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Obstacles plague prenatal cell-free DNA testing use
A recent California study examining cell-free DNA (cfDNA) testing suggests that the test generally performs well as a second-line screen for fetal aneuploidy. However, while the test itself is reliable, some physicians say gaps in patient education, limited availability of genetic counseling, and a lack of coordinated research and data collection are all standing in the way of its optimal utilization.
In some of the most recent data presented on cfDNA test performance, researchers in California found that the test had few false positives and was best at predicting Down syndrome, with a positive predictive value of 98.6%.
California offers prenatal screening as a public health program, with a structured system of screening tests and follow-up services, according to Dr. Currier, who is chief of the evaluation section of the state’s Genetic Disease Screening Program. First trimester screening includes screens for trisomies 18 and 21. During the second trimester, the screening adds on checks for neural tube defects and Smith-Lemli-Opitz syndrome, also known as 7-dehydrocholesterol reductase deficiency.
Overall, 20,852 patients were offered cfDNA screening during this period, and 63% (n = 12,960) went on to have the screen. Dr. Currier and his colleagues found that about a third of patients with a first- or second-trimester positive cfDNA test opted for diagnostic testing with either chorionic villus sampling or amniocentesis. If patients had a known karyotype, most were in agreement with the trisomy or sex-chromosome aneuploidies that had been picked up by cfDNA testing.
There were a small number of false-positive cfDNA results seen in the California data, Dr. Currier noted. Performance was best for Down syndrome, where cfDNA had a positive predictive value of 98.6%. Here, 214 of the 611 cfDNA positive results received diagnostic confirmation. Of those, 197 were true positives and 3 were false positives, while a karyotype other than trisomy 21 was revealed in 14 cases. Positive predictive values were lower in the less-common aneuploidies, he said.
A small number of test failures also occurred. Of the 148 failures reported, just 40 were followed by successful repeat tests.
“Cell-free DNA is a good second-tier screening test, but it does have false-positive and false-negative results, so pre- and post-test counseling addressing these limitations are essential,” Dr. Currier said.
Nancy Rose, MD, agrees with that assessment of the limitations of the cfDNA test. She helped write the American College of Obstetricians and Gynecologists 2015 opinion on cell-free DNA screening for aneuploidy, which states that conventional screening methods “remain the most appropriate choice for first-line screening for most women in the general obstetric population.”
While it is “perfectly reasonable” for general ob.gyns. to offer cfDNA screening, in her practice, “genetic counselors call out all the results for general providers because patients don’t really understand what a screen negative result is,” Dr. Rose said in an interview. “Certainly, screen positive results should go to a genetic counselor for sure.”
However, that level of follow-up may be hard to implement. “One issue that we’re all facing right now is that genetic counselors are a scarce commodity because of the competition with them working for labs or insurance companies,” said Dr. Rose, a maternal-fetal medicine specialist in Salt Lake City.
If the lack of appropriate counseling is an issue, are patients sometimes jumping the gun? The immediate past president of the Society for Maternal-Fetal Medicine, Mary Norton, MD, said maybe so.
When asked whether she thinks pregnancies are being terminated on the basis of cfDNA results alone, Dr. Norton said, “I absolutely think that is happening. How many is hard to know. I do know that we have many patients that we see who say, ‘My result here says that the chance of Down syndrome is greater than 99%,’ but that is not what that number means, and people don’t understand that.”
She added, “In some cases there are also ultrasound abnormalities, but there is no question that there is misunderstanding leading to the loss of normal fetuses.”
Patient misunderstandings about what’s entailed in first- and second-line screening tests persist, said Dr. Norton, professor of obstetrics and gynecology and reproductive sciences at the University of California, San Francisco. One example is ongoing hesitancy about amniocentesis. “Amnio has become very, very safe,” she said. “It’s much safer than it used to be. The miscarriage rate is nearly nonexistent.”
The care team needs to work to find time to educate patients about both older technologies and noninvasive prenatal testing (NIPT), Dr. Rose and Dr. Norton stressed.
“Even though ‘NIPT’ is easy to say – it rolls off the tongue – we really shouldn’t call it that. It’s misleading, because all of the other screening tests are noninvasive too,” Dr. Norton said. “I’ve had many patients who declined diagnostic testing, even though they want as much information as possible about what they should do.”
Dr. Rose added, “It’s a screening test; it’s not perfect. But screening tests are really what obstetricians do. They do pap smears; they do breast exams. So I think that isn’t the issue so much as that there is no time in an obstetrician’s office to really educate women about what they are accepting.”
Additional ethical issues revolving around the mother may arise in rare cases. Only about 10% of the DNA sampled is fetal, meaning that the rest is maternal DNA, Dr. Norton explained. “And they’re not separated,” she said. “So, the issue that is coming up is that they are finding things in the mother that are unanticipated, and women aren’t told that ahead of time.”
Some of these thorny – and still evolving – legal and ethical questions were addressed during a workshop at the 2017 Pregnancy Meeting. A working group that met there is developing a summary of their discussion for future publication.
For Dr. Rose, the larger issue is the lack of coordinated data collection and quality initiatives. She pointed out that the California outcomes study may not be generalizable to most of the rest of the country because most states don’t have such a coordinated public health approach to prenatal testing and data collection.
This reality is hampering knowledge advancement in the field, she said. When she was asked about terminations on the basis of cfDNA alone, Dr. Rose said, “Because there’s no outcome data on these patients, because there are no unbiased studies that cross through these companies, we actually don’t really know that on a national level. There are no unbiased outcome data. There may be small studies, but I think there are no national data to answer that question at the moment.”
Overall, Dr. Rose said that cfDNA screening is fairly reliable. “This is no different than what has been done before with serum analyte screening, and it’s probably a little bit better,” she said. “My feeling is the tragedy is really in the lack of companies either being able to work together or to have some unbiased funding so you could really actually know what test performance means.”
Dr. Norton reported receiving research funding from Natera and Ultragenyx. Dr. Rose reported no relevant disclosures. Dr. Currier’s study was funded by the California Department of Public Health, where he is employed.
[email protected]
On Twitter @karioakes
A recent California study examining cell-free DNA (cfDNA) testing suggests that the test generally performs well as a second-line screen for fetal aneuploidy. However, while the test itself is reliable, some physicians say gaps in patient education, limited availability of genetic counseling, and a lack of coordinated research and data collection are all standing in the way of its optimal utilization.
In some of the most recent data presented on cfDNA test performance, researchers in California found that the test had few false positives and was best at predicting Down syndrome, with a positive predictive value of 98.6%.
California offers prenatal screening as a public health program, with a structured system of screening tests and follow-up services, according to Dr. Currier, who is chief of the evaluation section of the state’s Genetic Disease Screening Program. First trimester screening includes screens for trisomies 18 and 21. During the second trimester, the screening adds on checks for neural tube defects and Smith-Lemli-Opitz syndrome, also known as 7-dehydrocholesterol reductase deficiency.
Overall, 20,852 patients were offered cfDNA screening during this period, and 63% (n = 12,960) went on to have the screen. Dr. Currier and his colleagues found that about a third of patients with a first- or second-trimester positive cfDNA test opted for diagnostic testing with either chorionic villus sampling or amniocentesis. If patients had a known karyotype, most were in agreement with the trisomy or sex-chromosome aneuploidies that had been picked up by cfDNA testing.
There were a small number of false-positive cfDNA results seen in the California data, Dr. Currier noted. Performance was best for Down syndrome, where cfDNA had a positive predictive value of 98.6%. Here, 214 of the 611 cfDNA positive results received diagnostic confirmation. Of those, 197 were true positives and 3 were false positives, while a karyotype other than trisomy 21 was revealed in 14 cases. Positive predictive values were lower in the less-common aneuploidies, he said.
A small number of test failures also occurred. Of the 148 failures reported, just 40 were followed by successful repeat tests.
“Cell-free DNA is a good second-tier screening test, but it does have false-positive and false-negative results, so pre- and post-test counseling addressing these limitations are essential,” Dr. Currier said.
Nancy Rose, MD, agrees with that assessment of the limitations of the cfDNA test. She helped write the American College of Obstetricians and Gynecologists 2015 opinion on cell-free DNA screening for aneuploidy, which states that conventional screening methods “remain the most appropriate choice for first-line screening for most women in the general obstetric population.”
While it is “perfectly reasonable” for general ob.gyns. to offer cfDNA screening, in her practice, “genetic counselors call out all the results for general providers because patients don’t really understand what a screen negative result is,” Dr. Rose said in an interview. “Certainly, screen positive results should go to a genetic counselor for sure.”
However, that level of follow-up may be hard to implement. “One issue that we’re all facing right now is that genetic counselors are a scarce commodity because of the competition with them working for labs or insurance companies,” said Dr. Rose, a maternal-fetal medicine specialist in Salt Lake City.
If the lack of appropriate counseling is an issue, are patients sometimes jumping the gun? The immediate past president of the Society for Maternal-Fetal Medicine, Mary Norton, MD, said maybe so.
When asked whether she thinks pregnancies are being terminated on the basis of cfDNA results alone, Dr. Norton said, “I absolutely think that is happening. How many is hard to know. I do know that we have many patients that we see who say, ‘My result here says that the chance of Down syndrome is greater than 99%,’ but that is not what that number means, and people don’t understand that.”
She added, “In some cases there are also ultrasound abnormalities, but there is no question that there is misunderstanding leading to the loss of normal fetuses.”
Patient misunderstandings about what’s entailed in first- and second-line screening tests persist, said Dr. Norton, professor of obstetrics and gynecology and reproductive sciences at the University of California, San Francisco. One example is ongoing hesitancy about amniocentesis. “Amnio has become very, very safe,” she said. “It’s much safer than it used to be. The miscarriage rate is nearly nonexistent.”
The care team needs to work to find time to educate patients about both older technologies and noninvasive prenatal testing (NIPT), Dr. Rose and Dr. Norton stressed.
“Even though ‘NIPT’ is easy to say – it rolls off the tongue – we really shouldn’t call it that. It’s misleading, because all of the other screening tests are noninvasive too,” Dr. Norton said. “I’ve had many patients who declined diagnostic testing, even though they want as much information as possible about what they should do.”
Dr. Rose added, “It’s a screening test; it’s not perfect. But screening tests are really what obstetricians do. They do pap smears; they do breast exams. So I think that isn’t the issue so much as that there is no time in an obstetrician’s office to really educate women about what they are accepting.”
Additional ethical issues revolving around the mother may arise in rare cases. Only about 10% of the DNA sampled is fetal, meaning that the rest is maternal DNA, Dr. Norton explained. “And they’re not separated,” she said. “So, the issue that is coming up is that they are finding things in the mother that are unanticipated, and women aren’t told that ahead of time.”
Some of these thorny – and still evolving – legal and ethical questions were addressed during a workshop at the 2017 Pregnancy Meeting. A working group that met there is developing a summary of their discussion for future publication.
For Dr. Rose, the larger issue is the lack of coordinated data collection and quality initiatives. She pointed out that the California outcomes study may not be generalizable to most of the rest of the country because most states don’t have such a coordinated public health approach to prenatal testing and data collection.
This reality is hampering knowledge advancement in the field, she said. When she was asked about terminations on the basis of cfDNA alone, Dr. Rose said, “Because there’s no outcome data on these patients, because there are no unbiased studies that cross through these companies, we actually don’t really know that on a national level. There are no unbiased outcome data. There may be small studies, but I think there are no national data to answer that question at the moment.”
Overall, Dr. Rose said that cfDNA screening is fairly reliable. “This is no different than what has been done before with serum analyte screening, and it’s probably a little bit better,” she said. “My feeling is the tragedy is really in the lack of companies either being able to work together or to have some unbiased funding so you could really actually know what test performance means.”
Dr. Norton reported receiving research funding from Natera and Ultragenyx. Dr. Rose reported no relevant disclosures. Dr. Currier’s study was funded by the California Department of Public Health, where he is employed.
[email protected]
On Twitter @karioakes
A recent California study examining cell-free DNA (cfDNA) testing suggests that the test generally performs well as a second-line screen for fetal aneuploidy. However, while the test itself is reliable, some physicians say gaps in patient education, limited availability of genetic counseling, and a lack of coordinated research and data collection are all standing in the way of its optimal utilization.
In some of the most recent data presented on cfDNA test performance, researchers in California found that the test had few false positives and was best at predicting Down syndrome, with a positive predictive value of 98.6%.
California offers prenatal screening as a public health program, with a structured system of screening tests and follow-up services, according to Dr. Currier, who is chief of the evaluation section of the state’s Genetic Disease Screening Program. First trimester screening includes screens for trisomies 18 and 21. During the second trimester, the screening adds on checks for neural tube defects and Smith-Lemli-Opitz syndrome, also known as 7-dehydrocholesterol reductase deficiency.
Overall, 20,852 patients were offered cfDNA screening during this period, and 63% (n = 12,960) went on to have the screen. Dr. Currier and his colleagues found that about a third of patients with a first- or second-trimester positive cfDNA test opted for diagnostic testing with either chorionic villus sampling or amniocentesis. If patients had a known karyotype, most were in agreement with the trisomy or sex-chromosome aneuploidies that had been picked up by cfDNA testing.
There were a small number of false-positive cfDNA results seen in the California data, Dr. Currier noted. Performance was best for Down syndrome, where cfDNA had a positive predictive value of 98.6%. Here, 214 of the 611 cfDNA positive results received diagnostic confirmation. Of those, 197 were true positives and 3 were false positives, while a karyotype other than trisomy 21 was revealed in 14 cases. Positive predictive values were lower in the less-common aneuploidies, he said.
A small number of test failures also occurred. Of the 148 failures reported, just 40 were followed by successful repeat tests.
“Cell-free DNA is a good second-tier screening test, but it does have false-positive and false-negative results, so pre- and post-test counseling addressing these limitations are essential,” Dr. Currier said.
Nancy Rose, MD, agrees with that assessment of the limitations of the cfDNA test. She helped write the American College of Obstetricians and Gynecologists 2015 opinion on cell-free DNA screening for aneuploidy, which states that conventional screening methods “remain the most appropriate choice for first-line screening for most women in the general obstetric population.”
While it is “perfectly reasonable” for general ob.gyns. to offer cfDNA screening, in her practice, “genetic counselors call out all the results for general providers because patients don’t really understand what a screen negative result is,” Dr. Rose said in an interview. “Certainly, screen positive results should go to a genetic counselor for sure.”
However, that level of follow-up may be hard to implement. “One issue that we’re all facing right now is that genetic counselors are a scarce commodity because of the competition with them working for labs or insurance companies,” said Dr. Rose, a maternal-fetal medicine specialist in Salt Lake City.
If the lack of appropriate counseling is an issue, are patients sometimes jumping the gun? The immediate past president of the Society for Maternal-Fetal Medicine, Mary Norton, MD, said maybe so.
When asked whether she thinks pregnancies are being terminated on the basis of cfDNA results alone, Dr. Norton said, “I absolutely think that is happening. How many is hard to know. I do know that we have many patients that we see who say, ‘My result here says that the chance of Down syndrome is greater than 99%,’ but that is not what that number means, and people don’t understand that.”
She added, “In some cases there are also ultrasound abnormalities, but there is no question that there is misunderstanding leading to the loss of normal fetuses.”
Patient misunderstandings about what’s entailed in first- and second-line screening tests persist, said Dr. Norton, professor of obstetrics and gynecology and reproductive sciences at the University of California, San Francisco. One example is ongoing hesitancy about amniocentesis. “Amnio has become very, very safe,” she said. “It’s much safer than it used to be. The miscarriage rate is nearly nonexistent.”
The care team needs to work to find time to educate patients about both older technologies and noninvasive prenatal testing (NIPT), Dr. Rose and Dr. Norton stressed.
“Even though ‘NIPT’ is easy to say – it rolls off the tongue – we really shouldn’t call it that. It’s misleading, because all of the other screening tests are noninvasive too,” Dr. Norton said. “I’ve had many patients who declined diagnostic testing, even though they want as much information as possible about what they should do.”
Dr. Rose added, “It’s a screening test; it’s not perfect. But screening tests are really what obstetricians do. They do pap smears; they do breast exams. So I think that isn’t the issue so much as that there is no time in an obstetrician’s office to really educate women about what they are accepting.”
Additional ethical issues revolving around the mother may arise in rare cases. Only about 10% of the DNA sampled is fetal, meaning that the rest is maternal DNA, Dr. Norton explained. “And they’re not separated,” she said. “So, the issue that is coming up is that they are finding things in the mother that are unanticipated, and women aren’t told that ahead of time.”
Some of these thorny – and still evolving – legal and ethical questions were addressed during a workshop at the 2017 Pregnancy Meeting. A working group that met there is developing a summary of their discussion for future publication.
For Dr. Rose, the larger issue is the lack of coordinated data collection and quality initiatives. She pointed out that the California outcomes study may not be generalizable to most of the rest of the country because most states don’t have such a coordinated public health approach to prenatal testing and data collection.
This reality is hampering knowledge advancement in the field, she said. When she was asked about terminations on the basis of cfDNA alone, Dr. Rose said, “Because there’s no outcome data on these patients, because there are no unbiased studies that cross through these companies, we actually don’t really know that on a national level. There are no unbiased outcome data. There may be small studies, but I think there are no national data to answer that question at the moment.”
Overall, Dr. Rose said that cfDNA screening is fairly reliable. “This is no different than what has been done before with serum analyte screening, and it’s probably a little bit better,” she said. “My feeling is the tragedy is really in the lack of companies either being able to work together or to have some unbiased funding so you could really actually know what test performance means.”
Dr. Norton reported receiving research funding from Natera and Ultragenyx. Dr. Rose reported no relevant disclosures. Dr. Currier’s study was funded by the California Department of Public Health, where he is employed.
[email protected]
On Twitter @karioakes
FROM THE PREGNANCY MEETING
Where we go from here: Successes and opportunities in the medtech arena
BOSTON – An array of potentially transformative technological innovations in gastroenterology with related effects on systemic health – including metabolic diseases – are showing promise at different stages of clinical testing, and gastroenterologists need to make sure they are not left behind in this opportunity to make a positive impact on patient health, according to an overview of recent medtech successes and coming trends presented at the 2017 AGA Tech Summit.
“Innovation in GI tech is continuing at a substantial pace because of the sustained interest among investors, entrepreneurs, and established industry players and the many opportunities and unmet needs,” Jay Pasricha, MD, MBBS, director of the Johns Hopkins Center for Neurogastroenterology, Baltimore, said in an interview. The obstacle for gastroenterologists is willingness to adapt.
The rapid, transformative changes in bariatric endoscopy provide an immediate example, according to Dr. Pasricha. There has been enormous innovation in this area with more devices coming. He suggested that meaningful participation in this growing field not only involves a commitment to mastering the technical challenges of available devices but also to providing comprehensive care.
“There needs to be a commitment to what might be described as the bookends of treatment. This means screening and appropriate selection of candidates for specific procedures and providing the follow-up and supportive care that lead to good outcomes. In other words, do it right or don’t do it,” Dr. Pasricha said.
He considers endoscopic approaches to weight loss — balloons, gastric restriction, or other strategies — emblematic of a flexion point in gastroenterology that has the potential to result in increasing polarization in the specialty. Those who adapt to deliver the advances in care permitted by new technology will participate in advancing the field. Those who do not may cede advanced procedures to those specialists who step in.
The AGA Obesity Practice Guide, for example, provides gastroenterologists with a comprehensive, multi-disciplinary process to personalize innovative obesity care for safe and effective weight management, including the use of endoscopic and surgical procedures. The accompanying episode-of-care framework helps gastroenterologists understand how to operationalize obesity management for financial success (www.gastro.org/obesity).
Endoscopic mucosal resection of localized cancers, an area in which technological innovations are also promising, is another opportunity for gastroenterologists. According to Dr. Pasricha, “Innovations with the potential to leapfrog over traditional procedures are very feasible from a technical perspective, but which specialists will be the ones who collaborate on these interventions to make them a reality?”
While acknowledging that the current reimbursement structure does not incentivize complex and potentially time-consuming procedures over bread-and-butter procedures such as screening colonoscopy, Dr. Pasricha maintained that innovation in these areas represents the future. Eventually, advances in technology will simplify complex procedures, but Dr. Pasricha suggested that gastroenterologists should be leading disruptive technologies to ensure a place in delivery of next generation solutions.
In a broad survey of the likely directions, Dr. Pasricha provided examples of several frontiers in which technological innovation has a potential role. Efforts to harness the microbiome, for example, include devices with the potential to improve bowel function. Vagal stimulators in various forms have the potential to address pathology along the gut-brain axis.
“Devices designed to modify gut-brain signaling are not just relevant to GI diseases but are being pursued for much broader indications, such as those relating to mood and cognitive function,” Dr. Pasricha reported.
Casting a large net to touch on the science and economics of medtech innovations across a wide variety of unmet needs in gastroenterology, Dr. Pasricha described a common barrier. At the stage when new devices are introduced, innovators are faced with obstacles, including uncertain reimbursement and potential medico-legal risk, yet innovations depend on finding a path.
“Who is going to make the leap?” asked Dr. Pasricha, describing several areas of device innovation in which “people are testing the waters with no one yet willing to jump in.” He made the point that in fields relevant to their expertise, gastroenterologists should be participating in opportunities that may lead to better patient care.
“Otherwise, we may end up in an unhappy compromise – a small subset of technically advanced GI docs will compete with a larger and growing cadre of surgeons who are becoming increasingly skilled in flexible endoscopy,” Dr. Pasricha explained.
“But, in either scenario, the cognitive components of what represents best care for a given patient, which is the epitome of personalized medicine, may get short shrift,” he added. He envisions a worst case scenario in which screening colonoscopy is replaced by a pill or a fecal test, “and our specialty is not ready for taking care of all the other unmet needs because we have been complacent.”
Still, there are large areas in which opportunities abound, such as motility and functional disorders, that represent a huge socioeconomic and clinical burden, according to Dr. Pasricha, who believes advances in this field should be embraced.
For entrepreneurs pursuing medtech overall and in GI diseases specifically, Dr. Pasricha had some specific advice. He suggested that efforts should not be restricted to the development of new devices or other solutions but should include developing a context for the innovation, such as training of those who will employ the innovation, creating awareness among physicians who will refer, and helping to ensure reimbursement.
“All stakeholders need to invest in the growth of their markets and not just in the technology,” Dr. Pasricha said. He emphasized that one of the most important roadblocks are the gatekeepers who fail to refer patients to specialists capable of implementing a new procedure.
However, he believes that there is enormous room for successful innovation in GI medtech.
“The future remains bright. The gut, the gut-brain axis, and the gut-metabolic axis are all keys to unlocking the potential for endoscopic interventions to impact so many chronic diseases,” Dr. Pasricha maintained. “It’s up to us to recognize this and take ownership of this space. This conference as always serves to highlight these opportunities and potential road maps to that future.”
BOSTON – An array of potentially transformative technological innovations in gastroenterology with related effects on systemic health – including metabolic diseases – are showing promise at different stages of clinical testing, and gastroenterologists need to make sure they are not left behind in this opportunity to make a positive impact on patient health, according to an overview of recent medtech successes and coming trends presented at the 2017 AGA Tech Summit.
“Innovation in GI tech is continuing at a substantial pace because of the sustained interest among investors, entrepreneurs, and established industry players and the many opportunities and unmet needs,” Jay Pasricha, MD, MBBS, director of the Johns Hopkins Center for Neurogastroenterology, Baltimore, said in an interview. The obstacle for gastroenterologists is willingness to adapt.
The rapid, transformative changes in bariatric endoscopy provide an immediate example, according to Dr. Pasricha. There has been enormous innovation in this area with more devices coming. He suggested that meaningful participation in this growing field not only involves a commitment to mastering the technical challenges of available devices but also to providing comprehensive care.
“There needs to be a commitment to what might be described as the bookends of treatment. This means screening and appropriate selection of candidates for specific procedures and providing the follow-up and supportive care that lead to good outcomes. In other words, do it right or don’t do it,” Dr. Pasricha said.
He considers endoscopic approaches to weight loss — balloons, gastric restriction, or other strategies — emblematic of a flexion point in gastroenterology that has the potential to result in increasing polarization in the specialty. Those who adapt to deliver the advances in care permitted by new technology will participate in advancing the field. Those who do not may cede advanced procedures to those specialists who step in.
The AGA Obesity Practice Guide, for example, provides gastroenterologists with a comprehensive, multi-disciplinary process to personalize innovative obesity care for safe and effective weight management, including the use of endoscopic and surgical procedures. The accompanying episode-of-care framework helps gastroenterologists understand how to operationalize obesity management for financial success (www.gastro.org/obesity).
Endoscopic mucosal resection of localized cancers, an area in which technological innovations are also promising, is another opportunity for gastroenterologists. According to Dr. Pasricha, “Innovations with the potential to leapfrog over traditional procedures are very feasible from a technical perspective, but which specialists will be the ones who collaborate on these interventions to make them a reality?”
While acknowledging that the current reimbursement structure does not incentivize complex and potentially time-consuming procedures over bread-and-butter procedures such as screening colonoscopy, Dr. Pasricha maintained that innovation in these areas represents the future. Eventually, advances in technology will simplify complex procedures, but Dr. Pasricha suggested that gastroenterologists should be leading disruptive technologies to ensure a place in delivery of next generation solutions.
In a broad survey of the likely directions, Dr. Pasricha provided examples of several frontiers in which technological innovation has a potential role. Efforts to harness the microbiome, for example, include devices with the potential to improve bowel function. Vagal stimulators in various forms have the potential to address pathology along the gut-brain axis.
“Devices designed to modify gut-brain signaling are not just relevant to GI diseases but are being pursued for much broader indications, such as those relating to mood and cognitive function,” Dr. Pasricha reported.
Casting a large net to touch on the science and economics of medtech innovations across a wide variety of unmet needs in gastroenterology, Dr. Pasricha described a common barrier. At the stage when new devices are introduced, innovators are faced with obstacles, including uncertain reimbursement and potential medico-legal risk, yet innovations depend on finding a path.
“Who is going to make the leap?” asked Dr. Pasricha, describing several areas of device innovation in which “people are testing the waters with no one yet willing to jump in.” He made the point that in fields relevant to their expertise, gastroenterologists should be participating in opportunities that may lead to better patient care.
“Otherwise, we may end up in an unhappy compromise – a small subset of technically advanced GI docs will compete with a larger and growing cadre of surgeons who are becoming increasingly skilled in flexible endoscopy,” Dr. Pasricha explained.
“But, in either scenario, the cognitive components of what represents best care for a given patient, which is the epitome of personalized medicine, may get short shrift,” he added. He envisions a worst case scenario in which screening colonoscopy is replaced by a pill or a fecal test, “and our specialty is not ready for taking care of all the other unmet needs because we have been complacent.”
Still, there are large areas in which opportunities abound, such as motility and functional disorders, that represent a huge socioeconomic and clinical burden, according to Dr. Pasricha, who believes advances in this field should be embraced.
For entrepreneurs pursuing medtech overall and in GI diseases specifically, Dr. Pasricha had some specific advice. He suggested that efforts should not be restricted to the development of new devices or other solutions but should include developing a context for the innovation, such as training of those who will employ the innovation, creating awareness among physicians who will refer, and helping to ensure reimbursement.
“All stakeholders need to invest in the growth of their markets and not just in the technology,” Dr. Pasricha said. He emphasized that one of the most important roadblocks are the gatekeepers who fail to refer patients to specialists capable of implementing a new procedure.
However, he believes that there is enormous room for successful innovation in GI medtech.
“The future remains bright. The gut, the gut-brain axis, and the gut-metabolic axis are all keys to unlocking the potential for endoscopic interventions to impact so many chronic diseases,” Dr. Pasricha maintained. “It’s up to us to recognize this and take ownership of this space. This conference as always serves to highlight these opportunities and potential road maps to that future.”
BOSTON – An array of potentially transformative technological innovations in gastroenterology with related effects on systemic health – including metabolic diseases – are showing promise at different stages of clinical testing, and gastroenterologists need to make sure they are not left behind in this opportunity to make a positive impact on patient health, according to an overview of recent medtech successes and coming trends presented at the 2017 AGA Tech Summit.
“Innovation in GI tech is continuing at a substantial pace because of the sustained interest among investors, entrepreneurs, and established industry players and the many opportunities and unmet needs,” Jay Pasricha, MD, MBBS, director of the Johns Hopkins Center for Neurogastroenterology, Baltimore, said in an interview. The obstacle for gastroenterologists is willingness to adapt.
The rapid, transformative changes in bariatric endoscopy provide an immediate example, according to Dr. Pasricha. There has been enormous innovation in this area with more devices coming. He suggested that meaningful participation in this growing field not only involves a commitment to mastering the technical challenges of available devices but also to providing comprehensive care.
“There needs to be a commitment to what might be described as the bookends of treatment. This means screening and appropriate selection of candidates for specific procedures and providing the follow-up and supportive care that lead to good outcomes. In other words, do it right or don’t do it,” Dr. Pasricha said.
He considers endoscopic approaches to weight loss — balloons, gastric restriction, or other strategies — emblematic of a flexion point in gastroenterology that has the potential to result in increasing polarization in the specialty. Those who adapt to deliver the advances in care permitted by new technology will participate in advancing the field. Those who do not may cede advanced procedures to those specialists who step in.
The AGA Obesity Practice Guide, for example, provides gastroenterologists with a comprehensive, multi-disciplinary process to personalize innovative obesity care for safe and effective weight management, including the use of endoscopic and surgical procedures. The accompanying episode-of-care framework helps gastroenterologists understand how to operationalize obesity management for financial success (www.gastro.org/obesity).
Endoscopic mucosal resection of localized cancers, an area in which technological innovations are also promising, is another opportunity for gastroenterologists. According to Dr. Pasricha, “Innovations with the potential to leapfrog over traditional procedures are very feasible from a technical perspective, but which specialists will be the ones who collaborate on these interventions to make them a reality?”
While acknowledging that the current reimbursement structure does not incentivize complex and potentially time-consuming procedures over bread-and-butter procedures such as screening colonoscopy, Dr. Pasricha maintained that innovation in these areas represents the future. Eventually, advances in technology will simplify complex procedures, but Dr. Pasricha suggested that gastroenterologists should be leading disruptive technologies to ensure a place in delivery of next generation solutions.
In a broad survey of the likely directions, Dr. Pasricha provided examples of several frontiers in which technological innovation has a potential role. Efforts to harness the microbiome, for example, include devices with the potential to improve bowel function. Vagal stimulators in various forms have the potential to address pathology along the gut-brain axis.
“Devices designed to modify gut-brain signaling are not just relevant to GI diseases but are being pursued for much broader indications, such as those relating to mood and cognitive function,” Dr. Pasricha reported.
Casting a large net to touch on the science and economics of medtech innovations across a wide variety of unmet needs in gastroenterology, Dr. Pasricha described a common barrier. At the stage when new devices are introduced, innovators are faced with obstacles, including uncertain reimbursement and potential medico-legal risk, yet innovations depend on finding a path.
“Who is going to make the leap?” asked Dr. Pasricha, describing several areas of device innovation in which “people are testing the waters with no one yet willing to jump in.” He made the point that in fields relevant to their expertise, gastroenterologists should be participating in opportunities that may lead to better patient care.
“Otherwise, we may end up in an unhappy compromise – a small subset of technically advanced GI docs will compete with a larger and growing cadre of surgeons who are becoming increasingly skilled in flexible endoscopy,” Dr. Pasricha explained.
“But, in either scenario, the cognitive components of what represents best care for a given patient, which is the epitome of personalized medicine, may get short shrift,” he added. He envisions a worst case scenario in which screening colonoscopy is replaced by a pill or a fecal test, “and our specialty is not ready for taking care of all the other unmet needs because we have been complacent.”
Still, there are large areas in which opportunities abound, such as motility and functional disorders, that represent a huge socioeconomic and clinical burden, according to Dr. Pasricha, who believes advances in this field should be embraced.
For entrepreneurs pursuing medtech overall and in GI diseases specifically, Dr. Pasricha had some specific advice. He suggested that efforts should not be restricted to the development of new devices or other solutions but should include developing a context for the innovation, such as training of those who will employ the innovation, creating awareness among physicians who will refer, and helping to ensure reimbursement.
“All stakeholders need to invest in the growth of their markets and not just in the technology,” Dr. Pasricha said. He emphasized that one of the most important roadblocks are the gatekeepers who fail to refer patients to specialists capable of implementing a new procedure.
However, he believes that there is enormous room for successful innovation in GI medtech.
“The future remains bright. The gut, the gut-brain axis, and the gut-metabolic axis are all keys to unlocking the potential for endoscopic interventions to impact so many chronic diseases,” Dr. Pasricha maintained. “It’s up to us to recognize this and take ownership of this space. This conference as always serves to highlight these opportunities and potential road maps to that future.”
FROM THE 2017 AGA TECH SUMMIT
21st Century Cures Act creates opportunities, risks
BOSTON – The recently passed 21st Century Cures Act has large implications for the pharmaceutical and medical device industry even if the impact will be better understood through the actions of the new presidential administration, according to the 2017 AGA Tech Summit keynote speaker.
“The Cures Act is a huge document with an array of provisions that seeks, among other goals, to create a pathway to streamline the [Food and Drug Administration] and the regulatory process,” Herbert Lerner, MD, senior director of regulatory and clinical sciences at the law firm Hogan Lovells in Washington, explained in an interview.
In his keynote address at the meeting, sponsored by the AGA Center for GI Innovation and Technology, Dr. Lerner described the 21st Century Cures Act with an emphasis on its intent relative to regulatory compliance by the device industry. As law, the provisions of the Act are relevant to planning for regulatory review of new products, but Dr. Lerner acknowledged that the health care industry should be considering both the intent of the Act and how it may unfold under the budgetary cuts planned by the current administration.
“One consequence of the current hiring freeze may result in personnel shortages that could substantially impact the ability of the FDA to perform its functions,” Dr. Lerner cautioned. In addition, he cited the emphasis placed by the administration on reducing the burden of regulation that surpasses the scope of the Cures Act.
“The new President has asked that two regulations be eliminated for any new regulation that is proposed. It is hard to predict how this would impact the FDA if it was enforced,” Dr. Lerner reported.
Passed after 2 years of political wrangling, the Cures Act addresses a wide spectrum of health policy, including increasing funding for cancer research, care of the mentally ill, and treatment of opioid addiction, but Dr. Lerner concentrated on the portions most likely to affect the medical tech industry. For example, he dissected provisions that have renewed the emphasis on the selection of experts serving on advisory panels that provide recommendations to the FDA on new product approvals, the language that has addressed the idea of centralized institutional review boards for clinical trials for device manufacturers, and new regulations outlining provisions that may affect how the industry addresses changes to devices that have already been marketed.
“There are important changes in a number of aspects of the regulatory process mandated by the Cures Act that will impose a meaningful effect on how the medical device and drug industry pursue new products or execute regulatory compliance with existing products,” Dr. Lerner said. The Cures Act also provides language to cover new directions in health care such as the exploding use of mobile medical apps to monitor health.
Understanding the intent of the Cures Act, which had substantial support by both major political parties, is important even if it is now unclear whether all parts of the Act will be implemented as planned under a new administration, according to Dr. Lerner. He suggested that support for a streamlined and more efficient FDA was the force behind the changes in regulatory review included in this new Act. Change is underway even if a complete understanding of how these changes will be enacted remains unclear.
Based on current staff shortages and expected budget cuts at the FDA, it does appear that the review process for submissions of devices will grow longer even if the Cures Act has been designed to streamline the process. Dr. Lerner, acknowledging this paradox, suggested that companies planning to submit an application for a new device to the FDA be particularly rigorous in ensuring that the application is complete.
“Spend a little extra time to make sure that what you are sending in is as good as it can be,” Dr. Lerner offered to industry representatives working in the evolving environment. He cautioned that with the expected additional time taken for regulatory review, revisions and resubmissions are likely to compound delays.
AGA supported passage of the 21st Century Cures Act and will continue to work with Congress to help ensure the regulations continue encouraging innovation, while also helping the gastroenterology community determine which treatments work best for patients.
BOSTON – The recently passed 21st Century Cures Act has large implications for the pharmaceutical and medical device industry even if the impact will be better understood through the actions of the new presidential administration, according to the 2017 AGA Tech Summit keynote speaker.
“The Cures Act is a huge document with an array of provisions that seeks, among other goals, to create a pathway to streamline the [Food and Drug Administration] and the regulatory process,” Herbert Lerner, MD, senior director of regulatory and clinical sciences at the law firm Hogan Lovells in Washington, explained in an interview.
In his keynote address at the meeting, sponsored by the AGA Center for GI Innovation and Technology, Dr. Lerner described the 21st Century Cures Act with an emphasis on its intent relative to regulatory compliance by the device industry. As law, the provisions of the Act are relevant to planning for regulatory review of new products, but Dr. Lerner acknowledged that the health care industry should be considering both the intent of the Act and how it may unfold under the budgetary cuts planned by the current administration.
“One consequence of the current hiring freeze may result in personnel shortages that could substantially impact the ability of the FDA to perform its functions,” Dr. Lerner cautioned. In addition, he cited the emphasis placed by the administration on reducing the burden of regulation that surpasses the scope of the Cures Act.
“The new President has asked that two regulations be eliminated for any new regulation that is proposed. It is hard to predict how this would impact the FDA if it was enforced,” Dr. Lerner reported.
Passed after 2 years of political wrangling, the Cures Act addresses a wide spectrum of health policy, including increasing funding for cancer research, care of the mentally ill, and treatment of opioid addiction, but Dr. Lerner concentrated on the portions most likely to affect the medical tech industry. For example, he dissected provisions that have renewed the emphasis on the selection of experts serving on advisory panels that provide recommendations to the FDA on new product approvals, the language that has addressed the idea of centralized institutional review boards for clinical trials for device manufacturers, and new regulations outlining provisions that may affect how the industry addresses changes to devices that have already been marketed.
“There are important changes in a number of aspects of the regulatory process mandated by the Cures Act that will impose a meaningful effect on how the medical device and drug industry pursue new products or execute regulatory compliance with existing products,” Dr. Lerner said. The Cures Act also provides language to cover new directions in health care such as the exploding use of mobile medical apps to monitor health.
Understanding the intent of the Cures Act, which had substantial support by both major political parties, is important even if it is now unclear whether all parts of the Act will be implemented as planned under a new administration, according to Dr. Lerner. He suggested that support for a streamlined and more efficient FDA was the force behind the changes in regulatory review included in this new Act. Change is underway even if a complete understanding of how these changes will be enacted remains unclear.
Based on current staff shortages and expected budget cuts at the FDA, it does appear that the review process for submissions of devices will grow longer even if the Cures Act has been designed to streamline the process. Dr. Lerner, acknowledging this paradox, suggested that companies planning to submit an application for a new device to the FDA be particularly rigorous in ensuring that the application is complete.
“Spend a little extra time to make sure that what you are sending in is as good as it can be,” Dr. Lerner offered to industry representatives working in the evolving environment. He cautioned that with the expected additional time taken for regulatory review, revisions and resubmissions are likely to compound delays.
AGA supported passage of the 21st Century Cures Act and will continue to work with Congress to help ensure the regulations continue encouraging innovation, while also helping the gastroenterology community determine which treatments work best for patients.
BOSTON – The recently passed 21st Century Cures Act has large implications for the pharmaceutical and medical device industry even if the impact will be better understood through the actions of the new presidential administration, according to the 2017 AGA Tech Summit keynote speaker.
“The Cures Act is a huge document with an array of provisions that seeks, among other goals, to create a pathway to streamline the [Food and Drug Administration] and the regulatory process,” Herbert Lerner, MD, senior director of regulatory and clinical sciences at the law firm Hogan Lovells in Washington, explained in an interview.
In his keynote address at the meeting, sponsored by the AGA Center for GI Innovation and Technology, Dr. Lerner described the 21st Century Cures Act with an emphasis on its intent relative to regulatory compliance by the device industry. As law, the provisions of the Act are relevant to planning for regulatory review of new products, but Dr. Lerner acknowledged that the health care industry should be considering both the intent of the Act and how it may unfold under the budgetary cuts planned by the current administration.
“One consequence of the current hiring freeze may result in personnel shortages that could substantially impact the ability of the FDA to perform its functions,” Dr. Lerner cautioned. In addition, he cited the emphasis placed by the administration on reducing the burden of regulation that surpasses the scope of the Cures Act.
“The new President has asked that two regulations be eliminated for any new regulation that is proposed. It is hard to predict how this would impact the FDA if it was enforced,” Dr. Lerner reported.
Passed after 2 years of political wrangling, the Cures Act addresses a wide spectrum of health policy, including increasing funding for cancer research, care of the mentally ill, and treatment of opioid addiction, but Dr. Lerner concentrated on the portions most likely to affect the medical tech industry. For example, he dissected provisions that have renewed the emphasis on the selection of experts serving on advisory panels that provide recommendations to the FDA on new product approvals, the language that has addressed the idea of centralized institutional review boards for clinical trials for device manufacturers, and new regulations outlining provisions that may affect how the industry addresses changes to devices that have already been marketed.
“There are important changes in a number of aspects of the regulatory process mandated by the Cures Act that will impose a meaningful effect on how the medical device and drug industry pursue new products or execute regulatory compliance with existing products,” Dr. Lerner said. The Cures Act also provides language to cover new directions in health care such as the exploding use of mobile medical apps to monitor health.
Understanding the intent of the Cures Act, which had substantial support by both major political parties, is important even if it is now unclear whether all parts of the Act will be implemented as planned under a new administration, according to Dr. Lerner. He suggested that support for a streamlined and more efficient FDA was the force behind the changes in regulatory review included in this new Act. Change is underway even if a complete understanding of how these changes will be enacted remains unclear.
Based on current staff shortages and expected budget cuts at the FDA, it does appear that the review process for submissions of devices will grow longer even if the Cures Act has been designed to streamline the process. Dr. Lerner, acknowledging this paradox, suggested that companies planning to submit an application for a new device to the FDA be particularly rigorous in ensuring that the application is complete.
“Spend a little extra time to make sure that what you are sending in is as good as it can be,” Dr. Lerner offered to industry representatives working in the evolving environment. He cautioned that with the expected additional time taken for regulatory review, revisions and resubmissions are likely to compound delays.
AGA supported passage of the 21st Century Cures Act and will continue to work with Congress to help ensure the regulations continue encouraging innovation, while also helping the gastroenterology community determine which treatments work best for patients.
FROM THE 2017 AGA TECH SUMMIT
OSA tool uncovers risks of postoperative complications
High scores on the symptomless multivariable apnea prediction index (sMVAP) showed a strong correlation with increased risk for postsurgery complications, according to a study approved by the University of Pennsylvania, Philadelphia.
This validation helps assert the benefits of using the sMVAP as a tool to screen for obstructive sleep apnea (OSA) before elective inpatient surgeries, a test that is highly underutilized but very important, wrote M. Melanie Lyons, PhD, of the Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, and her colleagues.
“Most patients having elective surgery are not screened for obstructive sleep apnea, even though OSA is a risk factor for postoperative complications,” wrote Dr. Lyons and her colleagues. “We observe that sMVAP correlates with higher risk for OSA, hypertension, and select postoperative complications, particularly in non-bariatric groups without routine preoperative screening for OSA.”
In a retrospective study of 40,432 patients undergoing elective surgery, high sMVAP scores were strongly correlated with postoperative complications including longer hospital stays (OR = 1.83), stays in the ICU (OR = 1.44), and respiratory complications (OR = 1.85) according to the researchers (Sleep. 2017 Jan 6. doi: 10.1093/sleep/zsw081).
Researchers separated participants into 10 categories according to the type of procedure: bariatric, orthopedic, cardiac, gastrointestinal, genitourinary, neurological, otorhinolaryngology/oral-maxillofacial/ear-nose-throat, pulmonary/thoracic, spine, and vascular.
The sMVAP calculates risk factors for OSA based on gender, age and body mass index, the researchers noted.
Those in the highest sMVAP score quintile were predominantly male (58%), with average age of 61 years, and average BMI of 40.9 kg/m2 (indicating morbid obesity). These patients reported the highest prevalence of having been previously diagnosed with OSA (26%). Comparatively, those patients in the lowest sMVAP quintile reported the lowest prevalence of an OSA diagnosis prior to undergoing their surgeries (9.3%).
Among non–bariatric surgery patients, those undergoing orthopedic procedures showed the highest correlation between complications and sMVAP scores.
The orthopedic surgery category reported a higher percentage of ICU-stay compared with bariatric surgery (14.3% vs 5.4%, P less than .0001), despite 23% of the patients who underwent an orthopedic surgery reporting previous OSA, compared with 50% of those who underwent surgery in the bariatric category.
This difference in previously reported OSA, according to Dr. Lyons and her colleagues, shows another example of the need for sMVAP in non–bariatric surgery preoperative procedure as a way to catch potentially undiagnosed OSA.
“[W]ork by Penn Bariatrics suggests that it is logical that the benefits of rigorous preoperative screening and diagnosis for OSA followed by a tailored team approach toward ensuring compliance toward treatment postoperation ... may be effective in limiting the likelihood of select postoperative complications,” the researchers wrote.
With 9.3% of all patients diagnosed with OSA, and a projected 14%-47% increase in specialty surgeries, there is an urgency in implementation of sMVAP and in conducting further studies, they noted.
This test was limited by the sample population, primarily male commercial truck drivers, the researchers noted. In addition, misclassification of OSA based on weight may have occurred in up to 20% of normal weight patients. Finally, data were collected from one hospital network, so generalizability may be limited.
Dr. M. Melanie Lyons and Dr. Junxin Li, another of the study’s authors, receive grants from the National Institutes of Health. The other authors reported no relevant disclosures.
High scores on the symptomless multivariable apnea prediction index (sMVAP) showed a strong correlation with increased risk for postsurgery complications, according to a study approved by the University of Pennsylvania, Philadelphia.
This validation helps assert the benefits of using the sMVAP as a tool to screen for obstructive sleep apnea (OSA) before elective inpatient surgeries, a test that is highly underutilized but very important, wrote M. Melanie Lyons, PhD, of the Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, and her colleagues.
“Most patients having elective surgery are not screened for obstructive sleep apnea, even though OSA is a risk factor for postoperative complications,” wrote Dr. Lyons and her colleagues. “We observe that sMVAP correlates with higher risk for OSA, hypertension, and select postoperative complications, particularly in non-bariatric groups without routine preoperative screening for OSA.”
In a retrospective study of 40,432 patients undergoing elective surgery, high sMVAP scores were strongly correlated with postoperative complications including longer hospital stays (OR = 1.83), stays in the ICU (OR = 1.44), and respiratory complications (OR = 1.85) according to the researchers (Sleep. 2017 Jan 6. doi: 10.1093/sleep/zsw081).
Researchers separated participants into 10 categories according to the type of procedure: bariatric, orthopedic, cardiac, gastrointestinal, genitourinary, neurological, otorhinolaryngology/oral-maxillofacial/ear-nose-throat, pulmonary/thoracic, spine, and vascular.
The sMVAP calculates risk factors for OSA based on gender, age and body mass index, the researchers noted.
Those in the highest sMVAP score quintile were predominantly male (58%), with average age of 61 years, and average BMI of 40.9 kg/m2 (indicating morbid obesity). These patients reported the highest prevalence of having been previously diagnosed with OSA (26%). Comparatively, those patients in the lowest sMVAP quintile reported the lowest prevalence of an OSA diagnosis prior to undergoing their surgeries (9.3%).
Among non–bariatric surgery patients, those undergoing orthopedic procedures showed the highest correlation between complications and sMVAP scores.
The orthopedic surgery category reported a higher percentage of ICU-stay compared with bariatric surgery (14.3% vs 5.4%, P less than .0001), despite 23% of the patients who underwent an orthopedic surgery reporting previous OSA, compared with 50% of those who underwent surgery in the bariatric category.
This difference in previously reported OSA, according to Dr. Lyons and her colleagues, shows another example of the need for sMVAP in non–bariatric surgery preoperative procedure as a way to catch potentially undiagnosed OSA.
“[W]ork by Penn Bariatrics suggests that it is logical that the benefits of rigorous preoperative screening and diagnosis for OSA followed by a tailored team approach toward ensuring compliance toward treatment postoperation ... may be effective in limiting the likelihood of select postoperative complications,” the researchers wrote.
With 9.3% of all patients diagnosed with OSA, and a projected 14%-47% increase in specialty surgeries, there is an urgency in implementation of sMVAP and in conducting further studies, they noted.
This test was limited by the sample population, primarily male commercial truck drivers, the researchers noted. In addition, misclassification of OSA based on weight may have occurred in up to 20% of normal weight patients. Finally, data were collected from one hospital network, so generalizability may be limited.
Dr. M. Melanie Lyons and Dr. Junxin Li, another of the study’s authors, receive grants from the National Institutes of Health. The other authors reported no relevant disclosures.
High scores on the symptomless multivariable apnea prediction index (sMVAP) showed a strong correlation with increased risk for postsurgery complications, according to a study approved by the University of Pennsylvania, Philadelphia.
This validation helps assert the benefits of using the sMVAP as a tool to screen for obstructive sleep apnea (OSA) before elective inpatient surgeries, a test that is highly underutilized but very important, wrote M. Melanie Lyons, PhD, of the Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, and her colleagues.
“Most patients having elective surgery are not screened for obstructive sleep apnea, even though OSA is a risk factor for postoperative complications,” wrote Dr. Lyons and her colleagues. “We observe that sMVAP correlates with higher risk for OSA, hypertension, and select postoperative complications, particularly in non-bariatric groups without routine preoperative screening for OSA.”
In a retrospective study of 40,432 patients undergoing elective surgery, high sMVAP scores were strongly correlated with postoperative complications including longer hospital stays (OR = 1.83), stays in the ICU (OR = 1.44), and respiratory complications (OR = 1.85) according to the researchers (Sleep. 2017 Jan 6. doi: 10.1093/sleep/zsw081).
Researchers separated participants into 10 categories according to the type of procedure: bariatric, orthopedic, cardiac, gastrointestinal, genitourinary, neurological, otorhinolaryngology/oral-maxillofacial/ear-nose-throat, pulmonary/thoracic, spine, and vascular.
The sMVAP calculates risk factors for OSA based on gender, age and body mass index, the researchers noted.
Those in the highest sMVAP score quintile were predominantly male (58%), with average age of 61 years, and average BMI of 40.9 kg/m2 (indicating morbid obesity). These patients reported the highest prevalence of having been previously diagnosed with OSA (26%). Comparatively, those patients in the lowest sMVAP quintile reported the lowest prevalence of an OSA diagnosis prior to undergoing their surgeries (9.3%).
Among non–bariatric surgery patients, those undergoing orthopedic procedures showed the highest correlation between complications and sMVAP scores.
The orthopedic surgery category reported a higher percentage of ICU-stay compared with bariatric surgery (14.3% vs 5.4%, P less than .0001), despite 23% of the patients who underwent an orthopedic surgery reporting previous OSA, compared with 50% of those who underwent surgery in the bariatric category.
This difference in previously reported OSA, according to Dr. Lyons and her colleagues, shows another example of the need for sMVAP in non–bariatric surgery preoperative procedure as a way to catch potentially undiagnosed OSA.
“[W]ork by Penn Bariatrics suggests that it is logical that the benefits of rigorous preoperative screening and diagnosis for OSA followed by a tailored team approach toward ensuring compliance toward treatment postoperation ... may be effective in limiting the likelihood of select postoperative complications,” the researchers wrote.
With 9.3% of all patients diagnosed with OSA, and a projected 14%-47% increase in specialty surgeries, there is an urgency in implementation of sMVAP and in conducting further studies, they noted.
This test was limited by the sample population, primarily male commercial truck drivers, the researchers noted. In addition, misclassification of OSA based on weight may have occurred in up to 20% of normal weight patients. Finally, data were collected from one hospital network, so generalizability may be limited.
Dr. M. Melanie Lyons and Dr. Junxin Li, another of the study’s authors, receive grants from the National Institutes of Health. The other authors reported no relevant disclosures.
FROM SLEEP
Key clinical point:
Major finding: Patients with high sMVAP scores had increased odds of complications, including extended length of stay (OR = 1.83), ICU stay (OR = 1.44), and respiratory complications (OR = 1.85).
Data source: Retrospective study of 40,432 elective surgery patient records collected from the Hospital of University of Pennsylvania, Pennsylvania Hospital, and Penn Presbyterian Medical Center between July 1, 2011, and June 30, 2014.
Disclosures: Dr. M. Melanie Lyons and Dr. Junxin Li receive grants from the National Institutes of Health. Other authors reported no relevant financial disclosures.
Procalcitonin guidance improves antibiotic stewardship
The case
A 72-year-old male with COPD presents to the emergency department with increased dyspnea and cough. He is afebrile, and oxygen saturation is 87% on room air. WBC count is 9.5 with a normal differential, and chest x-ray is read by the radiologist as atelectasis versus early consolidation in the left lower lobe. Should antibiotics be initiated?
Background
The problem: Antibiotic overuse
With the increasing prevalence of antibiotic resistance in our nation’s hospitals, the need for robust antibiotic stewardship programs has continued to rise in importance. In 2016, the CDC reported a fatal case of septic shock due to a carbapenem-resistant strain of Klebsiella resistant to all tested antibiotics.1 This case received much media coverage; moreover, this patient represented only one of the approximately 23,000 patients infected with antibiotic-resistant bacteria in the United States who die each year. Although various approaches to curbing antibiotic resistance are being pursued, judicious antibiotic use is central to success. Current evidence suggests that up to 30% of antibiotics are not optimally prescribed,2 leaving a significant opportunity for improvement.
Lower respiratory infections account for a substantial proportion of antibiotic utilization in the United States. In a recent study, acute respiratory conditions generated 221 antibiotic prescriptions per 1,000 population, but only half of these were deemed appropriate.2 The inability to reliably discern viral from bacterial etiology is a driver of excess antibiotic use.
The procalcitonin assay has been touted as a possible solution to this problem. Multiple studies have evaluated its utility as a tool to help discriminate between bacterial infection and viral or noninfectious etiologies.
What is procalcitonin?
Thyroidal c-cells convert the prohormone procalcitonin to calcitonin, which is stored in secretory granules for release in response to fluctuations in calcium levels via a classical neuroendocrine feedback loop. Alternatively, procalcitonin can be synthesized in nonthyroidal parenchymal cells, and high levels of proinflammatory mediators secreted in response to bacterial endotoxin drive increased procalcitonin production. Interestingly, interferon gamma, up-regulated in viral infections, reduces procalcitonin production. Nonthyroidal parenchymal cells lack mechanisms for efficient conversion of procalcitonin to calcitonin and do not contain secretory granules to facilitate its regulated release. Hence bacterial infections correlate with higher serum procalcitonin levels.3
Evidence
Can procalcitonin guide antibiotic therapy in patients with acute respiratory illness while reducing antibiotic utilization?
The ability of procalcitonin to selectively identify bacterial infection makes it a potentially promising tool to advance the antibiotic stewardship agenda. Multiple randomized controlled trials have explored the use of procalcitonin-guided antibiotic therapy for treatment of lower respiratory tract infections such as acute bronchitis, exacerbations of COPD, and pneumonia. Each study discussed below was done in Switzerland, involved the same key investigator (Mirjam Christ-Crain, MD, PhD), and shared a similar design in which a threshold for low procalcitonin values (less than 0.1 mcg/L) and high procalcitonin values (greater than 0.25 mcg/L) was prespecified. Antibiotic therapy was strongly discouraged for patients with low procalcitonin and encouraged for those with high procalcitonin; antibiotics were not recommended for patients with intermediate values, but the treating physician was allowed ultimate discretion (Figure 1). All studies compared a procalcitonin-guided treatment group to a standard care group, in which antibiotics were prescribed by the treating physician based on established clinical guidelines.
Figure 1. Procalcitonin treatment algorithm
Procalcitonin Level (mcg/L) | Likelihood of bacterial infection | Antibiotic treatment |
less than 0.1 | Absent | Strongly discouraged |
0.1-0.25 | Unlikely | Discouraged |
0.25-0.5 | Possible | Encouraged |
greater than 0.5 | Present | Strongly encouraged |
Figure 1. Procalcitonin treatment algorithm
In a study focusing on outpatients presenting to their primary care physicians with acute respiratory tract infection, 53 primary care physicians in Switzerland recruited 458 patients. There was no significant difference in time to symptom resolution, as determined by patient report during an interview 14 days after initial presentation; however, 97% of patients in the standard-care group received antibiotics, compared with 25% in the procalcitonin-guided group. Equal numbers of patients (30% in each group) reported persistent symptoms at 28-day follow-up. Among the cohort of patients with upper respiratory infections or acute bronchitis, procalcitonin guidance reduced antibiotic prescriptions by 80%.4
In a blinded, single-center, randomized, controlled trial of 226 patients presenting to a university hospital with a COPD exacerbation severe enough to require a change in the baseline medication regimen, procalcitonin-guided therapy allowed for an absolute reduction of antibiotic use by 32% without an impact on outcomes. Rates of clinical improvement, ICU utilization, recurrent exacerbations, hospital length of stay, and mortality did not differ between the groups.5
Limitations include the possible impact of the Hawthorne effect, as physicians knew their antibiotic usage patterns were being monitored, which may impact generalizability of the findings to a real-world setting. Similarly, it is difficult to control for a spillover effect as providers exposed to the procalcitonin-guided algorithm became more comfortable with a restrictive prescribing approach. The costs of the additional procalcitonin assay must be weighed against the benefits. Incidence and cost of other adverse effects of antibiotic use (rates of Clostridium difficile, renal insufficiency, urticarial drug eruptions, etc.) were not addressed. The rapid assay currently has limited availability in the United States, though that is changing. Finally, recent additional studies (unrelated to procalcitonin) have suggested shorter antibiotic treatment durations for patients with pneumonia.8
Is there evidence for using procalcitonin to guide treatment in the broader population of ICU patients?
While there is good evidence for using procalcitonin to guide antibiotic use in patients with acute respiratory illness, the evidence for using procalcitonin in the broader cohort of critically-ill patients with sepsis is less well established.
The most promising results were reported by the Stop Antibiotics on Procalcitonin guidance Study (SAPS). Published in July 2016, this was a prospective, multicenter, randomized, controlled, open-label study of patients admitted to the ICU (not limited to respiratory illness) in the Netherlands. A total of 1,575 patients were assigned to the procalcitonin-guided group or the standard-of-care group. In the procalcitonin-guided group, procalcitonin levels were checked daily, and physicians were given nonbinding advice to discontinue antibiotics if procalcitonin levels decreased by greater than 80% from peak levels or to below 0.5 mcg/L.
Patients received an average of 7.5 daily defined antibiotic doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group (P less than .0001). The median duration of antibiotic treatment in the procalcitonin arm was 5 days versus 7 days in the control group (P less than .0001). Mortality at 28 days was 20% in the procalcitonin group and 25% in the control group (P = .0122). At 1 year, mortality was 36% in the procalcitonin group and 43% in the control group (P = .0188). The authors hypothesized that the unexpected decrease in mortality in the procalcitonin group may have been due to earlier consideration of alternate illness etiologies in patients with a low procalcitonin level or decreased antibiotic side effects.9While the SAPS trial supports decreased antibiotic usage in ICU patients with the use of the procalcitonin assay, there are some important limitations. First, the trial was done in the Netherlands, where baseline antibiotic usage was comparatively low. Second, daily procalcitonin level monitoring was not continued for patients transferred out of the ICU while still on antibiotics. Further, guidelines for antibiotic discontinuation were nonbinding, and in many cases physicians did not stop antibiotics based on procalcitonin guidelines suggested by the study authors.
Earlier trials regarding the procalcitonin assay in the critical care setting similarly showed some promise but also concerns. One trial reported a 25% reduction in antibiotic exposure and noninferiority of 28-day mortality, but there was a nonsignificant 3.8% absolute increase in mortality at 60 days.10 Another trial reported similar survival in the procalcitonin group but more side effects and longer ICU stays.11Ultimately, while the SAPS trial supports the potential use of procalcitonin in critically-ill patients, these patients likely have complex sepsis physiology that requires clinicians to consider a number of clinical factors when making antibiotic decisions.
Back to the case
The case illustrates a common emergency department presentation where clinical and radiographic features are not convincing for bacterial infection. This patient has an acute respiratory illness, but is afebrile and lacks leukocytosis with left shift, and x-rays are indeterminate for pneumonia. The differential diagnosis also includes COPD exacerbation, viral infection, or noninfectious triggers of dyspnea.
In this scenario, obtaining procalcitonin levels is useful in the decision to initiate or withhold antibiotic treatment. An elevated procalcitonin level suggests a bacterial infection and would favor initiation of antibiotics for pneumonia. A low procalcitonin level makes a bacterial infection less likely, and a clinician may consider withholding antibiotics and consider alternate etiologies for the patient’s presentation.
Bottom line
Procalcitonin can be safely used to guide the decision to initiate antibiotics in patients presenting with acute respiratory illness. Use of the procalcitonin assay has been shown to reduce antibiotic utilization without an increase in adverse outcomes. There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
Bryan J. Huang, MD, FHM, and Gregory B. Seymann, MD, SFHM, are in the division of hospital medicine, University of California, San Diego.
- Key Points
- Elevated procalcitonin levels suggest the presence of bacterial infection.
- In patients presenting with acute respiratory illness, procalcitonin levels can be used to guide the decision to initiate or withhold antibiotics, improving antibiotic stewardship.
- Sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy.
- There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
References
1. Chen L, Todd R, Kiehlbauch J, Walters M, Kallen A. Notes from the field: pan-resistant New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae – Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017; 66(1):33.
2. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016;315(17):1864-73.
3. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31-32):451-60.
4. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs. a standard approach for acute respiratory tract infections in primary care. Arch Intern Med. 2008; 168(18): 2000-7.
5. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131(1): 9-19.
6. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174(1):84-93.
7. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302(10): 1059-66.
8. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-65.
9. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
10. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74.
11. Jensen J-U, Lundgren B, Hein L, et al. The procalcitonin and survival study (PASS) – a randomised multicenter investigator-initiated trial to investigate whether daily measurements biomarker procalcitonin and proactive diagnostic and therapeutic responses to abnormal procalcitonin levels, can improve survival in intensive care unit patients. BMC infectious diseases. 2008;8:91-100.
1. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66.
2. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;(9):CD007498.
The case
A 72-year-old male with COPD presents to the emergency department with increased dyspnea and cough. He is afebrile, and oxygen saturation is 87% on room air. WBC count is 9.5 with a normal differential, and chest x-ray is read by the radiologist as atelectasis versus early consolidation in the left lower lobe. Should antibiotics be initiated?
Background
The problem: Antibiotic overuse
With the increasing prevalence of antibiotic resistance in our nation’s hospitals, the need for robust antibiotic stewardship programs has continued to rise in importance. In 2016, the CDC reported a fatal case of septic shock due to a carbapenem-resistant strain of Klebsiella resistant to all tested antibiotics.1 This case received much media coverage; moreover, this patient represented only one of the approximately 23,000 patients infected with antibiotic-resistant bacteria in the United States who die each year. Although various approaches to curbing antibiotic resistance are being pursued, judicious antibiotic use is central to success. Current evidence suggests that up to 30% of antibiotics are not optimally prescribed,2 leaving a significant opportunity for improvement.
Lower respiratory infections account for a substantial proportion of antibiotic utilization in the United States. In a recent study, acute respiratory conditions generated 221 antibiotic prescriptions per 1,000 population, but only half of these were deemed appropriate.2 The inability to reliably discern viral from bacterial etiology is a driver of excess antibiotic use.
The procalcitonin assay has been touted as a possible solution to this problem. Multiple studies have evaluated its utility as a tool to help discriminate between bacterial infection and viral or noninfectious etiologies.
What is procalcitonin?
Thyroidal c-cells convert the prohormone procalcitonin to calcitonin, which is stored in secretory granules for release in response to fluctuations in calcium levels via a classical neuroendocrine feedback loop. Alternatively, procalcitonin can be synthesized in nonthyroidal parenchymal cells, and high levels of proinflammatory mediators secreted in response to bacterial endotoxin drive increased procalcitonin production. Interestingly, interferon gamma, up-regulated in viral infections, reduces procalcitonin production. Nonthyroidal parenchymal cells lack mechanisms for efficient conversion of procalcitonin to calcitonin and do not contain secretory granules to facilitate its regulated release. Hence bacterial infections correlate with higher serum procalcitonin levels.3
Evidence
Can procalcitonin guide antibiotic therapy in patients with acute respiratory illness while reducing antibiotic utilization?
The ability of procalcitonin to selectively identify bacterial infection makes it a potentially promising tool to advance the antibiotic stewardship agenda. Multiple randomized controlled trials have explored the use of procalcitonin-guided antibiotic therapy for treatment of lower respiratory tract infections such as acute bronchitis, exacerbations of COPD, and pneumonia. Each study discussed below was done in Switzerland, involved the same key investigator (Mirjam Christ-Crain, MD, PhD), and shared a similar design in which a threshold for low procalcitonin values (less than 0.1 mcg/L) and high procalcitonin values (greater than 0.25 mcg/L) was prespecified. Antibiotic therapy was strongly discouraged for patients with low procalcitonin and encouraged for those with high procalcitonin; antibiotics were not recommended for patients with intermediate values, but the treating physician was allowed ultimate discretion (Figure 1). All studies compared a procalcitonin-guided treatment group to a standard care group, in which antibiotics were prescribed by the treating physician based on established clinical guidelines.
Figure 1. Procalcitonin treatment algorithm
Procalcitonin Level (mcg/L) | Likelihood of bacterial infection | Antibiotic treatment |
less than 0.1 | Absent | Strongly discouraged |
0.1-0.25 | Unlikely | Discouraged |
0.25-0.5 | Possible | Encouraged |
greater than 0.5 | Present | Strongly encouraged |
Figure 1. Procalcitonin treatment algorithm
In a study focusing on outpatients presenting to their primary care physicians with acute respiratory tract infection, 53 primary care physicians in Switzerland recruited 458 patients. There was no significant difference in time to symptom resolution, as determined by patient report during an interview 14 days after initial presentation; however, 97% of patients in the standard-care group received antibiotics, compared with 25% in the procalcitonin-guided group. Equal numbers of patients (30% in each group) reported persistent symptoms at 28-day follow-up. Among the cohort of patients with upper respiratory infections or acute bronchitis, procalcitonin guidance reduced antibiotic prescriptions by 80%.4
In a blinded, single-center, randomized, controlled trial of 226 patients presenting to a university hospital with a COPD exacerbation severe enough to require a change in the baseline medication regimen, procalcitonin-guided therapy allowed for an absolute reduction of antibiotic use by 32% without an impact on outcomes. Rates of clinical improvement, ICU utilization, recurrent exacerbations, hospital length of stay, and mortality did not differ between the groups.5
Limitations include the possible impact of the Hawthorne effect, as physicians knew their antibiotic usage patterns were being monitored, which may impact generalizability of the findings to a real-world setting. Similarly, it is difficult to control for a spillover effect as providers exposed to the procalcitonin-guided algorithm became more comfortable with a restrictive prescribing approach. The costs of the additional procalcitonin assay must be weighed against the benefits. Incidence and cost of other adverse effects of antibiotic use (rates of Clostridium difficile, renal insufficiency, urticarial drug eruptions, etc.) were not addressed. The rapid assay currently has limited availability in the United States, though that is changing. Finally, recent additional studies (unrelated to procalcitonin) have suggested shorter antibiotic treatment durations for patients with pneumonia.8
Is there evidence for using procalcitonin to guide treatment in the broader population of ICU patients?
While there is good evidence for using procalcitonin to guide antibiotic use in patients with acute respiratory illness, the evidence for using procalcitonin in the broader cohort of critically-ill patients with sepsis is less well established.
The most promising results were reported by the Stop Antibiotics on Procalcitonin guidance Study (SAPS). Published in July 2016, this was a prospective, multicenter, randomized, controlled, open-label study of patients admitted to the ICU (not limited to respiratory illness) in the Netherlands. A total of 1,575 patients were assigned to the procalcitonin-guided group or the standard-of-care group. In the procalcitonin-guided group, procalcitonin levels were checked daily, and physicians were given nonbinding advice to discontinue antibiotics if procalcitonin levels decreased by greater than 80% from peak levels or to below 0.5 mcg/L.
Patients received an average of 7.5 daily defined antibiotic doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group (P less than .0001). The median duration of antibiotic treatment in the procalcitonin arm was 5 days versus 7 days in the control group (P less than .0001). Mortality at 28 days was 20% in the procalcitonin group and 25% in the control group (P = .0122). At 1 year, mortality was 36% in the procalcitonin group and 43% in the control group (P = .0188). The authors hypothesized that the unexpected decrease in mortality in the procalcitonin group may have been due to earlier consideration of alternate illness etiologies in patients with a low procalcitonin level or decreased antibiotic side effects.9While the SAPS trial supports decreased antibiotic usage in ICU patients with the use of the procalcitonin assay, there are some important limitations. First, the trial was done in the Netherlands, where baseline antibiotic usage was comparatively low. Second, daily procalcitonin level monitoring was not continued for patients transferred out of the ICU while still on antibiotics. Further, guidelines for antibiotic discontinuation were nonbinding, and in many cases physicians did not stop antibiotics based on procalcitonin guidelines suggested by the study authors.
Earlier trials regarding the procalcitonin assay in the critical care setting similarly showed some promise but also concerns. One trial reported a 25% reduction in antibiotic exposure and noninferiority of 28-day mortality, but there was a nonsignificant 3.8% absolute increase in mortality at 60 days.10 Another trial reported similar survival in the procalcitonin group but more side effects and longer ICU stays.11Ultimately, while the SAPS trial supports the potential use of procalcitonin in critically-ill patients, these patients likely have complex sepsis physiology that requires clinicians to consider a number of clinical factors when making antibiotic decisions.
Back to the case
The case illustrates a common emergency department presentation where clinical and radiographic features are not convincing for bacterial infection. This patient has an acute respiratory illness, but is afebrile and lacks leukocytosis with left shift, and x-rays are indeterminate for pneumonia. The differential diagnosis also includes COPD exacerbation, viral infection, or noninfectious triggers of dyspnea.
In this scenario, obtaining procalcitonin levels is useful in the decision to initiate or withhold antibiotic treatment. An elevated procalcitonin level suggests a bacterial infection and would favor initiation of antibiotics for pneumonia. A low procalcitonin level makes a bacterial infection less likely, and a clinician may consider withholding antibiotics and consider alternate etiologies for the patient’s presentation.
Bottom line
Procalcitonin can be safely used to guide the decision to initiate antibiotics in patients presenting with acute respiratory illness. Use of the procalcitonin assay has been shown to reduce antibiotic utilization without an increase in adverse outcomes. There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
Bryan J. Huang, MD, FHM, and Gregory B. Seymann, MD, SFHM, are in the division of hospital medicine, University of California, San Diego.
- Key Points
- Elevated procalcitonin levels suggest the presence of bacterial infection.
- In patients presenting with acute respiratory illness, procalcitonin levels can be used to guide the decision to initiate or withhold antibiotics, improving antibiotic stewardship.
- Sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy.
- There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
References
1. Chen L, Todd R, Kiehlbauch J, Walters M, Kallen A. Notes from the field: pan-resistant New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae – Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017; 66(1):33.
2. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016;315(17):1864-73.
3. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31-32):451-60.
4. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs. a standard approach for acute respiratory tract infections in primary care. Arch Intern Med. 2008; 168(18): 2000-7.
5. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131(1): 9-19.
6. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174(1):84-93.
7. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302(10): 1059-66.
8. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-65.
9. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
10. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74.
11. Jensen J-U, Lundgren B, Hein L, et al. The procalcitonin and survival study (PASS) – a randomised multicenter investigator-initiated trial to investigate whether daily measurements biomarker procalcitonin and proactive diagnostic and therapeutic responses to abnormal procalcitonin levels, can improve survival in intensive care unit patients. BMC infectious diseases. 2008;8:91-100.
1. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66.
2. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;(9):CD007498.
The case
A 72-year-old male with COPD presents to the emergency department with increased dyspnea and cough. He is afebrile, and oxygen saturation is 87% on room air. WBC count is 9.5 with a normal differential, and chest x-ray is read by the radiologist as atelectasis versus early consolidation in the left lower lobe. Should antibiotics be initiated?
Background
The problem: Antibiotic overuse
With the increasing prevalence of antibiotic resistance in our nation’s hospitals, the need for robust antibiotic stewardship programs has continued to rise in importance. In 2016, the CDC reported a fatal case of septic shock due to a carbapenem-resistant strain of Klebsiella resistant to all tested antibiotics.1 This case received much media coverage; moreover, this patient represented only one of the approximately 23,000 patients infected with antibiotic-resistant bacteria in the United States who die each year. Although various approaches to curbing antibiotic resistance are being pursued, judicious antibiotic use is central to success. Current evidence suggests that up to 30% of antibiotics are not optimally prescribed,2 leaving a significant opportunity for improvement.
Lower respiratory infections account for a substantial proportion of antibiotic utilization in the United States. In a recent study, acute respiratory conditions generated 221 antibiotic prescriptions per 1,000 population, but only half of these were deemed appropriate.2 The inability to reliably discern viral from bacterial etiology is a driver of excess antibiotic use.
The procalcitonin assay has been touted as a possible solution to this problem. Multiple studies have evaluated its utility as a tool to help discriminate between bacterial infection and viral or noninfectious etiologies.
What is procalcitonin?
Thyroidal c-cells convert the prohormone procalcitonin to calcitonin, which is stored in secretory granules for release in response to fluctuations in calcium levels via a classical neuroendocrine feedback loop. Alternatively, procalcitonin can be synthesized in nonthyroidal parenchymal cells, and high levels of proinflammatory mediators secreted in response to bacterial endotoxin drive increased procalcitonin production. Interestingly, interferon gamma, up-regulated in viral infections, reduces procalcitonin production. Nonthyroidal parenchymal cells lack mechanisms for efficient conversion of procalcitonin to calcitonin and do not contain secretory granules to facilitate its regulated release. Hence bacterial infections correlate with higher serum procalcitonin levels.3
Evidence
Can procalcitonin guide antibiotic therapy in patients with acute respiratory illness while reducing antibiotic utilization?
The ability of procalcitonin to selectively identify bacterial infection makes it a potentially promising tool to advance the antibiotic stewardship agenda. Multiple randomized controlled trials have explored the use of procalcitonin-guided antibiotic therapy for treatment of lower respiratory tract infections such as acute bronchitis, exacerbations of COPD, and pneumonia. Each study discussed below was done in Switzerland, involved the same key investigator (Mirjam Christ-Crain, MD, PhD), and shared a similar design in which a threshold for low procalcitonin values (less than 0.1 mcg/L) and high procalcitonin values (greater than 0.25 mcg/L) was prespecified. Antibiotic therapy was strongly discouraged for patients with low procalcitonin and encouraged for those with high procalcitonin; antibiotics were not recommended for patients with intermediate values, but the treating physician was allowed ultimate discretion (Figure 1). All studies compared a procalcitonin-guided treatment group to a standard care group, in which antibiotics were prescribed by the treating physician based on established clinical guidelines.
Figure 1. Procalcitonin treatment algorithm
Procalcitonin Level (mcg/L) | Likelihood of bacterial infection | Antibiotic treatment |
less than 0.1 | Absent | Strongly discouraged |
0.1-0.25 | Unlikely | Discouraged |
0.25-0.5 | Possible | Encouraged |
greater than 0.5 | Present | Strongly encouraged |
Figure 1. Procalcitonin treatment algorithm
In a study focusing on outpatients presenting to their primary care physicians with acute respiratory tract infection, 53 primary care physicians in Switzerland recruited 458 patients. There was no significant difference in time to symptom resolution, as determined by patient report during an interview 14 days after initial presentation; however, 97% of patients in the standard-care group received antibiotics, compared with 25% in the procalcitonin-guided group. Equal numbers of patients (30% in each group) reported persistent symptoms at 28-day follow-up. Among the cohort of patients with upper respiratory infections or acute bronchitis, procalcitonin guidance reduced antibiotic prescriptions by 80%.4
In a blinded, single-center, randomized, controlled trial of 226 patients presenting to a university hospital with a COPD exacerbation severe enough to require a change in the baseline medication regimen, procalcitonin-guided therapy allowed for an absolute reduction of antibiotic use by 32% without an impact on outcomes. Rates of clinical improvement, ICU utilization, recurrent exacerbations, hospital length of stay, and mortality did not differ between the groups.5
Limitations include the possible impact of the Hawthorne effect, as physicians knew their antibiotic usage patterns were being monitored, which may impact generalizability of the findings to a real-world setting. Similarly, it is difficult to control for a spillover effect as providers exposed to the procalcitonin-guided algorithm became more comfortable with a restrictive prescribing approach. The costs of the additional procalcitonin assay must be weighed against the benefits. Incidence and cost of other adverse effects of antibiotic use (rates of Clostridium difficile, renal insufficiency, urticarial drug eruptions, etc.) were not addressed. The rapid assay currently has limited availability in the United States, though that is changing. Finally, recent additional studies (unrelated to procalcitonin) have suggested shorter antibiotic treatment durations for patients with pneumonia.8
Is there evidence for using procalcitonin to guide treatment in the broader population of ICU patients?
While there is good evidence for using procalcitonin to guide antibiotic use in patients with acute respiratory illness, the evidence for using procalcitonin in the broader cohort of critically-ill patients with sepsis is less well established.
The most promising results were reported by the Stop Antibiotics on Procalcitonin guidance Study (SAPS). Published in July 2016, this was a prospective, multicenter, randomized, controlled, open-label study of patients admitted to the ICU (not limited to respiratory illness) in the Netherlands. A total of 1,575 patients were assigned to the procalcitonin-guided group or the standard-of-care group. In the procalcitonin-guided group, procalcitonin levels were checked daily, and physicians were given nonbinding advice to discontinue antibiotics if procalcitonin levels decreased by greater than 80% from peak levels or to below 0.5 mcg/L.
Patients received an average of 7.5 daily defined antibiotic doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group (P less than .0001). The median duration of antibiotic treatment in the procalcitonin arm was 5 days versus 7 days in the control group (P less than .0001). Mortality at 28 days was 20% in the procalcitonin group and 25% in the control group (P = .0122). At 1 year, mortality was 36% in the procalcitonin group and 43% in the control group (P = .0188). The authors hypothesized that the unexpected decrease in mortality in the procalcitonin group may have been due to earlier consideration of alternate illness etiologies in patients with a low procalcitonin level or decreased antibiotic side effects.9While the SAPS trial supports decreased antibiotic usage in ICU patients with the use of the procalcitonin assay, there are some important limitations. First, the trial was done in the Netherlands, where baseline antibiotic usage was comparatively low. Second, daily procalcitonin level monitoring was not continued for patients transferred out of the ICU while still on antibiotics. Further, guidelines for antibiotic discontinuation were nonbinding, and in many cases physicians did not stop antibiotics based on procalcitonin guidelines suggested by the study authors.
Earlier trials regarding the procalcitonin assay in the critical care setting similarly showed some promise but also concerns. One trial reported a 25% reduction in antibiotic exposure and noninferiority of 28-day mortality, but there was a nonsignificant 3.8% absolute increase in mortality at 60 days.10 Another trial reported similar survival in the procalcitonin group but more side effects and longer ICU stays.11Ultimately, while the SAPS trial supports the potential use of procalcitonin in critically-ill patients, these patients likely have complex sepsis physiology that requires clinicians to consider a number of clinical factors when making antibiotic decisions.
Back to the case
The case illustrates a common emergency department presentation where clinical and radiographic features are not convincing for bacterial infection. This patient has an acute respiratory illness, but is afebrile and lacks leukocytosis with left shift, and x-rays are indeterminate for pneumonia. The differential diagnosis also includes COPD exacerbation, viral infection, or noninfectious triggers of dyspnea.
In this scenario, obtaining procalcitonin levels is useful in the decision to initiate or withhold antibiotic treatment. An elevated procalcitonin level suggests a bacterial infection and would favor initiation of antibiotics for pneumonia. A low procalcitonin level makes a bacterial infection less likely, and a clinician may consider withholding antibiotics and consider alternate etiologies for the patient’s presentation.
Bottom line
Procalcitonin can be safely used to guide the decision to initiate antibiotics in patients presenting with acute respiratory illness. Use of the procalcitonin assay has been shown to reduce antibiotic utilization without an increase in adverse outcomes. There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
Bryan J. Huang, MD, FHM, and Gregory B. Seymann, MD, SFHM, are in the division of hospital medicine, University of California, San Diego.
- Key Points
- Elevated procalcitonin levels suggest the presence of bacterial infection.
- In patients presenting with acute respiratory illness, procalcitonin levels can be used to guide the decision to initiate or withhold antibiotics, improving antibiotic stewardship.
- Sequential monitoring of procalcitonin levels may help guide duration of antibiotic therapy.
- There is potential but less conclusive evidence for procalcitonin usage in the broader population of ICU patients with sepsis.
References
1. Chen L, Todd R, Kiehlbauch J, Walters M, Kallen A. Notes from the field: pan-resistant New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae – Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017; 66(1):33.
2. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016;315(17):1864-73.
3. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31-32):451-60.
4. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs. a standard approach for acute respiratory tract infections in primary care. Arch Intern Med. 2008; 168(18): 2000-7.
5. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131(1): 9-19.
6. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174(1):84-93.
7. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302(10): 1059-66.
8. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-65.
9. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
10. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74.
11. Jensen J-U, Lundgren B, Hein L, et al. The procalcitonin and survival study (PASS) – a randomised multicenter investigator-initiated trial to investigate whether daily measurements biomarker procalcitonin and proactive diagnostic and therapeutic responses to abnormal procalcitonin levels, can improve survival in intensive care unit patients. BMC infectious diseases. 2008;8:91-100.
1. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66.
2. de Jong E, van Oers JA, Beishiozen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;(9):CD007498.
Intervention may help stem weight gain tied to antipsychotics
SAN DIEGO – Extra pounds are a perennial problem for schizophrenia patients who take antipsychotic medications with weight-boosting side effects. Now, a new randomized study finds that veterans who took part in a 12-month behavioral intervention program performed better on weight-loss measurements than those in a control group.
The difference between the two groups was far from large, with those undergoing the intervention losing an average of 1.04 centimeters in waist circumference over a year, compared with an average gain of 0.25 centimeters in the control group (P less than .001).
A recent meta-analysis found that weight gain is a potential side effect from prolonged use of “virtually all” antipsychotic medications, especially in those who have not taken the drugs previously (PLoS One. 2014 Apr 24;9[4]:e94112).
“Some of the most effective medications are associated with the highest weight-gain liability,” Dr. Ames said in an interview, “and patients with medication-resistant psychosis who don’t want to gain weight will resist taking these medications.”
As the meta-analysis notes, research suggests that the weight gain prompted by antipsychotics may boost mortality risk in patients with severe mental illness. The metabolic havoc linked to schizophrenia may be another factor: A 2010 summary of research notes that newer second-generation antipsychotics “generally tend to cause more problems relating to metabolic syndrome, such as obesity and type 2 diabetes mellitus,” compared with first-generation antipsychotics (FGA).
Weight gain “can be rapid and difficult to control,” the summary authors write,” adding that “the effect is worse with clozapine and olanzapine; minimal with aripiprazole and ziprasidone; and intermediate with other antipsychotics, including low-potency FGAs” (Am Fam Physician. 2010 Mar 1;81[5]:617-22).
For the new study, researchers randomly assigned 121 overweight or obese subjects with serious mental illness to either a “lifestyle balance” (LB) program (n = 62) or a usual care (UC) program (n = 59). All had become obese while taking an antipsychotic.
Subjects in the LB program met with registered dietitians for individual health coaching, weekly for 8 weeks and then monthly for up to 10 months. They also took part in 16 group nutrition and exercise classes over 2 months.
The UC group, meanwhile, met with case managers weekly for 8 weeks and then monthly for up to 10 months. They answered health questionnaires, underwent weight checks, and received self-help materials, Dr. Ames reported at the International Congress on Schizophrenia Research.
All of the participants lost weight, although waist circumference only declined in the intervention group. Body fat percentage declined in both groups, but by more (0.4% vs. 0.2%) in the intervention group, compared with UC (P = .038).
Judging by food diaries kept by 92% of the intervention group participants, their average daily caloric intake declined from 2,055 to 1,650 (P less than 0.001). The UC participants did not keep food diaries, so their caloric intake isn’t available.
Shouldn’t the intervention participants have lost more weight in light of such a large caloric decline? “Not necessarily,” Dr. Ames said. “Participants who were successful at making dietary changes began making these changes at different times throughout the study, some early and some well into the yearlong study. Decreases made in the latter part of the study would result in less weight lost. Also, exercise activity was variable, so decreased caloric intake could be offset by decreased physical activity.”
Other findings: Women did better than men at losing weight, and reducing waist circumference and body fat. There wasn’t a significant difference in the level of exercise between the groups. And researchers linked psychiatric illness insight in the LB group to greater weight loss but not in the UC group.
The study is supported by a $1.9 million VA grant for research from 2010 to 2017, Dr. Ames said.
In regard to cost-effectiveness, she said “a psychiatrist, nurse, or other mental health professional could easily weave these interventions into the care of patients in mental health settings. And the cost savings to patients by even losing just a few pounds could be enormous.”
The researchers hope to examine whether the intervention reduces the cost of medications, emergency department visits, and hospitalizations, she said.
Dr. Ames reports no relevant disclosures.
SAN DIEGO – Extra pounds are a perennial problem for schizophrenia patients who take antipsychotic medications with weight-boosting side effects. Now, a new randomized study finds that veterans who took part in a 12-month behavioral intervention program performed better on weight-loss measurements than those in a control group.
The difference between the two groups was far from large, with those undergoing the intervention losing an average of 1.04 centimeters in waist circumference over a year, compared with an average gain of 0.25 centimeters in the control group (P less than .001).
A recent meta-analysis found that weight gain is a potential side effect from prolonged use of “virtually all” antipsychotic medications, especially in those who have not taken the drugs previously (PLoS One. 2014 Apr 24;9[4]:e94112).
“Some of the most effective medications are associated with the highest weight-gain liability,” Dr. Ames said in an interview, “and patients with medication-resistant psychosis who don’t want to gain weight will resist taking these medications.”
As the meta-analysis notes, research suggests that the weight gain prompted by antipsychotics may boost mortality risk in patients with severe mental illness. The metabolic havoc linked to schizophrenia may be another factor: A 2010 summary of research notes that newer second-generation antipsychotics “generally tend to cause more problems relating to metabolic syndrome, such as obesity and type 2 diabetes mellitus,” compared with first-generation antipsychotics (FGA).
Weight gain “can be rapid and difficult to control,” the summary authors write,” adding that “the effect is worse with clozapine and olanzapine; minimal with aripiprazole and ziprasidone; and intermediate with other antipsychotics, including low-potency FGAs” (Am Fam Physician. 2010 Mar 1;81[5]:617-22).
For the new study, researchers randomly assigned 121 overweight or obese subjects with serious mental illness to either a “lifestyle balance” (LB) program (n = 62) or a usual care (UC) program (n = 59). All had become obese while taking an antipsychotic.
Subjects in the LB program met with registered dietitians for individual health coaching, weekly for 8 weeks and then monthly for up to 10 months. They also took part in 16 group nutrition and exercise classes over 2 months.
The UC group, meanwhile, met with case managers weekly for 8 weeks and then monthly for up to 10 months. They answered health questionnaires, underwent weight checks, and received self-help materials, Dr. Ames reported at the International Congress on Schizophrenia Research.
All of the participants lost weight, although waist circumference only declined in the intervention group. Body fat percentage declined in both groups, but by more (0.4% vs. 0.2%) in the intervention group, compared with UC (P = .038).
Judging by food diaries kept by 92% of the intervention group participants, their average daily caloric intake declined from 2,055 to 1,650 (P less than 0.001). The UC participants did not keep food diaries, so their caloric intake isn’t available.
Shouldn’t the intervention participants have lost more weight in light of such a large caloric decline? “Not necessarily,” Dr. Ames said. “Participants who were successful at making dietary changes began making these changes at different times throughout the study, some early and some well into the yearlong study. Decreases made in the latter part of the study would result in less weight lost. Also, exercise activity was variable, so decreased caloric intake could be offset by decreased physical activity.”
Other findings: Women did better than men at losing weight, and reducing waist circumference and body fat. There wasn’t a significant difference in the level of exercise between the groups. And researchers linked psychiatric illness insight in the LB group to greater weight loss but not in the UC group.
The study is supported by a $1.9 million VA grant for research from 2010 to 2017, Dr. Ames said.
In regard to cost-effectiveness, she said “a psychiatrist, nurse, or other mental health professional could easily weave these interventions into the care of patients in mental health settings. And the cost savings to patients by even losing just a few pounds could be enormous.”
The researchers hope to examine whether the intervention reduces the cost of medications, emergency department visits, and hospitalizations, she said.
Dr. Ames reports no relevant disclosures.
SAN DIEGO – Extra pounds are a perennial problem for schizophrenia patients who take antipsychotic medications with weight-boosting side effects. Now, a new randomized study finds that veterans who took part in a 12-month behavioral intervention program performed better on weight-loss measurements than those in a control group.
The difference between the two groups was far from large, with those undergoing the intervention losing an average of 1.04 centimeters in waist circumference over a year, compared with an average gain of 0.25 centimeters in the control group (P less than .001).
A recent meta-analysis found that weight gain is a potential side effect from prolonged use of “virtually all” antipsychotic medications, especially in those who have not taken the drugs previously (PLoS One. 2014 Apr 24;9[4]:e94112).
“Some of the most effective medications are associated with the highest weight-gain liability,” Dr. Ames said in an interview, “and patients with medication-resistant psychosis who don’t want to gain weight will resist taking these medications.”
As the meta-analysis notes, research suggests that the weight gain prompted by antipsychotics may boost mortality risk in patients with severe mental illness. The metabolic havoc linked to schizophrenia may be another factor: A 2010 summary of research notes that newer second-generation antipsychotics “generally tend to cause more problems relating to metabolic syndrome, such as obesity and type 2 diabetes mellitus,” compared with first-generation antipsychotics (FGA).
Weight gain “can be rapid and difficult to control,” the summary authors write,” adding that “the effect is worse with clozapine and olanzapine; minimal with aripiprazole and ziprasidone; and intermediate with other antipsychotics, including low-potency FGAs” (Am Fam Physician. 2010 Mar 1;81[5]:617-22).
For the new study, researchers randomly assigned 121 overweight or obese subjects with serious mental illness to either a “lifestyle balance” (LB) program (n = 62) or a usual care (UC) program (n = 59). All had become obese while taking an antipsychotic.
Subjects in the LB program met with registered dietitians for individual health coaching, weekly for 8 weeks and then monthly for up to 10 months. They also took part in 16 group nutrition and exercise classes over 2 months.
The UC group, meanwhile, met with case managers weekly for 8 weeks and then monthly for up to 10 months. They answered health questionnaires, underwent weight checks, and received self-help materials, Dr. Ames reported at the International Congress on Schizophrenia Research.
All of the participants lost weight, although waist circumference only declined in the intervention group. Body fat percentage declined in both groups, but by more (0.4% vs. 0.2%) in the intervention group, compared with UC (P = .038).
Judging by food diaries kept by 92% of the intervention group participants, their average daily caloric intake declined from 2,055 to 1,650 (P less than 0.001). The UC participants did not keep food diaries, so their caloric intake isn’t available.
Shouldn’t the intervention participants have lost more weight in light of such a large caloric decline? “Not necessarily,” Dr. Ames said. “Participants who were successful at making dietary changes began making these changes at different times throughout the study, some early and some well into the yearlong study. Decreases made in the latter part of the study would result in less weight lost. Also, exercise activity was variable, so decreased caloric intake could be offset by decreased physical activity.”
Other findings: Women did better than men at losing weight, and reducing waist circumference and body fat. There wasn’t a significant difference in the level of exercise between the groups. And researchers linked psychiatric illness insight in the LB group to greater weight loss but not in the UC group.
The study is supported by a $1.9 million VA grant for research from 2010 to 2017, Dr. Ames said.
In regard to cost-effectiveness, she said “a psychiatrist, nurse, or other mental health professional could easily weave these interventions into the care of patients in mental health settings. And the cost savings to patients by even losing just a few pounds could be enormous.”
The researchers hope to examine whether the intervention reduces the cost of medications, emergency department visits, and hospitalizations, she said.
Dr. Ames reports no relevant disclosures.
AT THE ICSR BIENNIAL MEETING
Only some genes count in breast cancer panels
Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.
Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.
“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.
It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.
To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.
They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.
Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.
In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”
“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.
The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.
Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.
Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.
“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.
It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.
To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.
They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.
Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.
In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”
“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.
The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.
Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.
Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.
“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.
It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.
To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.
They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.
Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.
In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”
“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.
The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.
FROM JAMA ONCOLOGY
Key clinical point: Variants in 5 of 16 genes included in breast cancer panels were associated with increased risk.
Major finding: Germline variants in PALB2 were associated with a more than sevenfold greater risk for breast cancer, and four other variants were associated with moderate increases in risk.
Data source: Retrospective case control study of 65,057 women and a validation sample of 38,326 cases and 26,911 controls.
Disclosures: The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.
CHEST names Stephen J. Welch as EVP and CEO
The Board of Regents of the American College of Chest Physicians (CHEST) has finalized the appointment of Stephen J. Welch as executive vice president and chief executive officer.
“We appreciate the exceptional performance of Steve, his senior team, and the entire CHEST staff during this transition in executive leadership. We are excited about the opportunity to work with Steve in his new role going forward, as we begin outlining CHEST’s strategic plan for the next 5 years,” said CHEST President Gerard A. Silvestri, MD, MS, FCCP, in a statement.
The Board of Regents of the American College of Chest Physicians (CHEST) has finalized the appointment of Stephen J. Welch as executive vice president and chief executive officer.
“We appreciate the exceptional performance of Steve, his senior team, and the entire CHEST staff during this transition in executive leadership. We are excited about the opportunity to work with Steve in his new role going forward, as we begin outlining CHEST’s strategic plan for the next 5 years,” said CHEST President Gerard A. Silvestri, MD, MS, FCCP, in a statement.
The Board of Regents of the American College of Chest Physicians (CHEST) has finalized the appointment of Stephen J. Welch as executive vice president and chief executive officer.
“We appreciate the exceptional performance of Steve, his senior team, and the entire CHEST staff during this transition in executive leadership. We are excited about the opportunity to work with Steve in his new role going forward, as we begin outlining CHEST’s strategic plan for the next 5 years,” said CHEST President Gerard A. Silvestri, MD, MS, FCCP, in a statement.
VIDEO: Innovation fuels push toward therapeutic, safety advances in gastroenterology
BOSTON – In the next 5 years there is going to be a “huge swing” in gastroenterology to minimally invasive therapies, improved diagnostics, and additional therapeutics and disease management strategies that can be applied on an ambulatory basis and, perhaps, even in the office.
That’s the prediction of Michael L. Kochman, MD, AGAF, of the University of Pennsylvania, Philadelphia, who is the executive committee chair of the American Gastroenterological Association Center for GI Innovation and Technology. In a video interview conducted at the 2017 AGA Tech Summit, sponsored by the center, Dr. Kochman discussed five emerging trends in gastroenterology.
The trends include advances in endoscopic technologies and an expansion of the role of personalized medicine that would allow gastroenterologists to better target medications to individual patients. Office-based physicians will be able to evaluate patient risk for various diseases more easily through the use of stool or blood samples or cheek swabs and, then, steer toward additional tests for those found to be at high risk. Improvements in patient safety also are on the horizon, he said, as new technologies will provide earlier warning signs of failed therapies and potential complications.
Finally, as innovation continues in the area of minimally invasive surgery and transorifice surgery, “we need to look more and more to what we will end up calling organ-preserving surgeries, where we are able to treat just the area of pathology,” he noted. “We will be moving to leaving the patient without lasting scars and remembrances of having to have an organ removed.”
Dr. Kochman disclosed that he serves as a consultant to Boston Scientific and Dark Canyon Labs.
BOSTON – In the next 5 years there is going to be a “huge swing” in gastroenterology to minimally invasive therapies, improved diagnostics, and additional therapeutics and disease management strategies that can be applied on an ambulatory basis and, perhaps, even in the office.
That’s the prediction of Michael L. Kochman, MD, AGAF, of the University of Pennsylvania, Philadelphia, who is the executive committee chair of the American Gastroenterological Association Center for GI Innovation and Technology. In a video interview conducted at the 2017 AGA Tech Summit, sponsored by the center, Dr. Kochman discussed five emerging trends in gastroenterology.
The trends include advances in endoscopic technologies and an expansion of the role of personalized medicine that would allow gastroenterologists to better target medications to individual patients. Office-based physicians will be able to evaluate patient risk for various diseases more easily through the use of stool or blood samples or cheek swabs and, then, steer toward additional tests for those found to be at high risk. Improvements in patient safety also are on the horizon, he said, as new technologies will provide earlier warning signs of failed therapies and potential complications.
Finally, as innovation continues in the area of minimally invasive surgery and transorifice surgery, “we need to look more and more to what we will end up calling organ-preserving surgeries, where we are able to treat just the area of pathology,” he noted. “We will be moving to leaving the patient without lasting scars and remembrances of having to have an organ removed.”
Dr. Kochman disclosed that he serves as a consultant to Boston Scientific and Dark Canyon Labs.
BOSTON – In the next 5 years there is going to be a “huge swing” in gastroenterology to minimally invasive therapies, improved diagnostics, and additional therapeutics and disease management strategies that can be applied on an ambulatory basis and, perhaps, even in the office.
That’s the prediction of Michael L. Kochman, MD, AGAF, of the University of Pennsylvania, Philadelphia, who is the executive committee chair of the American Gastroenterological Association Center for GI Innovation and Technology. In a video interview conducted at the 2017 AGA Tech Summit, sponsored by the center, Dr. Kochman discussed five emerging trends in gastroenterology.
The trends include advances in endoscopic technologies and an expansion of the role of personalized medicine that would allow gastroenterologists to better target medications to individual patients. Office-based physicians will be able to evaluate patient risk for various diseases more easily through the use of stool or blood samples or cheek swabs and, then, steer toward additional tests for those found to be at high risk. Improvements in patient safety also are on the horizon, he said, as new technologies will provide earlier warning signs of failed therapies and potential complications.
Finally, as innovation continues in the area of minimally invasive surgery and transorifice surgery, “we need to look more and more to what we will end up calling organ-preserving surgeries, where we are able to treat just the area of pathology,” he noted. “We will be moving to leaving the patient without lasting scars and remembrances of having to have an organ removed.”
Dr. Kochman disclosed that he serves as a consultant to Boston Scientific and Dark Canyon Labs.
FROM THE 2017 AGA TECH SUMMIT
VIDEO: Five ‘revolutionary’ market forces poised to impact medical practice
BOSTON – Five “revolutionary” forces in medicine are going to impact patients and physicians, two health care consultants say, and the federal government will act either as a brake or an accelerator on those forces.
In a video interview conducted during the 2017 AGA Tech Summit, Patrick D. Pilch, managing director and national healthcare advisory leader at the BDO Center for Healthcare Excellence and Innovation, New York, and his colleague David B. Friend, MD, MBA, managing director and chief medical officer at the center, discussed these market forces and their potential effects on the practice of medicine.
One such force is the convergence of molecular biology and computer science, which will lead to the creation of new medical devices that use software and will require Food and Drug Administration approval, including devices that can remotely monitor patient compliance with taking medication. Some health care apps also would need FDA approval.
“Increasingly, health care will be mobile,” Dr. Friend continued. “The concept of the right care at the right place at the right time at the right cost is going to increase, and the ability to deliver this in the mobile setting is going to be very powerful.”
A change in who bears financial risk is another important driver. Insurance companies are decreasing their risk, Dr. Friend said, while health care providers and health systems are bearing more financial risk as they increasingly accept bundled payments and value-based payments. Physicians will need to understand and be prepared for this shift in risk, he warned.
Dr. Friend also noted a move toward an integrated supply chain model that will have “profound implications” throughout the delivery process and a movement of care away from the hospital to a nonhospital setting such as home care or skilled nursing facilities.
The summit was sponsored by the AGA Center for GI Innovation and Technology.
BOSTON – Five “revolutionary” forces in medicine are going to impact patients and physicians, two health care consultants say, and the federal government will act either as a brake or an accelerator on those forces.
In a video interview conducted during the 2017 AGA Tech Summit, Patrick D. Pilch, managing director and national healthcare advisory leader at the BDO Center for Healthcare Excellence and Innovation, New York, and his colleague David B. Friend, MD, MBA, managing director and chief medical officer at the center, discussed these market forces and their potential effects on the practice of medicine.
One such force is the convergence of molecular biology and computer science, which will lead to the creation of new medical devices that use software and will require Food and Drug Administration approval, including devices that can remotely monitor patient compliance with taking medication. Some health care apps also would need FDA approval.
“Increasingly, health care will be mobile,” Dr. Friend continued. “The concept of the right care at the right place at the right time at the right cost is going to increase, and the ability to deliver this in the mobile setting is going to be very powerful.”
A change in who bears financial risk is another important driver. Insurance companies are decreasing their risk, Dr. Friend said, while health care providers and health systems are bearing more financial risk as they increasingly accept bundled payments and value-based payments. Physicians will need to understand and be prepared for this shift in risk, he warned.
Dr. Friend also noted a move toward an integrated supply chain model that will have “profound implications” throughout the delivery process and a movement of care away from the hospital to a nonhospital setting such as home care or skilled nursing facilities.
The summit was sponsored by the AGA Center for GI Innovation and Technology.
BOSTON – Five “revolutionary” forces in medicine are going to impact patients and physicians, two health care consultants say, and the federal government will act either as a brake or an accelerator on those forces.
In a video interview conducted during the 2017 AGA Tech Summit, Patrick D. Pilch, managing director and national healthcare advisory leader at the BDO Center for Healthcare Excellence and Innovation, New York, and his colleague David B. Friend, MD, MBA, managing director and chief medical officer at the center, discussed these market forces and their potential effects on the practice of medicine.
One such force is the convergence of molecular biology and computer science, which will lead to the creation of new medical devices that use software and will require Food and Drug Administration approval, including devices that can remotely monitor patient compliance with taking medication. Some health care apps also would need FDA approval.
“Increasingly, health care will be mobile,” Dr. Friend continued. “The concept of the right care at the right place at the right time at the right cost is going to increase, and the ability to deliver this in the mobile setting is going to be very powerful.”
A change in who bears financial risk is another important driver. Insurance companies are decreasing their risk, Dr. Friend said, while health care providers and health systems are bearing more financial risk as they increasingly accept bundled payments and value-based payments. Physicians will need to understand and be prepared for this shift in risk, he warned.
Dr. Friend also noted a move toward an integrated supply chain model that will have “profound implications” throughout the delivery process and a movement of care away from the hospital to a nonhospital setting such as home care or skilled nursing facilities.
The summit was sponsored by the AGA Center for GI Innovation and Technology.
EXPERT ANALYSIS FROM THE AGA 2017 TECH SUMMIT
