These findings are preliminary, from a small sample, and require confirmation and validation, Dr. Sethuraman cautioned. And the team only analyzed saliva collected at diagnosis, so they have no data on potential changes in cytokines or miRNAs that occur as the disease progresses.

The next step is to “better characterize what happens with time to these profiles,” she explained. “The role of age, race, and gender differences in saliva biomarker profiles needs additional investigation as well.”

It would also be interesting to see whether varied expression of miRNAs “can help differentiate the various complications after COVID-19, like acute respiratory failure, MIS-C, and long COVID,” said Dr. Mohandas. “That would mean it could be used not only to potentially predict severity, but also to predict longer-term outcomes.”

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the National Institutes of Health’s Rapid Acceleration of Diagnostics (RADx) program. Coauthor Steven D. Hicks, MD, PhD, reports being a paid consultant for Quadrant Biosciences.

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

Two biomarkers could potentially indicate which children with SARS-CoV-2 infection will develop severe disease, according to research presented at the American Academy of Pediatrics 2021 National Conference.

“Most children with COVID-19 present with common symptoms, such as fever, vomiting, and abdominal pain, which are very similar to other common viruses,” said senior researcher Usha Sethuraman, MD, professor of pediatric emergency medicine at Central Michigan University in Detroit.

“It is impossible, in many instances, to predict which child, even after identification of SARS-CoV-2 infection, is going to develop severe consequences, such as multisystem inflammatory syndrome [MIS-C] or severe pneumonia,” she said in an interview.

“In fact, many of these kids have been sent home the first time around as they appeared clinically well, only to return a couple of days later in cardiogenic shock and requiring invasive interventions,” she added. “It would be invaluable to have the ability to know which child is likely to develop severe infection so appropriate disposition can be made and treatment initiated.”

In their prospective observational cohort study, Dr. Sethuraman and her colleagues collected saliva samples from children and adolescents when they were diagnosed with SARS-CoV-2 infection. They assessed the saliva for micro (mi)RNAs, which are small noncoding RNAs that help regulate gene expression and are “thought to play a role in the regulation of inflammation following an infection,” the researchers write in their poster.

Of the 129 young people assessed, 32 (25%) developed severe infection and 97 (75%) did not. The researchers defined severe infection as an MIS-C diagnosis, death in the 30 days after diagnosis, or the need for at least 2 L of oxygen, inotropes, mechanical ventilation, or extracorporeal membrane oxygenation.

The expression of 63 miRNAs was significantly different between young people who developed severe infection and those who did not (P < .05). In cases of severe disease, expression was downregulated for 38 of the 63 miRNAs (60%).

“A model of six miRNAs was able to discriminate between severe and nonsevere infections with high sensitivity and accuracy in a preliminary analysis,” Dr. Sethuraman reported. “While salivary miRNA has been shown in other studies to help differentiate persistent concussion in children, we did not expect them to be downregulated in children with severe COVID-19.”

The significant differences in miRNA expression in those with and without severe disease is “striking,” despite this being an interim analysis in a fairly small sample size, said Sindhu Mohandas, MD, a pediatric infectious disease specialist at Children’s Hospital Los Angeles.

“It will be interesting to see if these findings persist when larger numbers are analyzed,” she told this news organization. “Biomarkers that can predict potential severity can be very useful in making risk and management determinations. A child who has the biomarkers that indicate increased severity can be monitored more closely and complications can be preempted and prevented.”

The largest difference between severe and nonsevere cases was in the expression of miRNA 4495. In addition, miRNA 6125 appears to have prognostic potential, the researchers conclude. And three cytokines from saliva samples were elevated in cases of severe infection, but cytokine levels could not distinguish between severe and nonsevere infections, Dr. Sethuraman said.

If further research confirms these findings and determines that these miRNAs truly can provide insight into the likely course of an infection, it “would be a game changer, clinically,” she added, particularly because saliva samples are less invasive and less painful than blood draws.

The potential applications of these biomarkers could extend beyond children admitted to the hospital, Dr. Mohandas noted.

“For example, it would be a noninvasive and easy method to predict potential severity in a child seen in the emergency room and could help with deciding between observation, admission to the general floor, or admission to the ICU,” she told this news organization. “However, this test is not easily or routinely available at present, and cost and accessibility will be the main factors that will have to be overcome before it can be used for this purpose.”

These findings are preliminary, from a small sample, and require confirmation and validation, Dr. Sethuraman cautioned. And the team only analyzed saliva collected at diagnosis, so they have no data on potential changes in cytokines or miRNAs that occur as the disease progresses.

The next step is to “better characterize what happens with time to these profiles,” she explained. “The role of age, race, and gender differences in saliva biomarker profiles needs additional investigation as well.”

It would also be interesting to see whether varied expression of miRNAs “can help differentiate the various complications after COVID-19, like acute respiratory failure, MIS-C, and long COVID,” said Dr. Mohandas. “That would mean it could be used not only to potentially predict severity, but also to predict longer-term outcomes.”

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the National Institutes of Health’s Rapid Acceleration of Diagnostics (RADx) program. Coauthor Steven D. Hicks, MD, PhD, reports being a paid consultant for Quadrant Biosciences.

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

New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).

The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   

Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).

Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.

Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.

Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.  

“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.

Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.

He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).

These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.

Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.

“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”

Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”

The ULTIMATE trials were funded by TG Therapeutics.

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

New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).

The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   

Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).

Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.

Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.

Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.  

“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.

Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.

He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).

These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.

Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.

“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”

Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”

The ULTIMATE trials were funded by TG Therapeutics.

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

New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).

The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   

Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).

Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.

Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.

Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.  

“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.

Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.

He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).

These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.

Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.

“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”

Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”

The ULTIMATE trials were funded by TG Therapeutics.

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