MDedge Pediatrics

Burnout is seldom the result of a single factor. It is more often a tragic case of death by a thousand cuts: a balky user-unfriendly electronic medical record system, administrative pressure to see more patients and the resulting frustration of not being able to provide the care you feel they deserve, an overemphasis on documentation or you won’t get paid, the dark cloud of malpractice always overhead, and of course the difficult balance between family responsibilities and work. It often boils down to feeling that there aren’t enough hours in the day to get everything done and still have time to recharge your physical and psychological batteries.

A recent report in the Harvard Business School newsletter, Working Knowledge (“Commuting Hurts Productivity and Your Best Talent Suffers Most.” Lane Lambert. 2021 Mar 30) describes an interesting study by Andy Wu, assistant professor of business administration, in which he discovered that, for every 10 kilometers of commuting distance, there was a decrease in the productivity of high-tech inventors as measured by the number of patents registered by their companies. The quality of their inventions declined even more (7%) for each additional 10 kilometers of commute.

You might question the relevance of these findings with your work in an outpatient clinic, but a conscientious physician is also an inventor and a creator. Every patient, even those with what sounds like a routine complaint, presents a novel collection of management challenges. The best physicians treat their profession as an art and must be invent solutions on the fly.

There is abundant evidence that commuting also can have a negative effect on the physical and mental health of workers. (“The astonishing human potential wasted on commutes.” The Washington Post .Christopher Ingraham. 2016 Feb 25). Watching my father walk into the house after an hour-long train ride out of the city and listening to him grumble created an image that influenced every decision I made about where my wife and I would live and work.

Did I benefit from the luxury of growing up in a small suburban community? Of course I did and I shall be forever grateful for the sacrifice my father made to allow that to happen. But, I promised myself that, while I would make sacrifices for my family, a long or unpleasant commute was not going to be on that list. For a few years I tolerated a 10- to 12-minute car commute (three stoplights) but asked to dissolve the partnership because even that 9-mile ride was too much for me and instead spent the bulk of my 40-year career a 10-minute bike ride from my office and the two hospitals. It meant we didn’t have a view of the ocean or a gentleman’s farm but we had an extra hour together as a family and I arrived at work and at home happy.

The pandemic has been a wake-up call for many of the fortunate folks who have found that they can work from home, eliminating what may have been a time-gobbling commute that was creating more stress than they may have realized. Even if telemedicine continues to maintain some postpandemic presence, I suspect that most physicians will continue to be faced with the challenge of traveling to an office or hospital.

If work is losing some of its luster and/or you are arriving home grumpy from a long day in the office, it is easy to blame an insensitive office administrator or the clunky electronic medical record system ... they deserve it. But, it may be the journey and not just the destination that is the contributing to the problem. I realize that rethinking the decision about where one lives can be painful and the options may be limited. However, I hope that at least some of you can rethink the role your journey is playing in your life.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Burnout is seldom the result of a single factor. It is more often a tragic case of death by a thousand cuts: a balky user-unfriendly electronic medical record system, administrative pressure to see more patients and the resulting frustration of not being able to provide the care you feel they deserve, an overemphasis on documentation or you won’t get paid, the dark cloud of malpractice always overhead, and of course the difficult balance between family responsibilities and work. It often boils down to feeling that there aren’t enough hours in the day to get everything done and still have time to recharge your physical and psychological batteries.

A recent report in the Harvard Business School newsletter, Working Knowledge (“Commuting Hurts Productivity and Your Best Talent Suffers Most.” Lane Lambert. 2021 Mar 30) describes an interesting study by Andy Wu, assistant professor of business administration, in which he discovered that, for every 10 kilometers of commuting distance, there was a decrease in the productivity of high-tech inventors as measured by the number of patents registered by their companies. The quality of their inventions declined even more (7%) for each additional 10 kilometers of commute.

You might question the relevance of these findings with your work in an outpatient clinic, but a conscientious physician is also an inventor and a creator. Every patient, even those with what sounds like a routine complaint, presents a novel collection of management challenges. The best physicians treat their profession as an art and must be invent solutions on the fly.

There is abundant evidence that commuting also can have a negative effect on the physical and mental health of workers. (“The astonishing human potential wasted on commutes.” The Washington Post .Christopher Ingraham. 2016 Feb 25). Watching my father walk into the house after an hour-long train ride out of the city and listening to him grumble created an image that influenced every decision I made about where my wife and I would live and work.

Did I benefit from the luxury of growing up in a small suburban community? Of course I did and I shall be forever grateful for the sacrifice my father made to allow that to happen. But, I promised myself that, while I would make sacrifices for my family, a long or unpleasant commute was not going to be on that list. For a few years I tolerated a 10- to 12-minute car commute (three stoplights) but asked to dissolve the partnership because even that 9-mile ride was too much for me and instead spent the bulk of my 40-year career a 10-minute bike ride from my office and the two hospitals. It meant we didn’t have a view of the ocean or a gentleman’s farm but we had an extra hour together as a family and I arrived at work and at home happy.

The pandemic has been a wake-up call for many of the fortunate folks who have found that they can work from home, eliminating what may have been a time-gobbling commute that was creating more stress than they may have realized. Even if telemedicine continues to maintain some postpandemic presence, I suspect that most physicians will continue to be faced with the challenge of traveling to an office or hospital.

If work is losing some of its luster and/or you are arriving home grumpy from a long day in the office, it is easy to blame an insensitive office administrator or the clunky electronic medical record system ... they deserve it. But, it may be the journey and not just the destination that is the contributing to the problem. I realize that rethinking the decision about where one lives can be painful and the options may be limited. However, I hope that at least some of you can rethink the role your journey is playing in your life.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Burnout is seldom the result of a single factor. It is more often a tragic case of death by a thousand cuts: a balky user-unfriendly electronic medical record system, administrative pressure to see more patients and the resulting frustration of not being able to provide the care you feel they deserve, an overemphasis on documentation or you won’t get paid, the dark cloud of malpractice always overhead, and of course the difficult balance between family responsibilities and work. It often boils down to feeling that there aren’t enough hours in the day to get everything done and still have time to recharge your physical and psychological batteries.

A recent report in the Harvard Business School newsletter, Working Knowledge (“Commuting Hurts Productivity and Your Best Talent Suffers Most.” Lane Lambert. 2021 Mar 30) describes an interesting study by Andy Wu, assistant professor of business administration, in which he discovered that, for every 10 kilometers of commuting distance, there was a decrease in the productivity of high-tech inventors as measured by the number of patents registered by their companies. The quality of their inventions declined even more (7%) for each additional 10 kilometers of commute.

You might question the relevance of these findings with your work in an outpatient clinic, but a conscientious physician is also an inventor and a creator. Every patient, even those with what sounds like a routine complaint, presents a novel collection of management challenges. The best physicians treat their profession as an art and must be invent solutions on the fly.

There is abundant evidence that commuting also can have a negative effect on the physical and mental health of workers. (“The astonishing human potential wasted on commutes.” The Washington Post .Christopher Ingraham. 2016 Feb 25). Watching my father walk into the house after an hour-long train ride out of the city and listening to him grumble created an image that influenced every decision I made about where my wife and I would live and work.

Did I benefit from the luxury of growing up in a small suburban community? Of course I did and I shall be forever grateful for the sacrifice my father made to allow that to happen. But, I promised myself that, while I would make sacrifices for my family, a long or unpleasant commute was not going to be on that list. For a few years I tolerated a 10- to 12-minute car commute (three stoplights) but asked to dissolve the partnership because even that 9-mile ride was too much for me and instead spent the bulk of my 40-year career a 10-minute bike ride from my office and the two hospitals. It meant we didn’t have a view of the ocean or a gentleman’s farm but we had an extra hour together as a family and I arrived at work and at home happy.

The pandemic has been a wake-up call for many of the fortunate folks who have found that they can work from home, eliminating what may have been a time-gobbling commute that was creating more stress than they may have realized. Even if telemedicine continues to maintain some postpandemic presence, I suspect that most physicians will continue to be faced with the challenge of traveling to an office or hospital.

If work is losing some of its luster and/or you are arriving home grumpy from a long day in the office, it is easy to blame an insensitive office administrator or the clunky electronic medical record system ... they deserve it. But, it may be the journey and not just the destination that is the contributing to the problem. I realize that rethinking the decision about where one lives can be painful and the options may be limited. However, I hope that at least some of you can rethink the role your journey is playing in your life.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In the periurban slum of Lusaka, Zambia, asymptomatic pertussis infections were common among both mothers and infants, a surprising finding since asymptomatic infections are assumed to be rare in infants. The findings suggested that pertussis should be considered in cases of chronic cough, and that current standards of treating pertussis infections in low-resource settings may need to be reexamined.

The results come from testing of 1,320 infant-mother pairs who were first enrolled at a public health clinic, then followed over at least four visits. The researchers tracked pertussis infection using quantitative PCR (qPCR) on nasopharyngeal swabs. Over the course of the study, 8.9% tested positive, although only one infant developed clinical pertussis during the study.

The study was presented by Christian Gunning, a postdoctoral researcher at the University of Georgia, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. The group also included researchers at Boston University and the University of Zambia, where PCR tests were conducted.

“That was amazing,” said session moderator Vana Spoulou, MD, PhD, professor of pediatric infectious diseases at National and Kapodistrian University of Athens, who is associated with Aghia Sofia Children’s Hospital of Athens. She noted that the study found that many physicians misdiagnosed coughs, believing them to be caused by another agent. “It was very interesting that there was so much pertussis spreading around in that community, and that nobody knew that it was around,” said Dr. Spoulou.

It’s important that physicians provide appropriate treatment, since ampicillin, which is typically prescribed for childhood upper respiratory illnesses, is believed to be ineffective against pertussis, while macrolides are effective and can prevent transmission.

Dr. Spoulou also noted that Zambia uses a whole cell vaccine, which is contraindicated in pregnant women because of potential side effects. “The good thing, despite that there was [a lot of] infection, there were no deaths, which means that maybe because the mother was infected, maybe some antibodies of the mother had passed to the child and could help the child to develop milder symptoms. So these are the pros and cons of natural infection,” said Dr. Spoulou.

The study took place in 2015, and participants were seen at the Chawama Public Health Clinic from about age 1 week to 4 months (with a target of seven clinic visits). Researchers recorded respiratory symptoms and antibiotics use at each visit, and collected a nasopharyngeal swab that was tested retrospectively using qPCR for Bordetella pertussis.

Real-time PCR analysis of the samples yields the CT value, which represents the number of amplification cycles that the PCR test must complete before Bordetella pertussis is detectable. The fewer the cycles (and the lower the CT value), the more infectious particles must have been present in the sample. For pertussis testing, a value below 35 is considered a clinically positive result. Tests that come back with higher CT values are increasingly likely to be false positives.

The researchers plotted a value called evidence for infection (EFI), which combined a range of CT values with the number of positive tests over the seven clinic visits to group patients into none, weak, or strong EFI. Among infants with no symptoms, 77% were in the no EFI category, 16% were in the weak category, and 7% were in the strong EFI group. Of infants with minimal respiratory symptoms, 18% were in the strong group, and 20% with moderate to severe symptoms were in the strong EFI group. Among mothers, 13% with no symptoms were in the strong group. 19% in the minimal symptom group were categorized as strong EFI, as were 11% in the moderate to severe symptom group.

The study used a full range of CT, not just positive test results (for pertussis, CT ≤ 35). Beyond contributing to composite measures such as EFI, CT values can serve as leading indicators of infectious disease outbreaks in a population, according to Dr. Gunning. That’s because weaker qPCR signals (CT > 35) can provide additional information within a large sample population. Higher CT values are successively more prone to false positives, but that’s less important for disease surveillance where sensitivity is of the highest importance. The false positive “noise” tends to cancel out over time. “It may be the case that you don’t make that call (correctly) 100% of the time for 100% of the people, but if you get it right in 80 out of 100 people, that’s sufficient to say we see this pathogen circulating in the population,” said Dr. Gunning.

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Gunning and Dr. Spoulou have no relevant financial disclosures.

In the periurban slum of Lusaka, Zambia, asymptomatic pertussis infections were common among both mothers and infants, a surprising finding since asymptomatic infections are assumed to be rare in infants. The findings suggested that pertussis should be considered in cases of chronic cough, and that current standards of treating pertussis infections in low-resource settings may need to be reexamined.

The results come from testing of 1,320 infant-mother pairs who were first enrolled at a public health clinic, then followed over at least four visits. The researchers tracked pertussis infection using quantitative PCR (qPCR) on nasopharyngeal swabs. Over the course of the study, 8.9% tested positive, although only one infant developed clinical pertussis during the study.

The study was presented by Christian Gunning, a postdoctoral researcher at the University of Georgia, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. The group also included researchers at Boston University and the University of Zambia, where PCR tests were conducted.

“That was amazing,” said session moderator Vana Spoulou, MD, PhD, professor of pediatric infectious diseases at National and Kapodistrian University of Athens, who is associated with Aghia Sofia Children’s Hospital of Athens. She noted that the study found that many physicians misdiagnosed coughs, believing them to be caused by another agent. “It was very interesting that there was so much pertussis spreading around in that community, and that nobody knew that it was around,” said Dr. Spoulou.

It’s important that physicians provide appropriate treatment, since ampicillin, which is typically prescribed for childhood upper respiratory illnesses, is believed to be ineffective against pertussis, while macrolides are effective and can prevent transmission.

Dr. Spoulou also noted that Zambia uses a whole cell vaccine, which is contraindicated in pregnant women because of potential side effects. “The good thing, despite that there was [a lot of] infection, there were no deaths, which means that maybe because the mother was infected, maybe some antibodies of the mother had passed to the child and could help the child to develop milder symptoms. So these are the pros and cons of natural infection,” said Dr. Spoulou.

The study took place in 2015, and participants were seen at the Chawama Public Health Clinic from about age 1 week to 4 months (with a target of seven clinic visits). Researchers recorded respiratory symptoms and antibiotics use at each visit, and collected a nasopharyngeal swab that was tested retrospectively using qPCR for Bordetella pertussis.

Real-time PCR analysis of the samples yields the CT value, which represents the number of amplification cycles that the PCR test must complete before Bordetella pertussis is detectable. The fewer the cycles (and the lower the CT value), the more infectious particles must have been present in the sample. For pertussis testing, a value below 35 is considered a clinically positive result. Tests that come back with higher CT values are increasingly likely to be false positives.

The researchers plotted a value called evidence for infection (EFI), which combined a range of CT values with the number of positive tests over the seven clinic visits to group patients into none, weak, or strong EFI. Among infants with no symptoms, 77% were in the no EFI category, 16% were in the weak category, and 7% were in the strong EFI group. Of infants with minimal respiratory symptoms, 18% were in the strong group, and 20% with moderate to severe symptoms were in the strong EFI group. Among mothers, 13% with no symptoms were in the strong group. 19% in the minimal symptom group were categorized as strong EFI, as were 11% in the moderate to severe symptom group.

The study used a full range of CT, not just positive test results (for pertussis, CT ≤ 35). Beyond contributing to composite measures such as EFI, CT values can serve as leading indicators of infectious disease outbreaks in a population, according to Dr. Gunning. That’s because weaker qPCR signals (CT > 35) can provide additional information within a large sample population. Higher CT values are successively more prone to false positives, but that’s less important for disease surveillance where sensitivity is of the highest importance. The false positive “noise” tends to cancel out over time. “It may be the case that you don’t make that call (correctly) 100% of the time for 100% of the people, but if you get it right in 80 out of 100 people, that’s sufficient to say we see this pathogen circulating in the population,” said Dr. Gunning.

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Gunning and Dr. Spoulou have no relevant financial disclosures.

In the periurban slum of Lusaka, Zambia, asymptomatic pertussis infections were common among both mothers and infants, a surprising finding since asymptomatic infections are assumed to be rare in infants. The findings suggested that pertussis should be considered in cases of chronic cough, and that current standards of treating pertussis infections in low-resource settings may need to be reexamined.

The results come from testing of 1,320 infant-mother pairs who were first enrolled at a public health clinic, then followed over at least four visits. The researchers tracked pertussis infection using quantitative PCR (qPCR) on nasopharyngeal swabs. Over the course of the study, 8.9% tested positive, although only one infant developed clinical pertussis during the study.

The study was presented by Christian Gunning, a postdoctoral researcher at the University of Georgia, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. The group also included researchers at Boston University and the University of Zambia, where PCR tests were conducted.

“That was amazing,” said session moderator Vana Spoulou, MD, PhD, professor of pediatric infectious diseases at National and Kapodistrian University of Athens, who is associated with Aghia Sofia Children’s Hospital of Athens. She noted that the study found that many physicians misdiagnosed coughs, believing them to be caused by another agent. “It was very interesting that there was so much pertussis spreading around in that community, and that nobody knew that it was around,” said Dr. Spoulou.

It’s important that physicians provide appropriate treatment, since ampicillin, which is typically prescribed for childhood upper respiratory illnesses, is believed to be ineffective against pertussis, while macrolides are effective and can prevent transmission.

Dr. Spoulou also noted that Zambia uses a whole cell vaccine, which is contraindicated in pregnant women because of potential side effects. “The good thing, despite that there was [a lot of] infection, there were no deaths, which means that maybe because the mother was infected, maybe some antibodies of the mother had passed to the child and could help the child to develop milder symptoms. So these are the pros and cons of natural infection,” said Dr. Spoulou.

The study took place in 2015, and participants were seen at the Chawama Public Health Clinic from about age 1 week to 4 months (with a target of seven clinic visits). Researchers recorded respiratory symptoms and antibiotics use at each visit, and collected a nasopharyngeal swab that was tested retrospectively using qPCR for Bordetella pertussis.

Real-time PCR analysis of the samples yields the CT value, which represents the number of amplification cycles that the PCR test must complete before Bordetella pertussis is detectable. The fewer the cycles (and the lower the CT value), the more infectious particles must have been present in the sample. For pertussis testing, a value below 35 is considered a clinically positive result. Tests that come back with higher CT values are increasingly likely to be false positives.

The researchers plotted a value called evidence for infection (EFI), which combined a range of CT values with the number of positive tests over the seven clinic visits to group patients into none, weak, or strong EFI. Among infants with no symptoms, 77% were in the no EFI category, 16% were in the weak category, and 7% were in the strong EFI group. Of infants with minimal respiratory symptoms, 18% were in the strong group, and 20% with moderate to severe symptoms were in the strong EFI group. Among mothers, 13% with no symptoms were in the strong group. 19% in the minimal symptom group were categorized as strong EFI, as were 11% in the moderate to severe symptom group.

The study used a full range of CT, not just positive test results (for pertussis, CT ≤ 35). Beyond contributing to composite measures such as EFI, CT values can serve as leading indicators of infectious disease outbreaks in a population, according to Dr. Gunning. That’s because weaker qPCR signals (CT > 35) can provide additional information within a large sample population. Higher CT values are successively more prone to false positives, but that’s less important for disease surveillance where sensitivity is of the highest importance. The false positive “noise” tends to cancel out over time. “It may be the case that you don’t make that call (correctly) 100% of the time for 100% of the people, but if you get it right in 80 out of 100 people, that’s sufficient to say we see this pathogen circulating in the population,” said Dr. Gunning.

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Gunning and Dr. Spoulou have no relevant financial disclosures.

More children aged 12-15 years already have received at least one dose of a COVID-19 vaccine than have 16- and 17-year-olds, based on data from the Centers for Disease Control and Prevention.

As of May 30, almost 2.89 million children aged 12-15 years had received at least one dose, compared with nearly 2.73 million children aged 16-17, with those figures representing increases of 31.6% and 6.6% in the past week, respectively. Since the overall size of the 12-15 population is much larger, however, the proportion vaccinated is still smaller: 19.5% to 36.4%, according to the CDC’s COVID Data Tracker.

A look at full vaccination status shows that only 0.7% of those aged 12-15 years have received both doses of a two-dose vaccine or one dose of the single-shot variety, compared with 24% of those aged 16-17. For the country as a whole, 50.5% of all ages have received at least one dose and 40.7% are fully vaccinated, the CDC said.

Children aged 12-15 represent the largest share of the U.S. population (23.4%) initiating vaccination in the 14 days ending May 30, while children aged 16-17 made up just 4.5% of those getting their first dose. The younger group’s later entry into the vaccination pool shows up again when looking at completion rates, though, representing just 0.4% of all Americans who reached full vaccination during that same 14-day period, compared with 4.6% of the older children, the CDC data show.

Not all states are reporting data such as age for vaccine recipients, the CDC noted, and there are other variables that affect data collection. “Demographic data ... might differ by populations prioritized within each state or jurisdiction’s vaccination phase. Every geographic area has a different racial and ethnic composition, and not all are in the same vaccination phase,” the CDC said.

[email protected]

More children aged 12-15 years already have received at least one dose of a COVID-19 vaccine than have 16- and 17-year-olds, based on data from the Centers for Disease Control and Prevention.

As of May 30, almost 2.89 million children aged 12-15 years had received at least one dose, compared with nearly 2.73 million children aged 16-17, with those figures representing increases of 31.6% and 6.6% in the past week, respectively. Since the overall size of the 12-15 population is much larger, however, the proportion vaccinated is still smaller: 19.5% to 36.4%, according to the CDC’s COVID Data Tracker.

A look at full vaccination status shows that only 0.7% of those aged 12-15 years have received both doses of a two-dose vaccine or one dose of the single-shot variety, compared with 24% of those aged 16-17. For the country as a whole, 50.5% of all ages have received at least one dose and 40.7% are fully vaccinated, the CDC said.

Children aged 12-15 represent the largest share of the U.S. population (23.4%) initiating vaccination in the 14 days ending May 30, while children aged 16-17 made up just 4.5% of those getting their first dose. The younger group’s later entry into the vaccination pool shows up again when looking at completion rates, though, representing just 0.4% of all Americans who reached full vaccination during that same 14-day period, compared with 4.6% of the older children, the CDC data show.

Not all states are reporting data such as age for vaccine recipients, the CDC noted, and there are other variables that affect data collection. “Demographic data ... might differ by populations prioritized within each state or jurisdiction’s vaccination phase. Every geographic area has a different racial and ethnic composition, and not all are in the same vaccination phase,” the CDC said.

[email protected]

More children aged 12-15 years already have received at least one dose of a COVID-19 vaccine than have 16- and 17-year-olds, based on data from the Centers for Disease Control and Prevention.

As of May 30, almost 2.89 million children aged 12-15 years had received at least one dose, compared with nearly 2.73 million children aged 16-17, with those figures representing increases of 31.6% and 6.6% in the past week, respectively. Since the overall size of the 12-15 population is much larger, however, the proportion vaccinated is still smaller: 19.5% to 36.4%, according to the CDC’s COVID Data Tracker.

A look at full vaccination status shows that only 0.7% of those aged 12-15 years have received both doses of a two-dose vaccine or one dose of the single-shot variety, compared with 24% of those aged 16-17. For the country as a whole, 50.5% of all ages have received at least one dose and 40.7% are fully vaccinated, the CDC said.

Children aged 12-15 represent the largest share of the U.S. population (23.4%) initiating vaccination in the 14 days ending May 30, while children aged 16-17 made up just 4.5% of those getting their first dose. The younger group’s later entry into the vaccination pool shows up again when looking at completion rates, though, representing just 0.4% of all Americans who reached full vaccination during that same 14-day period, compared with 4.6% of the older children, the CDC data show.

Not all states are reporting data such as age for vaccine recipients, the CDC noted, and there are other variables that affect data collection. “Demographic data ... might differ by populations prioritized within each state or jurisdiction’s vaccination phase. Every geographic area has a different racial and ethnic composition, and not all are in the same vaccination phase,” the CDC said.

[email protected]

Among children with sickle cell disease who have not undergone hematopoietic stem cell transplant, Salmonella is now the leading cause of invasive bacterial infection (IBI), according to a new retrospective study (BACT-SPRING) conducted in Europe. Streptococcus pneumoniae was the second most common source of infection, marking a shift from years past, when S. pneumoniae was the most common source. The epidemiology of IBI in Europe has been altered by adoption of prophylaxis and the introduction of the pneumococcal conjugated vaccine (PCV13) in 2009.

Previous studies of IBI have been single center with small sample sizes, and few have been conducted since 2016, said Jean Gaschignard, MD, PhD, during his presentation of the study at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Dr. Gaschignard is head of pediatrics at Groupe Hospitalier Nord Essonne in Longjumeau, France.

The study produced some unexpected results. “We were surprised,” said Dr. Gaschignard, by results indicating that not all children aged under 10 years were undergoing prophylaxis. Instead, the figures were closer to 80% or 90%. Among children over 10, the rate of prophylaxis varies between countries. “Our study is a clue to discuss again the indications for the age limit for prophylaxis against pneumococcus,” said Dr. Gauschignard, during the question-and-answer session following his talk.

The data give clinicians an updated picture of the epidemiology in this population following introduction of the PCV13 vaccine. “It was very important to have new data on microbiology after this implementation,” said Marie Rohr, MD, who is a fellow in pediatric infectious diseases at the University Hospitals of Geneva. Dr. Rohr moderated the session where the study was presented.

Dr. Rohr noted the shift from the dominant cause of IBI after the introduction of the PCV10/13 vaccine, from S. pneumoniae to Salmonella. The researchers also found a preponderance of bacteremia and osteoarticular infections. “The mortality and morbidity are still considerable despite infection preventive measures,” said Dr. Rohr.

The results should also prompt a second look at prevention strategies. “Even if the antibiotic prophylaxis is prescribed for a large [proportion of children with sickle cell disease] under 10 years old, the median age of invasive bacterial infection is 7 years old. This calls into question systematic antibiotic prophylaxis and case-control studies are needed to evaluate this and possibly modify antibiotic prophylaxis recommendations in the future,” said Dr. Rohr.

The BACT-SPRING study was conducted between Jan. 1, 2014, and Dec. 31, 2019, using online data. It included 217 IBI episodes from 26 centers in five European countries. Just over half were from France, while about a quarter occurred in Spain. Other countries included Belgium, Portugal, and Great Britain. Participants were younger than 18 and had an IBI confirmed by bacterial culture or PCR from normally sterile fluid.

Thirty-eight episodes occurred in children who had undergone hematopoietic stem cell transplantation (HSCT), and 179 in children who had not undergone HSCT. The presentation focused exclusively on the latter group.

Among episodes in children without HSCT, the mean age was 7. Forty-eight patients had a history of acute chest syndrome, 47 had a history of ICU admission, 29 had a history of IBI, and 27 had a history of acute splenic sequestration. Thirteen underwent a splenectomy. Almost half of children had none of these characteristics, while about one-fourth had two or more.

In the HSCT group, 141 children were on prophylaxis at the time of the infection; 74 were on hydroxyurea, and 36 were currently or previously on a transfusion program. Sixty-eight cases were primary bacteremia and 55 were osteoarticular. Other syndromes included pneumonia empyema (n = 18), and meningitis (n = 17), among others. In 44 cases, the isolated bacteria was Salmonella, followed by S. pneumoniae in 32 cases. Escherichia coli accounted for 22. Haemophilus influenza was identified in six episodes, and group A Streptococcus in three.

The study is the first large European epidemiologic study investigating IBI in children with sickle cell disease, and one of its strengths was the strict inclusion criteria. However, it was limited by its retrospective nature.

Dr. Gaschignard and Dr. Rohr have no relevant financial disclosures.

Among children with sickle cell disease who have not undergone hematopoietic stem cell transplant, Salmonella is now the leading cause of invasive bacterial infection (IBI), according to a new retrospective study (BACT-SPRING) conducted in Europe. Streptococcus pneumoniae was the second most common source of infection, marking a shift from years past, when S. pneumoniae was the most common source. The epidemiology of IBI in Europe has been altered by adoption of prophylaxis and the introduction of the pneumococcal conjugated vaccine (PCV13) in 2009.

Previous studies of IBI have been single center with small sample sizes, and few have been conducted since 2016, said Jean Gaschignard, MD, PhD, during his presentation of the study at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Dr. Gaschignard is head of pediatrics at Groupe Hospitalier Nord Essonne in Longjumeau, France.

The study produced some unexpected results. “We were surprised,” said Dr. Gaschignard, by results indicating that not all children aged under 10 years were undergoing prophylaxis. Instead, the figures were closer to 80% or 90%. Among children over 10, the rate of prophylaxis varies between countries. “Our study is a clue to discuss again the indications for the age limit for prophylaxis against pneumococcus,” said Dr. Gauschignard, during the question-and-answer session following his talk.

The data give clinicians an updated picture of the epidemiology in this population following introduction of the PCV13 vaccine. “It was very important to have new data on microbiology after this implementation,” said Marie Rohr, MD, who is a fellow in pediatric infectious diseases at the University Hospitals of Geneva. Dr. Rohr moderated the session where the study was presented.

Dr. Rohr noted the shift from the dominant cause of IBI after the introduction of the PCV10/13 vaccine, from S. pneumoniae to Salmonella. The researchers also found a preponderance of bacteremia and osteoarticular infections. “The mortality and morbidity are still considerable despite infection preventive measures,” said Dr. Rohr.

The results should also prompt a second look at prevention strategies. “Even if the antibiotic prophylaxis is prescribed for a large [proportion of children with sickle cell disease] under 10 years old, the median age of invasive bacterial infection is 7 years old. This calls into question systematic antibiotic prophylaxis and case-control studies are needed to evaluate this and possibly modify antibiotic prophylaxis recommendations in the future,” said Dr. Rohr.

The BACT-SPRING study was conducted between Jan. 1, 2014, and Dec. 31, 2019, using online data. It included 217 IBI episodes from 26 centers in five European countries. Just over half were from France, while about a quarter occurred in Spain. Other countries included Belgium, Portugal, and Great Britain. Participants were younger than 18 and had an IBI confirmed by bacterial culture or PCR from normally sterile fluid.

Thirty-eight episodes occurred in children who had undergone hematopoietic stem cell transplantation (HSCT), and 179 in children who had not undergone HSCT. The presentation focused exclusively on the latter group.

Among episodes in children without HSCT, the mean age was 7. Forty-eight patients had a history of acute chest syndrome, 47 had a history of ICU admission, 29 had a history of IBI, and 27 had a history of acute splenic sequestration. Thirteen underwent a splenectomy. Almost half of children had none of these characteristics, while about one-fourth had two or more.

In the HSCT group, 141 children were on prophylaxis at the time of the infection; 74 were on hydroxyurea, and 36 were currently or previously on a transfusion program. Sixty-eight cases were primary bacteremia and 55 were osteoarticular. Other syndromes included pneumonia empyema (n = 18), and meningitis (n = 17), among others. In 44 cases, the isolated bacteria was Salmonella, followed by S. pneumoniae in 32 cases. Escherichia coli accounted for 22. Haemophilus influenza was identified in six episodes, and group A Streptococcus in three.

The study is the first large European epidemiologic study investigating IBI in children with sickle cell disease, and one of its strengths was the strict inclusion criteria. However, it was limited by its retrospective nature.

Dr. Gaschignard and Dr. Rohr have no relevant financial disclosures.

Among children with sickle cell disease who have not undergone hematopoietic stem cell transplant, Salmonella is now the leading cause of invasive bacterial infection (IBI), according to a new retrospective study (BACT-SPRING) conducted in Europe. Streptococcus pneumoniae was the second most common source of infection, marking a shift from years past, when S. pneumoniae was the most common source. The epidemiology of IBI in Europe has been altered by adoption of prophylaxis and the introduction of the pneumococcal conjugated vaccine (PCV13) in 2009.

Previous studies of IBI have been single center with small sample sizes, and few have been conducted since 2016, said Jean Gaschignard, MD, PhD, during his presentation of the study at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Dr. Gaschignard is head of pediatrics at Groupe Hospitalier Nord Essonne in Longjumeau, France.

The study produced some unexpected results. “We were surprised,” said Dr. Gaschignard, by results indicating that not all children aged under 10 years were undergoing prophylaxis. Instead, the figures were closer to 80% or 90%. Among children over 10, the rate of prophylaxis varies between countries. “Our study is a clue to discuss again the indications for the age limit for prophylaxis against pneumococcus,” said Dr. Gauschignard, during the question-and-answer session following his talk.

The data give clinicians an updated picture of the epidemiology in this population following introduction of the PCV13 vaccine. “It was very important to have new data on microbiology after this implementation,” said Marie Rohr, MD, who is a fellow in pediatric infectious diseases at the University Hospitals of Geneva. Dr. Rohr moderated the session where the study was presented.

Dr. Rohr noted the shift from the dominant cause of IBI after the introduction of the PCV10/13 vaccine, from S. pneumoniae to Salmonella. The researchers also found a preponderance of bacteremia and osteoarticular infections. “The mortality and morbidity are still considerable despite infection preventive measures,” said Dr. Rohr.

The results should also prompt a second look at prevention strategies. “Even if the antibiotic prophylaxis is prescribed for a large [proportion of children with sickle cell disease] under 10 years old, the median age of invasive bacterial infection is 7 years old. This calls into question systematic antibiotic prophylaxis and case-control studies are needed to evaluate this and possibly modify antibiotic prophylaxis recommendations in the future,” said Dr. Rohr.

The BACT-SPRING study was conducted between Jan. 1, 2014, and Dec. 31, 2019, using online data. It included 217 IBI episodes from 26 centers in five European countries. Just over half were from France, while about a quarter occurred in Spain. Other countries included Belgium, Portugal, and Great Britain. Participants were younger than 18 and had an IBI confirmed by bacterial culture or PCR from normally sterile fluid.

Thirty-eight episodes occurred in children who had undergone hematopoietic stem cell transplantation (HSCT), and 179 in children who had not undergone HSCT. The presentation focused exclusively on the latter group.

Among episodes in children without HSCT, the mean age was 7. Forty-eight patients had a history of acute chest syndrome, 47 had a history of ICU admission, 29 had a history of IBI, and 27 had a history of acute splenic sequestration. Thirteen underwent a splenectomy. Almost half of children had none of these characteristics, while about one-fourth had two or more.

In the HSCT group, 141 children were on prophylaxis at the time of the infection; 74 were on hydroxyurea, and 36 were currently or previously on a transfusion program. Sixty-eight cases were primary bacteremia and 55 were osteoarticular. Other syndromes included pneumonia empyema (n = 18), and meningitis (n = 17), among others. In 44 cases, the isolated bacteria was Salmonella, followed by S. pneumoniae in 32 cases. Escherichia coli accounted for 22. Haemophilus influenza was identified in six episodes, and group A Streptococcus in three.

The study is the first large European epidemiologic study investigating IBI in children with sickle cell disease, and one of its strengths was the strict inclusion criteria. However, it was limited by its retrospective nature.

Dr. Gaschignard and Dr. Rohr have no relevant financial disclosures.

Infants with isolated sensorineural hearing loss as a result of congenital cytomegalovirus (cCMV) infection may benefit from treatment with valganciclovir, according to results from the CONCERT nonrandomized trial.

Subjects were found through the Newborn Hearing Screening program, using dried blood spot screening to confirm cCMV Infection. As a result of 6 weeks of therapy, more patients in the treatment group had improvements in hearing at age 20 months, and fewer had deterioration compared with untreated controls.

There is a general consensus that symptomatic cCMV should be treated with valganciclovir for 6 weeks or 6 months, but treatment of patients with only hearing loss is still under debate. The average age of participants was 8 weeks.

The study was presented by Pui Khi Chung, MD, a clinical microbiologist at the Leiden University Medical Center, the Netherlands, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Out of 1,377 NHS-referred infants, 59 were diagnosed with cCMV (4.3%), and 35 were included in the study. Twenty-five patients received 6 weeks of valganciclovir, while 10 patients received placebo. The control group was expanded to 12 when two additional subjects were identified retrospectively and were successfully followed up at 20 months. Subjects in the treatment group were an average of 8 weeks old when treatment began. Both groups had similar neurodevelopmental outcomes at 20 months, as measured by the Bayley Scales of Infant and Toddler Development (BSID-III) and the Child Development Inventory (CDI). There were no serious adverse events associated with treatment.

To measure efficacy, the researchers used a random intercept, random slope model that accounted for repeated measurements. The differences in slopes for analyses of the best ear were significantly different between the treatment and control groups (estimated difference in slopes, –0.93; P = .0071). Further analyses of total hearing found that improvement was more common in the treatment group, and deterioration/no change was more common in the nontreatment group (P = .044). In another analysis that excluded the most profoundly impaired ears (> 70 db hearing loss), none in the control group experienced improvement and almost half deteriorated. In the treatment group, most were unchanged and a small number improved, with almost none deteriorating (P = .006).

Asked whether the treatment has any effect on the most profoundly impaired ears, Dr. Chung said she had not yet completed that analysis, but the hypothesis is that the treatment is unlikely to lead to any improvement. “When you take out the severely impaired ears, you can see a greater [treatment] effect, so it does suggest that it doesn’t do anything for those ears,” Dr. Chung said during the Q&A session following her talk.

She was also asked why the treatment period was 6 weeks, rather than 6 months – a period of treatment that has shown a better effect on long-term hearing and developmental outcomes than 6 weeks of treatment in symptomatic patients. Dr. Chung replied that she wasn’t involved in the study design, but said that at her center, the 6-month regimen is not standard.

There were two key weaknesses in the study. One was the small sample size, and the other was its nonrandomized nature, which could have led to bias in the treated versus untreated group. “Although we don’t see any baseline differences between the groups, we have to be wary in analyses. Unfortunately, an RCT proved impossible in our setting. The CONCERT Trial started as randomized but this was amended to nonrandomized, as both parents and pediatricians had a clear preference for treatment,” said Dr. Chung.

The study could provide useful information about the timing of oral antiviral medication, according to Vana Spoulou, MD, who moderated the session where the research was presented. “The earliest you can give it is best, but sometimes it’s not easy to get them diagnosed immediately after birth. What they showed us is that even giving it so late, there was some improvement,” Dr. Spoulou said in an interview.

Dr. Spoulou isn’t ready to change practice based on the results, because she noted that some other studies have shown no benefit of treatment at 3 months. “But this was a hint that maybe even in these later diagnosed cases there could be some benefit,” she said.

Dr. Chung and Dr. Spoulou have no relevant financial disclosures.

Infants with isolated sensorineural hearing loss as a result of congenital cytomegalovirus (cCMV) infection may benefit from treatment with valganciclovir, according to results from the CONCERT nonrandomized trial.

Subjects were found through the Newborn Hearing Screening program, using dried blood spot screening to confirm cCMV Infection. As a result of 6 weeks of therapy, more patients in the treatment group had improvements in hearing at age 20 months, and fewer had deterioration compared with untreated controls.

There is a general consensus that symptomatic cCMV should be treated with valganciclovir for 6 weeks or 6 months, but treatment of patients with only hearing loss is still under debate. The average age of participants was 8 weeks.

The study was presented by Pui Khi Chung, MD, a clinical microbiologist at the Leiden University Medical Center, the Netherlands, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Out of 1,377 NHS-referred infants, 59 were diagnosed with cCMV (4.3%), and 35 were included in the study. Twenty-five patients received 6 weeks of valganciclovir, while 10 patients received placebo. The control group was expanded to 12 when two additional subjects were identified retrospectively and were successfully followed up at 20 months. Subjects in the treatment group were an average of 8 weeks old when treatment began. Both groups had similar neurodevelopmental outcomes at 20 months, as measured by the Bayley Scales of Infant and Toddler Development (BSID-III) and the Child Development Inventory (CDI). There were no serious adverse events associated with treatment.

To measure efficacy, the researchers used a random intercept, random slope model that accounted for repeated measurements. The differences in slopes for analyses of the best ear were significantly different between the treatment and control groups (estimated difference in slopes, –0.93; P = .0071). Further analyses of total hearing found that improvement was more common in the treatment group, and deterioration/no change was more common in the nontreatment group (P = .044). In another analysis that excluded the most profoundly impaired ears (> 70 db hearing loss), none in the control group experienced improvement and almost half deteriorated. In the treatment group, most were unchanged and a small number improved, with almost none deteriorating (P = .006).

Asked whether the treatment has any effect on the most profoundly impaired ears, Dr. Chung said she had not yet completed that analysis, but the hypothesis is that the treatment is unlikely to lead to any improvement. “When you take out the severely impaired ears, you can see a greater [treatment] effect, so it does suggest that it doesn’t do anything for those ears,” Dr. Chung said during the Q&A session following her talk.

She was also asked why the treatment period was 6 weeks, rather than 6 months – a period of treatment that has shown a better effect on long-term hearing and developmental outcomes than 6 weeks of treatment in symptomatic patients. Dr. Chung replied that she wasn’t involved in the study design, but said that at her center, the 6-month regimen is not standard.

There were two key weaknesses in the study. One was the small sample size, and the other was its nonrandomized nature, which could have led to bias in the treated versus untreated group. “Although we don’t see any baseline differences between the groups, we have to be wary in analyses. Unfortunately, an RCT proved impossible in our setting. The CONCERT Trial started as randomized but this was amended to nonrandomized, as both parents and pediatricians had a clear preference for treatment,” said Dr. Chung.

The study could provide useful information about the timing of oral antiviral medication, according to Vana Spoulou, MD, who moderated the session where the research was presented. “The earliest you can give it is best, but sometimes it’s not easy to get them diagnosed immediately after birth. What they showed us is that even giving it so late, there was some improvement,” Dr. Spoulou said in an interview.

Dr. Spoulou isn’t ready to change practice based on the results, because she noted that some other studies have shown no benefit of treatment at 3 months. “But this was a hint that maybe even in these later diagnosed cases there could be some benefit,” she said.

Dr. Chung and Dr. Spoulou have no relevant financial disclosures.

Infants with isolated sensorineural hearing loss as a result of congenital cytomegalovirus (cCMV) infection may benefit from treatment with valganciclovir, according to results from the CONCERT nonrandomized trial.

Subjects were found through the Newborn Hearing Screening program, using dried blood spot screening to confirm cCMV Infection. As a result of 6 weeks of therapy, more patients in the treatment group had improvements in hearing at age 20 months, and fewer had deterioration compared with untreated controls.

There is a general consensus that symptomatic cCMV should be treated with valganciclovir for 6 weeks or 6 months, but treatment of patients with only hearing loss is still under debate. The average age of participants was 8 weeks.

The study was presented by Pui Khi Chung, MD, a clinical microbiologist at the Leiden University Medical Center, the Netherlands, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Out of 1,377 NHS-referred infants, 59 were diagnosed with cCMV (4.3%), and 35 were included in the study. Twenty-five patients received 6 weeks of valganciclovir, while 10 patients received placebo. The control group was expanded to 12 when two additional subjects were identified retrospectively and were successfully followed up at 20 months. Subjects in the treatment group were an average of 8 weeks old when treatment began. Both groups had similar neurodevelopmental outcomes at 20 months, as measured by the Bayley Scales of Infant and Toddler Development (BSID-III) and the Child Development Inventory (CDI). There were no serious adverse events associated with treatment.

To measure efficacy, the researchers used a random intercept, random slope model that accounted for repeated measurements. The differences in slopes for analyses of the best ear were significantly different between the treatment and control groups (estimated difference in slopes, –0.93; P = .0071). Further analyses of total hearing found that improvement was more common in the treatment group, and deterioration/no change was more common in the nontreatment group (P = .044). In another analysis that excluded the most profoundly impaired ears (> 70 db hearing loss), none in the control group experienced improvement and almost half deteriorated. In the treatment group, most were unchanged and a small number improved, with almost none deteriorating (P = .006).

Asked whether the treatment has any effect on the most profoundly impaired ears, Dr. Chung said she had not yet completed that analysis, but the hypothesis is that the treatment is unlikely to lead to any improvement. “When you take out the severely impaired ears, you can see a greater [treatment] effect, so it does suggest that it doesn’t do anything for those ears,” Dr. Chung said during the Q&A session following her talk.

She was also asked why the treatment period was 6 weeks, rather than 6 months – a period of treatment that has shown a better effect on long-term hearing and developmental outcomes than 6 weeks of treatment in symptomatic patients. Dr. Chung replied that she wasn’t involved in the study design, but said that at her center, the 6-month regimen is not standard.

There were two key weaknesses in the study. One was the small sample size, and the other was its nonrandomized nature, which could have led to bias in the treated versus untreated group. “Although we don’t see any baseline differences between the groups, we have to be wary in analyses. Unfortunately, an RCT proved impossible in our setting. The CONCERT Trial started as randomized but this was amended to nonrandomized, as both parents and pediatricians had a clear preference for treatment,” said Dr. Chung.

The study could provide useful information about the timing of oral antiviral medication, according to Vana Spoulou, MD, who moderated the session where the research was presented. “The earliest you can give it is best, but sometimes it’s not easy to get them diagnosed immediately after birth. What they showed us is that even giving it so late, there was some improvement,” Dr. Spoulou said in an interview.

Dr. Spoulou isn’t ready to change practice based on the results, because she noted that some other studies have shown no benefit of treatment at 3 months. “But this was a hint that maybe even in these later diagnosed cases there could be some benefit,” she said.

Dr. Chung and Dr. Spoulou have no relevant financial disclosures.

Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.

Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.

“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.

To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.

They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).

The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.

There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.

All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.

As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).

At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
 

Early studies

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.

“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.

She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.

The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.

Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.

Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.

“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.

To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.

They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).

The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.

There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.

All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.

As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).

At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
 

Early studies

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.

“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.

She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.

The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.

Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.

Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.

“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.

To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.

They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).

The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.

There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.

All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.

As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).

At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
 

Early studies

Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.

“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.

She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.

The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.

Treating port wine birthmarks with pulsed dye laser (PDL) can be safely done within the first few days after birth as an in-office procedure without any complications, results from a single-center study showed.

Courtesy RegionalDerm.com

“The current modality of choice for the treatment of port wine birthmarks is pulsed dye laser,” Chelsea Grimes Fidai, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “When performed by a highly trained expert at efficient frequencies, PDL is a safe, effective treatment that is successful in the majority of patients. We know that earlier treatment yields maximal clearance. However, just how early can you initiate treatment?”

To find out, Dr. Fidai, Roy G. Geronemus, MD, and colleagues at the Laser and Skin Surgery Center of New York, conducted a retrospective chart review of 39 infants with port wine birthmarks who were treated with a 595-nm PDL between 2015 and 2020 at the center. Of the 39 infants, the average age at first treatment was 18 days, with a range from 5 to 29 days. The youngest patient was born prematurely at 35 weeks’ gestation and presented for his first treatment even before his expected due date. Most (74%) had facial lesions with the remaining distributed on the trunk or extremities. The average number of treatments was 15 over the course of 15 months.

The initial settings chosen for facial lesions were a 10-mm spot size, a fluence of 8.0 J/cm², and a 1.5-millisecond pulse duration. For body lesions, the typical initial settings were a 12-mm spot size, a fluence of 6.7 J/cm², and 1.5-millisecond pulse duration. Corneal eye shields were placed for all cases with port wine birthmarks approaching the eyelid. “We do recommend a treatment interval of every 2-3 weeks, with longer intervals for patients of darker skin type until the child is 2 years old, at which time the interval is increased to every 3-6 months,” said Dr. Fidai.

Patients in the study experienced the expected short-term side effects of erythema, edema, purpura, and mild transient postinflammatory hyperpigmentation, but there were no cases of atrophy, scarring, infection, or permanent pigmentary change.

“Families seeking early treatment of port wine birthmarks can be reassured that it can be safely initiated within the first few days after birth,” Dr. Fidai concluded. “This procedure can be quickly and confidently performed as an in-office procedure without any complications. The early intervention allows for treatment without general anesthesia and it maximizes the chance of significant clearance as early in life as possible.”

During a question-and-answer session, the abstract section chair, Albert Wolkerstorfer, MD, PhD, expressed concern about the effect of PDL on developing infants. “We do repeated treatments at this young age without any type of anesthesia,” said Dr. Wolkerstorfer, a dermatologist at the Netherlands Institute for Pigment Disorders, department of dermatology, University of Amsterdam.

“Will that influence the development of the child, especially when I hear there might be 15 or 20 treatments done within the first year of life? I think this is a problem where we need to ask the experts in the field of pain management in children, like pediatric anesthesiologists, to find the right way, because I think that the results that you showed are fantastic. I don’t think we can achieve that at a later age, although there’s no direct comparison at this moment.”

Dr. Fidai said that she understood the concern, but pointed to a 2020 article by Dr. Geronemus and colleagues that assessed treatment tolerance and parental perspective of outpatient PDL treatment for port-wine birthmarks without general anesthesia in infants and toddlers. “The kids recover pretty quickly after the treatment,” she said. “There has never been any longstanding issue from the parents’ perspective.”

Dr. Fidai reported having no financial disclosures. Dr. Geronemus disclosed having financial conflicts with numerous device and pharmaceutical companies. Dr. Wolkerstorfer disclosed that he has received consulting fees from Lumenis and InCyte and equipment from Humeca and PerfAction Technologies. He has also received grant funding from Novartis and InCyte and he is a member of InCyte’s advisory board.

[email protected]

Treating port wine birthmarks with pulsed dye laser (PDL) can be safely done within the first few days after birth as an in-office procedure without any complications, results from a single-center study showed.

Courtesy RegionalDerm.com

“The current modality of choice for the treatment of port wine birthmarks is pulsed dye laser,” Chelsea Grimes Fidai, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “When performed by a highly trained expert at efficient frequencies, PDL is a safe, effective treatment that is successful in the majority of patients. We know that earlier treatment yields maximal clearance. However, just how early can you initiate treatment?”

To find out, Dr. Fidai, Roy G. Geronemus, MD, and colleagues at the Laser and Skin Surgery Center of New York, conducted a retrospective chart review of 39 infants with port wine birthmarks who were treated with a 595-nm PDL between 2015 and 2020 at the center. Of the 39 infants, the average age at first treatment was 18 days, with a range from 5 to 29 days. The youngest patient was born prematurely at 35 weeks’ gestation and presented for his first treatment even before his expected due date. Most (74%) had facial lesions with the remaining distributed on the trunk or extremities. The average number of treatments was 15 over the course of 15 months.

The initial settings chosen for facial lesions were a 10-mm spot size, a fluence of 8.0 J/cm², and a 1.5-millisecond pulse duration. For body lesions, the typical initial settings were a 12-mm spot size, a fluence of 6.7 J/cm², and 1.5-millisecond pulse duration. Corneal eye shields were placed for all cases with port wine birthmarks approaching the eyelid. “We do recommend a treatment interval of every 2-3 weeks, with longer intervals for patients of darker skin type until the child is 2 years old, at which time the interval is increased to every 3-6 months,” said Dr. Fidai.

Patients in the study experienced the expected short-term side effects of erythema, edema, purpura, and mild transient postinflammatory hyperpigmentation, but there were no cases of atrophy, scarring, infection, or permanent pigmentary change.

“Families seeking early treatment of port wine birthmarks can be reassured that it can be safely initiated within the first few days after birth,” Dr. Fidai concluded. “This procedure can be quickly and confidently performed as an in-office procedure without any complications. The early intervention allows for treatment without general anesthesia and it maximizes the chance of significant clearance as early in life as possible.”

During a question-and-answer session, the abstract section chair, Albert Wolkerstorfer, MD, PhD, expressed concern about the effect of PDL on developing infants. “We do repeated treatments at this young age without any type of anesthesia,” said Dr. Wolkerstorfer, a dermatologist at the Netherlands Institute for Pigment Disorders, department of dermatology, University of Amsterdam.

“Will that influence the development of the child, especially when I hear there might be 15 or 20 treatments done within the first year of life? I think this is a problem where we need to ask the experts in the field of pain management in children, like pediatric anesthesiologists, to find the right way, because I think that the results that you showed are fantastic. I don’t think we can achieve that at a later age, although there’s no direct comparison at this moment.”

Dr. Fidai said that she understood the concern, but pointed to a 2020 article by Dr. Geronemus and colleagues that assessed treatment tolerance and parental perspective of outpatient PDL treatment for port-wine birthmarks without general anesthesia in infants and toddlers. “The kids recover pretty quickly after the treatment,” she said. “There has never been any longstanding issue from the parents’ perspective.”

Dr. Fidai reported having no financial disclosures. Dr. Geronemus disclosed having financial conflicts with numerous device and pharmaceutical companies. Dr. Wolkerstorfer disclosed that he has received consulting fees from Lumenis and InCyte and equipment from Humeca and PerfAction Technologies. He has also received grant funding from Novartis and InCyte and he is a member of InCyte’s advisory board.

[email protected]

Treating port wine birthmarks with pulsed dye laser (PDL) can be safely done within the first few days after birth as an in-office procedure without any complications, results from a single-center study showed.

Courtesy RegionalDerm.com

“The current modality of choice for the treatment of port wine birthmarks is pulsed dye laser,” Chelsea Grimes Fidai, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “When performed by a highly trained expert at efficient frequencies, PDL is a safe, effective treatment that is successful in the majority of patients. We know that earlier treatment yields maximal clearance. However, just how early can you initiate treatment?”

To find out, Dr. Fidai, Roy G. Geronemus, MD, and colleagues at the Laser and Skin Surgery Center of New York, conducted a retrospective chart review of 39 infants with port wine birthmarks who were treated with a 595-nm PDL between 2015 and 2020 at the center. Of the 39 infants, the average age at first treatment was 18 days, with a range from 5 to 29 days. The youngest patient was born prematurely at 35 weeks’ gestation and presented for his first treatment even before his expected due date. Most (74%) had facial lesions with the remaining distributed on the trunk or extremities. The average number of treatments was 15 over the course of 15 months.

The initial settings chosen for facial lesions were a 10-mm spot size, a fluence of 8.0 J/cm², and a 1.5-millisecond pulse duration. For body lesions, the typical initial settings were a 12-mm spot size, a fluence of 6.7 J/cm², and 1.5-millisecond pulse duration. Corneal eye shields were placed for all cases with port wine birthmarks approaching the eyelid. “We do recommend a treatment interval of every 2-3 weeks, with longer intervals for patients of darker skin type until the child is 2 years old, at which time the interval is increased to every 3-6 months,” said Dr. Fidai.

Patients in the study experienced the expected short-term side effects of erythema, edema, purpura, and mild transient postinflammatory hyperpigmentation, but there were no cases of atrophy, scarring, infection, or permanent pigmentary change.

“Families seeking early treatment of port wine birthmarks can be reassured that it can be safely initiated within the first few days after birth,” Dr. Fidai concluded. “This procedure can be quickly and confidently performed as an in-office procedure without any complications. The early intervention allows for treatment without general anesthesia and it maximizes the chance of significant clearance as early in life as possible.”

During a question-and-answer session, the abstract section chair, Albert Wolkerstorfer, MD, PhD, expressed concern about the effect of PDL on developing infants. “We do repeated treatments at this young age without any type of anesthesia,” said Dr. Wolkerstorfer, a dermatologist at the Netherlands Institute for Pigment Disorders, department of dermatology, University of Amsterdam.

“Will that influence the development of the child, especially when I hear there might be 15 or 20 treatments done within the first year of life? I think this is a problem where we need to ask the experts in the field of pain management in children, like pediatric anesthesiologists, to find the right way, because I think that the results that you showed are fantastic. I don’t think we can achieve that at a later age, although there’s no direct comparison at this moment.”

Dr. Fidai said that she understood the concern, but pointed to a 2020 article by Dr. Geronemus and colleagues that assessed treatment tolerance and parental perspective of outpatient PDL treatment for port-wine birthmarks without general anesthesia in infants and toddlers. “The kids recover pretty quickly after the treatment,” she said. “There has never been any longstanding issue from the parents’ perspective.”

Dr. Fidai reported having no financial disclosures. Dr. Geronemus disclosed having financial conflicts with numerous device and pharmaceutical companies. Dr. Wolkerstorfer disclosed that he has received consulting fees from Lumenis and InCyte and equipment from Humeca and PerfAction Technologies. He has also received grant funding from Novartis and InCyte and he is a member of InCyte’s advisory board.

[email protected]

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

Fewer doctors are opting to run their own small private practices, with more seeking jobs in hospitals or larger medical groups, according to a new report.

These patterns likely reflect broader trends toward consolidation in health care, with both insurance companies and hospitals also having grown in size in recent years.

The latest biennial analysis of doctors’ practices by the American Medical Association showed an acceleration of a trend away from private practice, defined as a practice wholly owned by physicians. The 2020 results found less than half – 49.1 % – of doctors involved in patient care worked in a private practice, the AMA said in a report released in May 2021.

This marked the first time private practice was not the dominant approach since the AMA analysis began in 2012. What’s more, the trend appears to be gaining steam, with a drop of almost 5 percentage points from 54.0% in private practice in 2018. The percent of doctors in private practice declined at a slower rate in previous AMA surveys, slipping to 55.8% in 2016 from 56.8% in 2018 and 60.1% in 2012.

Employment and ownership structures have become so varied that no single approach or size of organization “can or should be considered the typical physician practice,” the report noted.

The AMA, for example, added to its 2020 benchmark survey an option to identify private equity organizations as employers. The survey found 4% of doctors involved in patient care worked in practices owned by these kinds of firms. Other options include practices wholly or jointly owned by hospital and health systems and insurers, as well as direct employment and contracting.

There are signs that the shift away from smaller private practices will continue, with younger doctors appearing more likely to seek employment.

The survey found 42% of doctors ages 55 and older were employed by someone else, compared with 51.2% of doctors ages 40-54 and 70% of physicians under the age of 40.

The AMA surveyed 3,500 U.S. doctors through the 2020 Physician Practice Benchmark Survey. The survey was conducted from September to October 2020, roughly 6 months into the COVID-19 pandemic, and therefore may not reflect its full impact.

“Physician practices were hit hard by the economic impact of the early pandemic as patient volume and revenues shrank while medical supply expenses spiked. The impact of these economic forces on physician practice arrangements is ongoing and may not be fully realized for some time,” AMA President Susan R. Bailey, MD, said in a statement.

In a survey released in 2020 by McKinsey & Company, 53% of independent doctors reported that they were worried about their practices surviving the stresses of the pandemic, this news organization reported.
 

Challenging environment

It’s not just money leading to the shift away from private practice, according to a 2020 report from the American Hospital Association, titled “Evolving Physician-Practice Ownership Models.”

Many recent graduates of medical schools have significant debt and are more likely to opt for employment, which offers more financial stability and work-life balance, the report said.

Doctors also need to keep up with expectations of their patients that have been shaped by advances in other sectors, like banking, the AHA noted. People are used to working on their own schedules, and want to make appointments through apps, get test results rapidly and on their mobile devices, and communicate with their providers virtually.

“It is challenging to meet these expectations and make the necessary technology investments as a solo or small group practice,” the AHA report said.

Hospitals face competition for doctors from insurers, which have been looking in some cases to directly employ more physicians, the AHA also noted. The report cites insurance giant UnitedHealth Group’s Optum unit as the most visible example of this trend.

On a January call about corporate earnings, David Wichmann, then chief executive of UnitedHealth, spoke about the firm’s “aim to reinvent health care delivery,” including efforts to have its own primary and multispecialty care practices.

“OptumCare entered 2021 with over 50,000 physicians and 1,400 clinics,” Mr. Wichmann said. “Over the course of this year, we expect to grow our employed and affiliated physicians by at least 10,000. This work of building local physician-led systems of care continues to be central to our mission. “

UnitedHealth’s new CEO is Andrew Witty, who had led the Optum unit.
 

Attractions of larger groups

Older doctors – those 55 years and up – were significantly more likely to work in small practices than those younger than 40, the 2020 survey found. Results showed 40.9% of doctors under 40 worked in practices of 10 or fewer colleagues, compared with 61.4% of those age 55 and older.

The large difference between age groups suggests that attrition is one reason for the shift in practice size. Retiring doctors who leave small practices are not being replaced on a one-for-one basis by younger doctors, AMA said. The same reason also appears to be a factor in the shift in practice ownership to larger systems.

Doctors in larger group practices can count on a stable business model, with a better ability to survive disruptive market trends, including those of a more extreme nature, like COVID-19, said Fred Horton, president of AMGA Consulting.

AMGA Consulting is a wholly-owned subsidiary of AMGA, formerly called American Medical Group Association. Its more than 400 members include well-known multispecialty groups and health care systems such as the Mayo Clinic, Cleveland Clinic, Geisinger, the Permanente Medical Group, and Intermountain Healthcare as well as many smaller physician practices.

Mr. Horton, who holds a master’s degree in health administration, said some doctors may want to participate in alternative payment programs offered by insurers, who are seeking to shift away from the fee-for-service model

“Larger organizations can dedicate more resources to continuous quality improvement,” Mr. Horton said. “This is especially important for physicians who are taking on risk-based contracts, as quality can directly impact how much they earn.”

For one oncologist, it was turning to alternative payment methods that helped him keep his private practice afloat.

Kashyap Patel, MD, chief executive of the Carolina Blood and Cancer Care Associates in Rock Hill, S.C., said he maintained the independence of his practice amid pressure from a large health system, which had been buying medical groups in the area. That began to interfere with referrals of patients from other doctors, which are key for cancer specialists, said Dr. Patel, who also is president of the Community Oncology Alliance.

In response, Dr. Patel worked with Blue Cross Blue Shield of South Carolina on an arrangement where his practice sought certifications from the National Committee for Quality Assurance to get better rates.

The effort has allowed Dr. Patel’s clinic to focus more on preventing hospitalizations and visits to the emergency room he said.

In Dr. Patel’s view, his patients benefit from his efforts to remain in independent practice. A switch to ownership by a large health care organization would have put them at risk for higher medical bills, jeopardizing their access to treatment, he said. The reason? Hospitals can charge more for services provided by doctors they employ.

“Nothing would change. I would be the same. The building would be the same, but the cost would go up,” Dr. Patel said.

For its part, the AHA has repeatedly challenged arguments that acquisitions and mergers result in higher costs for patients.

Instead, the AHA has raised alarms about consolidation of health insurers, a concern it shares with AMA. In a 2020 report examining competition among insurers, AMA noted doctors working in small practices can be put at a disadvantage if mergers and acquisitions leave an insurer with too much market power.

“Under antitrust law, independent physicians cannot negotiate collectively with health

Insurers,” the AMA said in the report. “This imbalance in relative size leaves most physicians with a weak bargaining position relative to commercial payers.”

AMA’s research on the effects of insurers’ wielding significant market clout has been used in effort to thwart mergers in this industry.
 

‘Dramatic restructuring’

The Federal Trade Commission also has taken note of the trends discussed in the new AMA report, saying that “U.S. physician markets are undergoing a dramatic restructuring.”

The FTC in January announced a study of the impact of the consolidation of doctors groups and health care facilities. FTC is seeking data for inpatient, outpatient, and doctors services in 15 states from 2015 through 2020. To gather this data, the commission has issued orders to six major insurers – Aetna, Anthem, Florida Blue, Cigna, Health Care Service Corporation and United Healthcare.

The FTC is concerned that acquired practices may have to alter their referral patterns to favor their affiliated hospital system over competing hospital systems. But FTC staff also said it might be that these acquisitions result in efficiencies, such as enhanced coordination of care between doctors and hospitals “that outweigh potential competitive harms.”

The research project will likely take several years to complete because of its scope, the FTC said. For that reason, the FTC said its Bureau of Economics will release a series of research papers examining different aspects of this inquiry rather than a single paper containing all of the analyses.
 

Private equity ‘roll-ups’

On the day the FTC announced the study of the impact of doctors groups, one of the panel’s commissioners argued for a closer look at how private equity firms make their purchases.

In a Jan. 15 tweet, FTC Commissioner Rohit Chopra said his agency needs to challenge their “roll-ups of small physician practices” as well as clinics and labs. This is a practice of using a series of acquisitions too small to trigger the federal threshold for a serious look from the FTC and Department of Justice. (The threshold for 2021 stands around the $92 million mark. This benchmark is known as Hart-Scott-Rodino notification after a 1976 law that set a reporting standard.)

Mr. Chopra attached to his Jan. 15 tweet a 2020 statement in which he called for stepped-up scrutiny of private-equity firms’ acquisitions of doctors’ practices. Mr. Chopra noted that private-equity firms have been buying practices focused on anesthesiology and emergency medicine, fields which triggered consumer complaints about surprise billing for emergency care.

“Given trends in today’s markets, it is critical that the FTC find new ways to ensure the agency has a rigorous, data-driven approach to market monitoring and enforcement,” Mr. Chopra wrote.

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

Fewer doctors are opting to run their own small private practices, with more seeking jobs in hospitals or larger medical groups, according to a new report.

These patterns likely reflect broader trends toward consolidation in health care, with both insurance companies and hospitals also having grown in size in recent years.

The latest biennial analysis of doctors’ practices by the American Medical Association showed an acceleration of a trend away from private practice, defined as a practice wholly owned by physicians. The 2020 results found less than half – 49.1 % – of doctors involved in patient care worked in a private practice, the AMA said in a report released in May 2021.

This marked the first time private practice was not the dominant approach since the AMA analysis began in 2012. What’s more, the trend appears to be gaining steam, with a drop of almost 5 percentage points from 54.0% in private practice in 2018. The percent of doctors in private practice declined at a slower rate in previous AMA surveys, slipping to 55.8% in 2016 from 56.8% in 2018 and 60.1% in 2012.

Employment and ownership structures have become so varied that no single approach or size of organization “can or should be considered the typical physician practice,” the report noted.

The AMA, for example, added to its 2020 benchmark survey an option to identify private equity organizations as employers. The survey found 4% of doctors involved in patient care worked in practices owned by these kinds of firms. Other options include practices wholly or jointly owned by hospital and health systems and insurers, as well as direct employment and contracting.

There are signs that the shift away from smaller private practices will continue, with younger doctors appearing more likely to seek employment.

The survey found 42% of doctors ages 55 and older were employed by someone else, compared with 51.2% of doctors ages 40-54 and 70% of physicians under the age of 40.

The AMA surveyed 3,500 U.S. doctors through the 2020 Physician Practice Benchmark Survey. The survey was conducted from September to October 2020, roughly 6 months into the COVID-19 pandemic, and therefore may not reflect its full impact.

“Physician practices were hit hard by the economic impact of the early pandemic as patient volume and revenues shrank while medical supply expenses spiked. The impact of these economic forces on physician practice arrangements is ongoing and may not be fully realized for some time,” AMA President Susan R. Bailey, MD, said in a statement.

In a survey released in 2020 by McKinsey & Company, 53% of independent doctors reported that they were worried about their practices surviving the stresses of the pandemic, this news organization reported.
 

Challenging environment

It’s not just money leading to the shift away from private practice, according to a 2020 report from the American Hospital Association, titled “Evolving Physician-Practice Ownership Models.”

Many recent graduates of medical schools have significant debt and are more likely to opt for employment, which offers more financial stability and work-life balance, the report said.

Doctors also need to keep up with expectations of their patients that have been shaped by advances in other sectors, like banking, the AHA noted. People are used to working on their own schedules, and want to make appointments through apps, get test results rapidly and on their mobile devices, and communicate with their providers virtually.

“It is challenging to meet these expectations and make the necessary technology investments as a solo or small group practice,” the AHA report said.

Hospitals face competition for doctors from insurers, which have been looking in some cases to directly employ more physicians, the AHA also noted. The report cites insurance giant UnitedHealth Group’s Optum unit as the most visible example of this trend.

On a January call about corporate earnings, David Wichmann, then chief executive of UnitedHealth, spoke about the firm’s “aim to reinvent health care delivery,” including efforts to have its own primary and multispecialty care practices.

“OptumCare entered 2021 with over 50,000 physicians and 1,400 clinics,” Mr. Wichmann said. “Over the course of this year, we expect to grow our employed and affiliated physicians by at least 10,000. This work of building local physician-led systems of care continues to be central to our mission. “

UnitedHealth’s new CEO is Andrew Witty, who had led the Optum unit.
 

Attractions of larger groups

Older doctors – those 55 years and up – were significantly more likely to work in small practices than those younger than 40, the 2020 survey found. Results showed 40.9% of doctors under 40 worked in practices of 10 or fewer colleagues, compared with 61.4% of those age 55 and older.

The large difference between age groups suggests that attrition is one reason for the shift in practice size. Retiring doctors who leave small practices are not being replaced on a one-for-one basis by younger doctors, AMA said. The same reason also appears to be a factor in the shift in practice ownership to larger systems.

Doctors in larger group practices can count on a stable business model, with a better ability to survive disruptive market trends, including those of a more extreme nature, like COVID-19, said Fred Horton, president of AMGA Consulting.

AMGA Consulting is a wholly-owned subsidiary of AMGA, formerly called American Medical Group Association. Its more than 400 members include well-known multispecialty groups and health care systems such as the Mayo Clinic, Cleveland Clinic, Geisinger, the Permanente Medical Group, and Intermountain Healthcare as well as many smaller physician practices.

Mr. Horton, who holds a master’s degree in health administration, said some doctors may want to participate in alternative payment programs offered by insurers, who are seeking to shift away from the fee-for-service model

“Larger organizations can dedicate more resources to continuous quality improvement,” Mr. Horton said. “This is especially important for physicians who are taking on risk-based contracts, as quality can directly impact how much they earn.”

For one oncologist, it was turning to alternative payment methods that helped him keep his private practice afloat.

Kashyap Patel, MD, chief executive of the Carolina Blood and Cancer Care Associates in Rock Hill, S.C., said he maintained the independence of his practice amid pressure from a large health system, which had been buying medical groups in the area. That began to interfere with referrals of patients from other doctors, which are key for cancer specialists, said Dr. Patel, who also is president of the Community Oncology Alliance.

In response, Dr. Patel worked with Blue Cross Blue Shield of South Carolina on an arrangement where his practice sought certifications from the National Committee for Quality Assurance to get better rates.

The effort has allowed Dr. Patel’s clinic to focus more on preventing hospitalizations and visits to the emergency room he said.

In Dr. Patel’s view, his patients benefit from his efforts to remain in independent practice. A switch to ownership by a large health care organization would have put them at risk for higher medical bills, jeopardizing their access to treatment, he said. The reason? Hospitals can charge more for services provided by doctors they employ.

“Nothing would change. I would be the same. The building would be the same, but the cost would go up,” Dr. Patel said.

For its part, the AHA has repeatedly challenged arguments that acquisitions and mergers result in higher costs for patients.

Instead, the AHA has raised alarms about consolidation of health insurers, a concern it shares with AMA. In a 2020 report examining competition among insurers, AMA noted doctors working in small practices can be put at a disadvantage if mergers and acquisitions leave an insurer with too much market power.

“Under antitrust law, independent physicians cannot negotiate collectively with health

Insurers,” the AMA said in the report. “This imbalance in relative size leaves most physicians with a weak bargaining position relative to commercial payers.”

AMA’s research on the effects of insurers’ wielding significant market clout has been used in effort to thwart mergers in this industry.
 

‘Dramatic restructuring’

The Federal Trade Commission also has taken note of the trends discussed in the new AMA report, saying that “U.S. physician markets are undergoing a dramatic restructuring.”

The FTC in January announced a study of the impact of the consolidation of doctors groups and health care facilities. FTC is seeking data for inpatient, outpatient, and doctors services in 15 states from 2015 through 2020. To gather this data, the commission has issued orders to six major insurers – Aetna, Anthem, Florida Blue, Cigna, Health Care Service Corporation and United Healthcare.

The FTC is concerned that acquired practices may have to alter their referral patterns to favor their affiliated hospital system over competing hospital systems. But FTC staff also said it might be that these acquisitions result in efficiencies, such as enhanced coordination of care between doctors and hospitals “that outweigh potential competitive harms.”

The research project will likely take several years to complete because of its scope, the FTC said. For that reason, the FTC said its Bureau of Economics will release a series of research papers examining different aspects of this inquiry rather than a single paper containing all of the analyses.
 

Private equity ‘roll-ups’

On the day the FTC announced the study of the impact of doctors groups, one of the panel’s commissioners argued for a closer look at how private equity firms make their purchases.

In a Jan. 15 tweet, FTC Commissioner Rohit Chopra said his agency needs to challenge their “roll-ups of small physician practices” as well as clinics and labs. This is a practice of using a series of acquisitions too small to trigger the federal threshold for a serious look from the FTC and Department of Justice. (The threshold for 2021 stands around the $92 million mark. This benchmark is known as Hart-Scott-Rodino notification after a 1976 law that set a reporting standard.)

Mr. Chopra attached to his Jan. 15 tweet a 2020 statement in which he called for stepped-up scrutiny of private-equity firms’ acquisitions of doctors’ practices. Mr. Chopra noted that private-equity firms have been buying practices focused on anesthesiology and emergency medicine, fields which triggered consumer complaints about surprise billing for emergency care.

“Given trends in today’s markets, it is critical that the FTC find new ways to ensure the agency has a rigorous, data-driven approach to market monitoring and enforcement,” Mr. Chopra wrote.

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

Fewer doctors are opting to run their own small private practices, with more seeking jobs in hospitals or larger medical groups, according to a new report.

These patterns likely reflect broader trends toward consolidation in health care, with both insurance companies and hospitals also having grown in size in recent years.

The latest biennial analysis of doctors’ practices by the American Medical Association showed an acceleration of a trend away from private practice, defined as a practice wholly owned by physicians. The 2020 results found less than half – 49.1 % – of doctors involved in patient care worked in a private practice, the AMA said in a report released in May 2021.

This marked the first time private practice was not the dominant approach since the AMA analysis began in 2012. What’s more, the trend appears to be gaining steam, with a drop of almost 5 percentage points from 54.0% in private practice in 2018. The percent of doctors in private practice declined at a slower rate in previous AMA surveys, slipping to 55.8% in 2016 from 56.8% in 2018 and 60.1% in 2012.

Employment and ownership structures have become so varied that no single approach or size of organization “can or should be considered the typical physician practice,” the report noted.

The AMA, for example, added to its 2020 benchmark survey an option to identify private equity organizations as employers. The survey found 4% of doctors involved in patient care worked in practices owned by these kinds of firms. Other options include practices wholly or jointly owned by hospital and health systems and insurers, as well as direct employment and contracting.

There are signs that the shift away from smaller private practices will continue, with younger doctors appearing more likely to seek employment.

The survey found 42% of doctors ages 55 and older were employed by someone else, compared with 51.2% of doctors ages 40-54 and 70% of physicians under the age of 40.

The AMA surveyed 3,500 U.S. doctors through the 2020 Physician Practice Benchmark Survey. The survey was conducted from September to October 2020, roughly 6 months into the COVID-19 pandemic, and therefore may not reflect its full impact.

“Physician practices were hit hard by the economic impact of the early pandemic as patient volume and revenues shrank while medical supply expenses spiked. The impact of these economic forces on physician practice arrangements is ongoing and may not be fully realized for some time,” AMA President Susan R. Bailey, MD, said in a statement.

In a survey released in 2020 by McKinsey & Company, 53% of independent doctors reported that they were worried about their practices surviving the stresses of the pandemic, this news organization reported.
 

Challenging environment

It’s not just money leading to the shift away from private practice, according to a 2020 report from the American Hospital Association, titled “Evolving Physician-Practice Ownership Models.”

Many recent graduates of medical schools have significant debt and are more likely to opt for employment, which offers more financial stability and work-life balance, the report said.

Doctors also need to keep up with expectations of their patients that have been shaped by advances in other sectors, like banking, the AHA noted. People are used to working on their own schedules, and want to make appointments through apps, get test results rapidly and on their mobile devices, and communicate with their providers virtually.

“It is challenging to meet these expectations and make the necessary technology investments as a solo or small group practice,” the AHA report said.

Hospitals face competition for doctors from insurers, which have been looking in some cases to directly employ more physicians, the AHA also noted. The report cites insurance giant UnitedHealth Group’s Optum unit as the most visible example of this trend.

On a January call about corporate earnings, David Wichmann, then chief executive of UnitedHealth, spoke about the firm’s “aim to reinvent health care delivery,” including efforts to have its own primary and multispecialty care practices.

“OptumCare entered 2021 with over 50,000 physicians and 1,400 clinics,” Mr. Wichmann said. “Over the course of this year, we expect to grow our employed and affiliated physicians by at least 10,000. This work of building local physician-led systems of care continues to be central to our mission. “

UnitedHealth’s new CEO is Andrew Witty, who had led the Optum unit.
 

Attractions of larger groups

Older doctors – those 55 years and up – were significantly more likely to work in small practices than those younger than 40, the 2020 survey found. Results showed 40.9% of doctors under 40 worked in practices of 10 or fewer colleagues, compared with 61.4% of those age 55 and older.

The large difference between age groups suggests that attrition is one reason for the shift in practice size. Retiring doctors who leave small practices are not being replaced on a one-for-one basis by younger doctors, AMA said. The same reason also appears to be a factor in the shift in practice ownership to larger systems.

Doctors in larger group practices can count on a stable business model, with a better ability to survive disruptive market trends, including those of a more extreme nature, like COVID-19, said Fred Horton, president of AMGA Consulting.

AMGA Consulting is a wholly-owned subsidiary of AMGA, formerly called American Medical Group Association. Its more than 400 members include well-known multispecialty groups and health care systems such as the Mayo Clinic, Cleveland Clinic, Geisinger, the Permanente Medical Group, and Intermountain Healthcare as well as many smaller physician practices.

Mr. Horton, who holds a master’s degree in health administration, said some doctors may want to participate in alternative payment programs offered by insurers, who are seeking to shift away from the fee-for-service model

“Larger organizations can dedicate more resources to continuous quality improvement,” Mr. Horton said. “This is especially important for physicians who are taking on risk-based contracts, as quality can directly impact how much they earn.”

For one oncologist, it was turning to alternative payment methods that helped him keep his private practice afloat.

Kashyap Patel, MD, chief executive of the Carolina Blood and Cancer Care Associates in Rock Hill, S.C., said he maintained the independence of his practice amid pressure from a large health system, which had been buying medical groups in the area. That began to interfere with referrals of patients from other doctors, which are key for cancer specialists, said Dr. Patel, who also is president of the Community Oncology Alliance.

In response, Dr. Patel worked with Blue Cross Blue Shield of South Carolina on an arrangement where his practice sought certifications from the National Committee for Quality Assurance to get better rates.

The effort has allowed Dr. Patel’s clinic to focus more on preventing hospitalizations and visits to the emergency room he said.

In Dr. Patel’s view, his patients benefit from his efforts to remain in independent practice. A switch to ownership by a large health care organization would have put them at risk for higher medical bills, jeopardizing their access to treatment, he said. The reason? Hospitals can charge more for services provided by doctors they employ.

“Nothing would change. I would be the same. The building would be the same, but the cost would go up,” Dr. Patel said.

For its part, the AHA has repeatedly challenged arguments that acquisitions and mergers result in higher costs for patients.

Instead, the AHA has raised alarms about consolidation of health insurers, a concern it shares with AMA. In a 2020 report examining competition among insurers, AMA noted doctors working in small practices can be put at a disadvantage if mergers and acquisitions leave an insurer with too much market power.

“Under antitrust law, independent physicians cannot negotiate collectively with health

Insurers,” the AMA said in the report. “This imbalance in relative size leaves most physicians with a weak bargaining position relative to commercial payers.”

AMA’s research on the effects of insurers’ wielding significant market clout has been used in effort to thwart mergers in this industry.
 

‘Dramatic restructuring’

The Federal Trade Commission also has taken note of the trends discussed in the new AMA report, saying that “U.S. physician markets are undergoing a dramatic restructuring.”

The FTC in January announced a study of the impact of the consolidation of doctors groups and health care facilities. FTC is seeking data for inpatient, outpatient, and doctors services in 15 states from 2015 through 2020. To gather this data, the commission has issued orders to six major insurers – Aetna, Anthem, Florida Blue, Cigna, Health Care Service Corporation and United Healthcare.

The FTC is concerned that acquired practices may have to alter their referral patterns to favor their affiliated hospital system over competing hospital systems. But FTC staff also said it might be that these acquisitions result in efficiencies, such as enhanced coordination of care between doctors and hospitals “that outweigh potential competitive harms.”

The research project will likely take several years to complete because of its scope, the FTC said. For that reason, the FTC said its Bureau of Economics will release a series of research papers examining different aspects of this inquiry rather than a single paper containing all of the analyses.
 

Private equity ‘roll-ups’

On the day the FTC announced the study of the impact of doctors groups, one of the panel’s commissioners argued for a closer look at how private equity firms make their purchases.

In a Jan. 15 tweet, FTC Commissioner Rohit Chopra said his agency needs to challenge their “roll-ups of small physician practices” as well as clinics and labs. This is a practice of using a series of acquisitions too small to trigger the federal threshold for a serious look from the FTC and Department of Justice. (The threshold for 2021 stands around the $92 million mark. This benchmark is known as Hart-Scott-Rodino notification after a 1976 law that set a reporting standard.)

Mr. Chopra attached to his Jan. 15 tweet a 2020 statement in which he called for stepped-up scrutiny of private-equity firms’ acquisitions of doctors’ practices. Mr. Chopra noted that private-equity firms have been buying practices focused on anesthesiology and emergency medicine, fields which triggered consumer complaints about surprise billing for emergency care.

“Given trends in today’s markets, it is critical that the FTC find new ways to ensure the agency has a rigorous, data-driven approach to market monitoring and enforcement,” Mr. Chopra wrote.

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

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show. At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided “sustained, durable efficacy, with all patients alive and without the need for permanent ventilation,” reported Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.
 

Single infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children with SMA and younger than 2 years of age.

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1 gene to halt disease progression. A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves chances of survival, as well as muscle movement and function.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children’s Hospital between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; three infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Dr. Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death. The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators noted, no new safety signals or “adverse events of special interest” emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledged that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients. “However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec,” Dr. Mendell and colleagues said. 

The study was supported by Novartis Gene Therapies. Dr. Mendell and several co-investigators have disclosed financial relationships with the company.

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

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show. At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided “sustained, durable efficacy, with all patients alive and without the need for permanent ventilation,” reported Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.
 

Single infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children with SMA and younger than 2 years of age.

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1 gene to halt disease progression. A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves chances of survival, as well as muscle movement and function.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children’s Hospital between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; three infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Dr. Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death. The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators noted, no new safety signals or “adverse events of special interest” emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledged that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients. “However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec,” Dr. Mendell and colleagues said. 

The study was supported by Novartis Gene Therapies. Dr. Mendell and several co-investigators have disclosed financial relationships with the company.

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

For children with spinal muscular atrophy (SMA), gene therapy with onasemnogene abeparvovec (Zolgensma, Novartis) provides long-lasting benefits with a favorable safety profile, new long-term follow-up data show. At a median of 5.2 years since receiving the approved therapeutic dose, onasemnogene abeparvovec provided “sustained, durable efficacy, with all patients alive and without the need for permanent ventilation,” reported Jerry Mendell, MD, with the Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, Ohio, and colleagues.

The study was published online May 17 in JAMA Neurology.
 

Single infusion

SMA is a rare genetic disease that can lead to paralysis, breathing difficulty, and death. The disorder is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein critical for maintenance and function of motor neurons.

In 2019, Zolgensma was approved in the United States for children with SMA and younger than 2 years of age.

Zolgensma is an adeno-associated virus vector-based gene therapy that addresses the genetic root cause of SMA by replacing the defective or missing SMN1 gene to halt disease progression. A single, one-time intravenous infusion results in expression of the SMN protein motor neurons, which improves chances of survival, as well as muscle movement and function.

In the phase 1 START study, 15 infants with SMA type 1 were treated with either a low or therapeutic dose of Zolgensma at Nationwide Children’s Hospital between 2014 and 2017.

The START long-term follow-up study (START LTFU) is an ongoing, observational study assessing safety and durability of response over 15 years in 13 of the infants; three infants received the low dose and 10 received the approved high dose.

Prior to baseline, four patients (40%) in the therapeutic dose cohort required noninvasive ventilatory support, and six (60%) did not require regular ventilatory support, which did not change in long-term follow-up.

All 10 patients who received the therapeutic dose remained alive and without the need for permanent ventilation up to 6.2 years after dosing, Dr. Mendell and colleagues report.

These patients also maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen (Spinraza, Biogen). 

Serious adverse events occurred in eight patients (62%), none of which resulted in study discontinuation or death. The most common serious adverse events were related to the underlying SMA disease process and included acute respiratory failure (31%), pneumonia (31%), dehydration (23%), respiratory distress (15%), and bronchiolitis (15%).

Importantly, the investigators noted, no new safety signals or “adverse events of special interest” emerged during follow-up, including liver function enzyme elevations, new incidences of malignancy or hematologic disorders, and new incidences or exacerbations of existing neurologic or autoimmune disorders.

The investigators acknowledged that this follow-up study is limited by the small sample size of the patient population and confounded by treatment with nusinersen in several patients. “However, given that the two patients who acquired the new motor milestone of standing with assistance did not receive nusinersen at any time, this benefit can be attributed solely to onasemnogene abeparvovec,” Dr. Mendell and colleagues said. 

The study was supported by Novartis Gene Therapies. Dr. Mendell and several co-investigators have disclosed financial relationships with the company.

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