A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.

The study was published online in Neurology.
 

Epilepsy then depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
 

Depression then epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
 

Clinical implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.

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

A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.

The study was published online in Neurology.
 

Epilepsy then depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
 

Depression then epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
 

Clinical implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.

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

A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.

The study was published online in Neurology.
 

Epilepsy then depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
 

Depression then epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
 

Clinical implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.

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

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

New research suggests that body mass index (BMI) may influence response to topical corticosteroid (tCS) therapy for eosinophilic esophagitis (EoE).

The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.

Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.

For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.

Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.

To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.

Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).

Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).

Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).

Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).

In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).

Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).

On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.

This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
 

Different treatment algorithm?

The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.

The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.

As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.

The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.

However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.

“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.

Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.

“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.

“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.

Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.

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

New research suggests that body mass index (BMI) may influence response to topical corticosteroid (tCS) therapy for eosinophilic esophagitis (EoE).

The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.

Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.

For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.

Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.

To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.

Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).

Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).

Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).

Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).

In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).

Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).

On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.

This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
 

Different treatment algorithm?

The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.

The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.

As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.

The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.

However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.

“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.

Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.

“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.

“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.

Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.

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

New research suggests that body mass index (BMI) may influence response to topical corticosteroid (tCS) therapy for eosinophilic esophagitis (EoE).

The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.

Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.

For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.

Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.

To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.

Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).

Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).

Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).

Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).

In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).

Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).

On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.

This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
 

Different treatment algorithm?

The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.

The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.

As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.

The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.

However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.

“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.

Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.

“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.

“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.

Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

As a severe shortage drags on and prices soar, transplant centers have been struggling to cope with the paucity and price of fludarabine, a chemotherapy drug that has become an essential component of stem-cell transplants for some blood cancers.

At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.

Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.

“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”

In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
 

In new treatment era, fludarabine remains crucial

In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.

Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.

But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.

Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
 

As shortage continues, price hike brings yet another hit

The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.

Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.

In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”

“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.

In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.

Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”

The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
 

Alternatives abound, but do they suffice?

There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.

Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.

The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”

In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”

If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”

Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”

Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.

As a severe shortage drags on and prices soar, transplant centers have been struggling to cope with the paucity and price of fludarabine, a chemotherapy drug that has become an essential component of stem-cell transplants for some blood cancers.

At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.

Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.

“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”

In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
 

In new treatment era, fludarabine remains crucial

In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.

Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.

But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.

Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
 

As shortage continues, price hike brings yet another hit

The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.

Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.

In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”

“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.

In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.

Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”

The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
 

Alternatives abound, but do they suffice?

There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.

Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.

The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”

In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”

If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”

Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”

Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.

As a severe shortage drags on and prices soar, transplant centers have been struggling to cope with the paucity and price of fludarabine, a chemotherapy drug that has become an essential component of stem-cell transplants for some blood cancers.

At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.

Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.

“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”

In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
 

In new treatment era, fludarabine remains crucial

In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.

Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.

But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.

Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
 

As shortage continues, price hike brings yet another hit

The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.

Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.

In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”

“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.

In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.

Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”

The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
 

Alternatives abound, but do they suffice?

There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.

Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.

The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”

In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”

If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”

Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”

Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.

Visceral adipose tissue is significantly reduced with the green Mediterranean diet (MED), which consists of polyphenols and reduced red meat intake, according to a new analysis of the 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT-PLUS) trial.

The new results indicate that the green Mediterranean diet lowered visceral fat by twice as much as the standard Mediterranean diet (14% vs. 7%), reported Iris Shai, PhD, of Ben-Gurion University of the Negev in Be’er Sheva, Israel, and colleagues.

“This study may suggest an improved dietary protocol for treating visceral adiposity,” the authors wrote in their article, published recently in BMC Medicine.

“A healthy lifestyle is a strong basis for any weight-loss program. We learned from the results of our experiment that the quality of food is no less important than the number of calories consumed and the goal today is to understand the mechanisms of various nutrients, for example, positive ones such as the polyphenols, and negative ones such as empty carbohydrates and processed red meat, on the pace of fat cell differentiation and their aggregation in the viscera,” Dr. Shai said in a press release from Ben‐Gurion University.

“A 14% reduction in visceral fat is a dramatic achievement for making simple changes to your diet and lifestyle. Weight loss is an important goal only if it is accompanied by impressive results in reducing adipose tissue,” added coauthor Hila Zelicha, RD, PhD, also of Ben‐Gurion University of the Negev.

Previous randomized controlled trials have shown that dietary changes with a higher polyphenol content tend to produce better cardiometabolic outcomes and appear to mobilize particular ectopic fat depots, the researchers noted.

The main results of the DIRECT-PLUS trial were published in 2020 in Heart. Almost 300 participants with abdominal obesity/dyslipidemia were randomized to one of three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean diet, and the so-called green Mediterranean diet. The mean age of participants was 51 years, and men comprised 88% of the study cohort.

Participants in both Mediterranean diet groups ate 28 grams/day of walnuts, which accounted for about 440 mg/day of polyphenols. Participants in the green Mediterranean group also ate 100 grams/day of frozen cubes of a Wolffia globosa (duckweed strain) plant green shake, and three to four cups/day of green tea, which contributed to consumption of 800 mg/day of polyphenols, and decreased red meat consumption.

Both the green and standard Mediterranean diet groups achieved similar weight loss (–6.2 kg and –5.4 kg) compared with the HDG group (–1.5 kg; P < .001). However, the green Mediterranean diet group had a greater reduction in waist circumference (–8.6 cm) than the standard Mediterranean diet group (–6.8 cm; P = .033) and HDG group (–4.3 cm; P < .001). Stratification by gender showed these differences were significant only among men.

Explaining the rationale for the study, the researchers noted that visceral adipose tissue accumulation is a key factor that differentiates metabolic healthy and unhealthy obese individuals, is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, and type 2 diabetes, and is an independent marker of mortality.

Now, their latest data show the green Mediterranean diet group lost approximately twice as much visceral adipose tissue compared with the standard Mediterranean diet and HDG groups (−14.1%, −6.0%, and − 4.2%; P < .05 independent of weight loss, sex, waist circumference, or age).

Lower red meat consumption, greater dietary consumption of walnuts, Wolffia globosa, and green tea, increased urine urolithin A polyphenol, and elevated total plasma polyphenols were significantly associated with greater visceral adipose tissue loss (P < .05, multivariate models).

“A green Mediterranean diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the Mediterranean diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity,” the study authors concluded.

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

Visceral adipose tissue is significantly reduced with the green Mediterranean diet (MED), which consists of polyphenols and reduced red meat intake, according to a new analysis of the 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT-PLUS) trial.

The new results indicate that the green Mediterranean diet lowered visceral fat by twice as much as the standard Mediterranean diet (14% vs. 7%), reported Iris Shai, PhD, of Ben-Gurion University of the Negev in Be’er Sheva, Israel, and colleagues.

“This study may suggest an improved dietary protocol for treating visceral adiposity,” the authors wrote in their article, published recently in BMC Medicine.

“A healthy lifestyle is a strong basis for any weight-loss program. We learned from the results of our experiment that the quality of food is no less important than the number of calories consumed and the goal today is to understand the mechanisms of various nutrients, for example, positive ones such as the polyphenols, and negative ones such as empty carbohydrates and processed red meat, on the pace of fat cell differentiation and their aggregation in the viscera,” Dr. Shai said in a press release from Ben‐Gurion University.

“A 14% reduction in visceral fat is a dramatic achievement for making simple changes to your diet and lifestyle. Weight loss is an important goal only if it is accompanied by impressive results in reducing adipose tissue,” added coauthor Hila Zelicha, RD, PhD, also of Ben‐Gurion University of the Negev.

Previous randomized controlled trials have shown that dietary changes with a higher polyphenol content tend to produce better cardiometabolic outcomes and appear to mobilize particular ectopic fat depots, the researchers noted.

The main results of the DIRECT-PLUS trial were published in 2020 in Heart. Almost 300 participants with abdominal obesity/dyslipidemia were randomized to one of three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean diet, and the so-called green Mediterranean diet. The mean age of participants was 51 years, and men comprised 88% of the study cohort.

Participants in both Mediterranean diet groups ate 28 grams/day of walnuts, which accounted for about 440 mg/day of polyphenols. Participants in the green Mediterranean group also ate 100 grams/day of frozen cubes of a Wolffia globosa (duckweed strain) plant green shake, and three to four cups/day of green tea, which contributed to consumption of 800 mg/day of polyphenols, and decreased red meat consumption.

Both the green and standard Mediterranean diet groups achieved similar weight loss (–6.2 kg and –5.4 kg) compared with the HDG group (–1.5 kg; P < .001). However, the green Mediterranean diet group had a greater reduction in waist circumference (–8.6 cm) than the standard Mediterranean diet group (–6.8 cm; P = .033) and HDG group (–4.3 cm; P < .001). Stratification by gender showed these differences were significant only among men.

Explaining the rationale for the study, the researchers noted that visceral adipose tissue accumulation is a key factor that differentiates metabolic healthy and unhealthy obese individuals, is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, and type 2 diabetes, and is an independent marker of mortality.

Now, their latest data show the green Mediterranean diet group lost approximately twice as much visceral adipose tissue compared with the standard Mediterranean diet and HDG groups (−14.1%, −6.0%, and − 4.2%; P < .05 independent of weight loss, sex, waist circumference, or age).

Lower red meat consumption, greater dietary consumption of walnuts, Wolffia globosa, and green tea, increased urine urolithin A polyphenol, and elevated total plasma polyphenols were significantly associated with greater visceral adipose tissue loss (P < .05, multivariate models).

“A green Mediterranean diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the Mediterranean diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity,” the study authors concluded.

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

Visceral adipose tissue is significantly reduced with the green Mediterranean diet (MED), which consists of polyphenols and reduced red meat intake, according to a new analysis of the 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT-PLUS) trial.

The new results indicate that the green Mediterranean diet lowered visceral fat by twice as much as the standard Mediterranean diet (14% vs. 7%), reported Iris Shai, PhD, of Ben-Gurion University of the Negev in Be’er Sheva, Israel, and colleagues.

“This study may suggest an improved dietary protocol for treating visceral adiposity,” the authors wrote in their article, published recently in BMC Medicine.

“A healthy lifestyle is a strong basis for any weight-loss program. We learned from the results of our experiment that the quality of food is no less important than the number of calories consumed and the goal today is to understand the mechanisms of various nutrients, for example, positive ones such as the polyphenols, and negative ones such as empty carbohydrates and processed red meat, on the pace of fat cell differentiation and their aggregation in the viscera,” Dr. Shai said in a press release from Ben‐Gurion University.

“A 14% reduction in visceral fat is a dramatic achievement for making simple changes to your diet and lifestyle. Weight loss is an important goal only if it is accompanied by impressive results in reducing adipose tissue,” added coauthor Hila Zelicha, RD, PhD, also of Ben‐Gurion University of the Negev.

Previous randomized controlled trials have shown that dietary changes with a higher polyphenol content tend to produce better cardiometabolic outcomes and appear to mobilize particular ectopic fat depots, the researchers noted.

The main results of the DIRECT-PLUS trial were published in 2020 in Heart. Almost 300 participants with abdominal obesity/dyslipidemia were randomized to one of three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean diet, and the so-called green Mediterranean diet. The mean age of participants was 51 years, and men comprised 88% of the study cohort.

Participants in both Mediterranean diet groups ate 28 grams/day of walnuts, which accounted for about 440 mg/day of polyphenols. Participants in the green Mediterranean group also ate 100 grams/day of frozen cubes of a Wolffia globosa (duckweed strain) plant green shake, and three to four cups/day of green tea, which contributed to consumption of 800 mg/day of polyphenols, and decreased red meat consumption.

Both the green and standard Mediterranean diet groups achieved similar weight loss (–6.2 kg and –5.4 kg) compared with the HDG group (–1.5 kg; P < .001). However, the green Mediterranean diet group had a greater reduction in waist circumference (–8.6 cm) than the standard Mediterranean diet group (–6.8 cm; P = .033) and HDG group (–4.3 cm; P < .001). Stratification by gender showed these differences were significant only among men.

Explaining the rationale for the study, the researchers noted that visceral adipose tissue accumulation is a key factor that differentiates metabolic healthy and unhealthy obese individuals, is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, and type 2 diabetes, and is an independent marker of mortality.

Now, their latest data show the green Mediterranean diet group lost approximately twice as much visceral adipose tissue compared with the standard Mediterranean diet and HDG groups (−14.1%, −6.0%, and − 4.2%; P < .05 independent of weight loss, sex, waist circumference, or age).

Lower red meat consumption, greater dietary consumption of walnuts, Wolffia globosa, and green tea, increased urine urolithin A polyphenol, and elevated total plasma polyphenols were significantly associated with greater visceral adipose tissue loss (P < .05, multivariate models).

“A green Mediterranean diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the Mediterranean diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity,” the study authors concluded.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.

Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.

“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.

Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.

In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:

• A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
• Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
• In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
• Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
• Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.

The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.

A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.

This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.

Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.

The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.

Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.

“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.

Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.

In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:

• A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
• Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
• In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
• Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
• Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.

The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.

A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.

This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.

Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.

The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.

Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.

“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.

Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.

In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:

• A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
• Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
• In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
• Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
• Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.

The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.

A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.

This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.

Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

A new study supports the hypothesis that changes in levels of amyloid and tau occur many years before the emergence of clinical symptoms of Alzheimer’s disease (AD).

“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.

“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

The study was published online in Alzheimer’s and Dementia.
 

Novel long-term CSF data

The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.

The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.

“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.

During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).

Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.

Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
 

Clear impact of APOE4

The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.

“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.

“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.

“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.

Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.

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

A new study supports the hypothesis that changes in levels of amyloid and tau occur many years before the emergence of clinical symptoms of Alzheimer’s disease (AD).

“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.

“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

The study was published online in Alzheimer’s and Dementia.
 

Novel long-term CSF data

The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.

The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.

“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.

During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).

Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.

Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
 

Clear impact of APOE4

The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.

“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.

“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.

“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.

Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.

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

A new study supports the hypothesis that changes in levels of amyloid and tau occur many years before the emergence of clinical symptoms of Alzheimer’s disease (AD).

“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.

“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

The study was published online in Alzheimer’s and Dementia.
 

Novel long-term CSF data

The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.

The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.

“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.

During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).

Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.

Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
 

Clear impact of APOE4

The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.

“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.

“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.

“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.

Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.

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