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Fecal microbiota transplant designated a biologic, requiring IND status
BETHESDA, MD. – The Food and Drug Administration has designated stool for transplant as a biologic drug, necessitating that any gastroenterologist performing fecal microbiota transplants obtain an Investigational New Drug permit.
By designating stool for transplant as a biologic drug, anyone who performs fecal microbiota transplants (FMTs) – whether they perform a single transplant for one patient or recruit dozens for a study – needs to have an IND permit.
The announcement was made at a 2-day public workshop convened by the National Institutes of Health and the Food and Drug Administration to sift through some of the evidence surrounding FMTs.
The intent of the IND requirement, said Dr. Jay Slater, director of FDA’s Division of Bacterial, Parasitic, and Allergenic Products, is not to stamp out the care that patients can now receive, but to make sure it’s safe, effective, and data driven.
"This is a low-tech procedure that already has a CPT code. A ‘how-to’ guide recently appeared online, and it walks you right through how to do the procedure. There are a very large number of people doing this off the grid. What we need are long-term controlled trials on this that will enhance our understanding of its safety and efficacy."
Although neither the biologic designation nor the IND requirement is brand new, they have not been well publicized, according to one of the innovators of FMT, Dr. Lawrence Brandt, of Albert Einstein Medical Center in New York.
"I am struck by the fact that FDA wants these INDs and yet FDA has never publicly set forth any message on it. So from this moment on, all of us who continue to do this without an IND are violating FDA’s policy," he said at the meeting.
One of the primary concerns now, according to Dr. Brandt, is a burgeoning public interest in FMTs, even to the point of do-it-yourself treatments. With online instructions for self-treatment, and a procedure that is rife with variations, regulators can no longer tacitly ignore the issue.
There’s no standardization of how the stool is prepared and filtered – it could be blended in a kitchen blender or by hand with a tongue depressor, or strained through gauze or a coffee filter, he said. Dosing is all over the place, listed as spoonfuls, grams, and milliliters. Different institutions screen donors in different ways. Some patients get a bowel prep, which can be mild or aggressive, and some don’t get one at all. Should the stool be fresh, and if so, how fresh? Is frozen okay? These are all issues that need to be examined from a safety and efficacy perspective and standardized.
Even the method of delivery varies. The transplant can be administered via nasogastric tube or colonoscope, or by enema. There’s no standardization of data collection either. Some large institutions keep records of everything from the first workup to the last visit. Doctors who perform transplants occasionally may not be as conscientious. And no one knows anything about the do-it-yourselfers, at home with a family member’s donation and a squeeze enema.
Dr. Brandt – and a number of clinicians at the meeting – agreed that answers must be found for all these questions. And they agree that well-conducted clinical trials are the best way to go forward.
Dr. Colleen Kelly, one of the gastroenterologists launching one of 22 currently recruiting studies on FMT, started doing the procedure 5 years ago. Her first patient was a 26-year-old medical student with recurrent bouts of a Clostridium difficile infection.
"I’d heard of [FMT], but never, ever thought of doing one," said Dr. Kelly, of Brown University Medical Center, Providence, R.I. "I thought it was something at the far fringes of medicine."
At her patient’s insistence, Dr. Kelly contacted Dr. Brandt and learned about his process for performing FMT. The following year, she performed 10 FMTs. She is now undertaking a study with Dr. Brandt to recruit about 48 patients with relapsing C. difficile to be randomized to FMT or to a sham treatment with their own stool. Patients who have clinical failure in the sham group will be offered FMT; patients in the active arm who fail on initial FMT will get another FMT from a different donor.
While most trials are examining the utility of FMT in patients with recurrent C. difficile, a few are investigating FMT for use in patients with Crohn’s disease and inflammatory bowel disease. Some clinicians and individual patients are now using FMTs for this condition outside a clinical trial, with no understanding of how a compromised intestinal mucosa might react to transplanted stool.
It will take years to accumulate the data necessary to fully understand FMT and all its implications, Dr. Kelly said. In the interim, the IND requirement will likely shrink the already-small pool of gastroenterologists performing FMTs. "Some will be motivated to get an IND, but the average person in practice won’t," she predicted. "You need to put hours and hours of work into it, and then you’re still under FDA’s oversight because this is not an approved therapy. So that means you have to submit adverse events reports, keep records, and report annually on your program. And at any time, without any warning, [the FDA] can come and inspect your facility."
Dr. Brandt agreed. "It’s a huge amount of paperwork documentation, record-keeping, and follow-up that the average practitioner is simply not going to do." The requirement for an IND means there are simply going to be fewer and fewer physicians who do them, he said.
Admittedly, though, the risks of no regulation can endanger patients, Dr. Kelly said. "If things go on completely unregulated, stupid things will happen," including the spread of infectious diseases like hepatitis C and parasitic infestations.
Indeed, Dr. Alexander Khoruts of the University of Minnesota, Minneapolis, who spoke at the workshop, described the case of an FMT "do-it-yourselfer" who called for some advice on improving her outcomes. Specifically, she had mixed stool from a neighbor and her son’s mother-in-law and administered it to herself without results. "She wanted to know if maybe the chlorine in the water killed off everything. ... Six months later she called me back and said her C. diff was gone, but now she had parasites."
"There are already predatory practices out there [performing FMTs]," Dr. Khoruts said. "I got an e-mail from someone who couldn’t make the drive up to see me, but she found someone near her who would do it for $10,000."
Well-designed and well-executed studies would not only address these immediate safety questions, but would also examine the more nebulous concerns about the long-term effects of tampering with an individual’s unique ecosystem of gut microbes. In recent years, research has begun to document how the balance and proportion of microbial species in the gut can either protect from – or predispose to – metabolic syndrome, obesity, diabetes, cardiovascular disease, arthritis, and even cognitive disorders.
An engrafting microbial transplant could predispose the recipient to develop illnesses that would otherwise never have been destined to occur, Dr. Slater said. "All of the evidence we have suggests that manipulating the gut microbiome is a powerful act that may have long-reaching and subtle effects."
The move toward a standardized FMT product and process is inevitable, Dr. Brandt said. "We’re not going to be doing fecal transplants much longer. This is a temporary situation. We’re already developing compounds that will do the same thing."
Researchers at the University of Guelph, Ontario, have developed a machine that distills and cultures microbes from human feces, producing a kind of super-probiotic that can be used in place of fresh stool.
Also, the Canadian biotech company Rebiotix is working on a similar product, which it intends to test in a phase II randomized controlled trial.
But until those machine-made products are available, physicians and patients with have to stay with the man-made version. "We have access to a substance that is free and has a virtually unlimited supply," Dr. Kelly said. "We cannot deny this effective therapy to these patients who’ve failed all other available treatments."
None of the sources quoted in this article had any financial declarations.
BETHESDA, MD. – The Food and Drug Administration has designated stool for transplant as a biologic drug, necessitating that any gastroenterologist performing fecal microbiota transplants obtain an Investigational New Drug permit.
By designating stool for transplant as a biologic drug, anyone who performs fecal microbiota transplants (FMTs) – whether they perform a single transplant for one patient or recruit dozens for a study – needs to have an IND permit.
The announcement was made at a 2-day public workshop convened by the National Institutes of Health and the Food and Drug Administration to sift through some of the evidence surrounding FMTs.
The intent of the IND requirement, said Dr. Jay Slater, director of FDA’s Division of Bacterial, Parasitic, and Allergenic Products, is not to stamp out the care that patients can now receive, but to make sure it’s safe, effective, and data driven.
"This is a low-tech procedure that already has a CPT code. A ‘how-to’ guide recently appeared online, and it walks you right through how to do the procedure. There are a very large number of people doing this off the grid. What we need are long-term controlled trials on this that will enhance our understanding of its safety and efficacy."
Although neither the biologic designation nor the IND requirement is brand new, they have not been well publicized, according to one of the innovators of FMT, Dr. Lawrence Brandt, of Albert Einstein Medical Center in New York.
"I am struck by the fact that FDA wants these INDs and yet FDA has never publicly set forth any message on it. So from this moment on, all of us who continue to do this without an IND are violating FDA’s policy," he said at the meeting.
One of the primary concerns now, according to Dr. Brandt, is a burgeoning public interest in FMTs, even to the point of do-it-yourself treatments. With online instructions for self-treatment, and a procedure that is rife with variations, regulators can no longer tacitly ignore the issue.
There’s no standardization of how the stool is prepared and filtered – it could be blended in a kitchen blender or by hand with a tongue depressor, or strained through gauze or a coffee filter, he said. Dosing is all over the place, listed as spoonfuls, grams, and milliliters. Different institutions screen donors in different ways. Some patients get a bowel prep, which can be mild or aggressive, and some don’t get one at all. Should the stool be fresh, and if so, how fresh? Is frozen okay? These are all issues that need to be examined from a safety and efficacy perspective and standardized.
Even the method of delivery varies. The transplant can be administered via nasogastric tube or colonoscope, or by enema. There’s no standardization of data collection either. Some large institutions keep records of everything from the first workup to the last visit. Doctors who perform transplants occasionally may not be as conscientious. And no one knows anything about the do-it-yourselfers, at home with a family member’s donation and a squeeze enema.
Dr. Brandt – and a number of clinicians at the meeting – agreed that answers must be found for all these questions. And they agree that well-conducted clinical trials are the best way to go forward.
Dr. Colleen Kelly, one of the gastroenterologists launching one of 22 currently recruiting studies on FMT, started doing the procedure 5 years ago. Her first patient was a 26-year-old medical student with recurrent bouts of a Clostridium difficile infection.
"I’d heard of [FMT], but never, ever thought of doing one," said Dr. Kelly, of Brown University Medical Center, Providence, R.I. "I thought it was something at the far fringes of medicine."
At her patient’s insistence, Dr. Kelly contacted Dr. Brandt and learned about his process for performing FMT. The following year, she performed 10 FMTs. She is now undertaking a study with Dr. Brandt to recruit about 48 patients with relapsing C. difficile to be randomized to FMT or to a sham treatment with their own stool. Patients who have clinical failure in the sham group will be offered FMT; patients in the active arm who fail on initial FMT will get another FMT from a different donor.
While most trials are examining the utility of FMT in patients with recurrent C. difficile, a few are investigating FMT for use in patients with Crohn’s disease and inflammatory bowel disease. Some clinicians and individual patients are now using FMTs for this condition outside a clinical trial, with no understanding of how a compromised intestinal mucosa might react to transplanted stool.
It will take years to accumulate the data necessary to fully understand FMT and all its implications, Dr. Kelly said. In the interim, the IND requirement will likely shrink the already-small pool of gastroenterologists performing FMTs. "Some will be motivated to get an IND, but the average person in practice won’t," she predicted. "You need to put hours and hours of work into it, and then you’re still under FDA’s oversight because this is not an approved therapy. So that means you have to submit adverse events reports, keep records, and report annually on your program. And at any time, without any warning, [the FDA] can come and inspect your facility."
Dr. Brandt agreed. "It’s a huge amount of paperwork documentation, record-keeping, and follow-up that the average practitioner is simply not going to do." The requirement for an IND means there are simply going to be fewer and fewer physicians who do them, he said.
Admittedly, though, the risks of no regulation can endanger patients, Dr. Kelly said. "If things go on completely unregulated, stupid things will happen," including the spread of infectious diseases like hepatitis C and parasitic infestations.
Indeed, Dr. Alexander Khoruts of the University of Minnesota, Minneapolis, who spoke at the workshop, described the case of an FMT "do-it-yourselfer" who called for some advice on improving her outcomes. Specifically, she had mixed stool from a neighbor and her son’s mother-in-law and administered it to herself without results. "She wanted to know if maybe the chlorine in the water killed off everything. ... Six months later she called me back and said her C. diff was gone, but now she had parasites."
"There are already predatory practices out there [performing FMTs]," Dr. Khoruts said. "I got an e-mail from someone who couldn’t make the drive up to see me, but she found someone near her who would do it for $10,000."
Well-designed and well-executed studies would not only address these immediate safety questions, but would also examine the more nebulous concerns about the long-term effects of tampering with an individual’s unique ecosystem of gut microbes. In recent years, research has begun to document how the balance and proportion of microbial species in the gut can either protect from – or predispose to – metabolic syndrome, obesity, diabetes, cardiovascular disease, arthritis, and even cognitive disorders.
An engrafting microbial transplant could predispose the recipient to develop illnesses that would otherwise never have been destined to occur, Dr. Slater said. "All of the evidence we have suggests that manipulating the gut microbiome is a powerful act that may have long-reaching and subtle effects."
The move toward a standardized FMT product and process is inevitable, Dr. Brandt said. "We’re not going to be doing fecal transplants much longer. This is a temporary situation. We’re already developing compounds that will do the same thing."
Researchers at the University of Guelph, Ontario, have developed a machine that distills and cultures microbes from human feces, producing a kind of super-probiotic that can be used in place of fresh stool.
Also, the Canadian biotech company Rebiotix is working on a similar product, which it intends to test in a phase II randomized controlled trial.
But until those machine-made products are available, physicians and patients with have to stay with the man-made version. "We have access to a substance that is free and has a virtually unlimited supply," Dr. Kelly said. "We cannot deny this effective therapy to these patients who’ve failed all other available treatments."
None of the sources quoted in this article had any financial declarations.
BETHESDA, MD. – The Food and Drug Administration has designated stool for transplant as a biologic drug, necessitating that any gastroenterologist performing fecal microbiota transplants obtain an Investigational New Drug permit.
By designating stool for transplant as a biologic drug, anyone who performs fecal microbiota transplants (FMTs) – whether they perform a single transplant for one patient or recruit dozens for a study – needs to have an IND permit.
The announcement was made at a 2-day public workshop convened by the National Institutes of Health and the Food and Drug Administration to sift through some of the evidence surrounding FMTs.
The intent of the IND requirement, said Dr. Jay Slater, director of FDA’s Division of Bacterial, Parasitic, and Allergenic Products, is not to stamp out the care that patients can now receive, but to make sure it’s safe, effective, and data driven.
"This is a low-tech procedure that already has a CPT code. A ‘how-to’ guide recently appeared online, and it walks you right through how to do the procedure. There are a very large number of people doing this off the grid. What we need are long-term controlled trials on this that will enhance our understanding of its safety and efficacy."
Although neither the biologic designation nor the IND requirement is brand new, they have not been well publicized, according to one of the innovators of FMT, Dr. Lawrence Brandt, of Albert Einstein Medical Center in New York.
"I am struck by the fact that FDA wants these INDs and yet FDA has never publicly set forth any message on it. So from this moment on, all of us who continue to do this without an IND are violating FDA’s policy," he said at the meeting.
One of the primary concerns now, according to Dr. Brandt, is a burgeoning public interest in FMTs, even to the point of do-it-yourself treatments. With online instructions for self-treatment, and a procedure that is rife with variations, regulators can no longer tacitly ignore the issue.
There’s no standardization of how the stool is prepared and filtered – it could be blended in a kitchen blender or by hand with a tongue depressor, or strained through gauze or a coffee filter, he said. Dosing is all over the place, listed as spoonfuls, grams, and milliliters. Different institutions screen donors in different ways. Some patients get a bowel prep, which can be mild or aggressive, and some don’t get one at all. Should the stool be fresh, and if so, how fresh? Is frozen okay? These are all issues that need to be examined from a safety and efficacy perspective and standardized.
Even the method of delivery varies. The transplant can be administered via nasogastric tube or colonoscope, or by enema. There’s no standardization of data collection either. Some large institutions keep records of everything from the first workup to the last visit. Doctors who perform transplants occasionally may not be as conscientious. And no one knows anything about the do-it-yourselfers, at home with a family member’s donation and a squeeze enema.
Dr. Brandt – and a number of clinicians at the meeting – agreed that answers must be found for all these questions. And they agree that well-conducted clinical trials are the best way to go forward.
Dr. Colleen Kelly, one of the gastroenterologists launching one of 22 currently recruiting studies on FMT, started doing the procedure 5 years ago. Her first patient was a 26-year-old medical student with recurrent bouts of a Clostridium difficile infection.
"I’d heard of [FMT], but never, ever thought of doing one," said Dr. Kelly, of Brown University Medical Center, Providence, R.I. "I thought it was something at the far fringes of medicine."
At her patient’s insistence, Dr. Kelly contacted Dr. Brandt and learned about his process for performing FMT. The following year, she performed 10 FMTs. She is now undertaking a study with Dr. Brandt to recruit about 48 patients with relapsing C. difficile to be randomized to FMT or to a sham treatment with their own stool. Patients who have clinical failure in the sham group will be offered FMT; patients in the active arm who fail on initial FMT will get another FMT from a different donor.
While most trials are examining the utility of FMT in patients with recurrent C. difficile, a few are investigating FMT for use in patients with Crohn’s disease and inflammatory bowel disease. Some clinicians and individual patients are now using FMTs for this condition outside a clinical trial, with no understanding of how a compromised intestinal mucosa might react to transplanted stool.
It will take years to accumulate the data necessary to fully understand FMT and all its implications, Dr. Kelly said. In the interim, the IND requirement will likely shrink the already-small pool of gastroenterologists performing FMTs. "Some will be motivated to get an IND, but the average person in practice won’t," she predicted. "You need to put hours and hours of work into it, and then you’re still under FDA’s oversight because this is not an approved therapy. So that means you have to submit adverse events reports, keep records, and report annually on your program. And at any time, without any warning, [the FDA] can come and inspect your facility."
Dr. Brandt agreed. "It’s a huge amount of paperwork documentation, record-keeping, and follow-up that the average practitioner is simply not going to do." The requirement for an IND means there are simply going to be fewer and fewer physicians who do them, he said.
Admittedly, though, the risks of no regulation can endanger patients, Dr. Kelly said. "If things go on completely unregulated, stupid things will happen," including the spread of infectious diseases like hepatitis C and parasitic infestations.
Indeed, Dr. Alexander Khoruts of the University of Minnesota, Minneapolis, who spoke at the workshop, described the case of an FMT "do-it-yourselfer" who called for some advice on improving her outcomes. Specifically, she had mixed stool from a neighbor and her son’s mother-in-law and administered it to herself without results. "She wanted to know if maybe the chlorine in the water killed off everything. ... Six months later she called me back and said her C. diff was gone, but now she had parasites."
"There are already predatory practices out there [performing FMTs]," Dr. Khoruts said. "I got an e-mail from someone who couldn’t make the drive up to see me, but she found someone near her who would do it for $10,000."
Well-designed and well-executed studies would not only address these immediate safety questions, but would also examine the more nebulous concerns about the long-term effects of tampering with an individual’s unique ecosystem of gut microbes. In recent years, research has begun to document how the balance and proportion of microbial species in the gut can either protect from – or predispose to – metabolic syndrome, obesity, diabetes, cardiovascular disease, arthritis, and even cognitive disorders.
An engrafting microbial transplant could predispose the recipient to develop illnesses that would otherwise never have been destined to occur, Dr. Slater said. "All of the evidence we have suggests that manipulating the gut microbiome is a powerful act that may have long-reaching and subtle effects."
The move toward a standardized FMT product and process is inevitable, Dr. Brandt said. "We’re not going to be doing fecal transplants much longer. This is a temporary situation. We’re already developing compounds that will do the same thing."
Researchers at the University of Guelph, Ontario, have developed a machine that distills and cultures microbes from human feces, producing a kind of super-probiotic that can be used in place of fresh stool.
Also, the Canadian biotech company Rebiotix is working on a similar product, which it intends to test in a phase II randomized controlled trial.
But until those machine-made products are available, physicians and patients with have to stay with the man-made version. "We have access to a substance that is free and has a virtually unlimited supply," Dr. Kelly said. "We cannot deny this effective therapy to these patients who’ve failed all other available treatments."
None of the sources quoted in this article had any financial declarations.
Vaccine-resistant pertussis strains found in Philadelphia
WASHINGTON – Vaccine-resistant isolates of Bordetella pertussis have appeared in Philadelphia – the first such strains to be seen in the United States.
Of 30 samples analyzed, 18 (60%) showed a variant that conferred resistance to the current vaccine formulation, Dr. Jennifer Vodzak said at the annual meeting of the Pediatric Academic Societies. The strains had developed two different mutations, each of which deleted their expression of pertactin, an outer membrane protein that helps the bacteria adhere to respiratory epithelium. Pertactin is used as an antigen in the acellular pertussis component of the Tdap vaccine.
"It seems that, responding to vaccine pressure, B. pertussis has acquired several adaptations to halt the production of pertactin," said Dr. Vodzak, an infectious disease specialist at St. Christopher’s Hospital for Children, Philadelphia.
For the past decade, pertactin-negative strains have been reported in Japan, France, and Finland. Although the bacteria lack pertactin, French studies have shown that they are just as virulent as the nonmutated strains. The bacteria have simply found a way to cause disease without that particular protein.
Dr. Vodzak and her colleagues first reported their findings in a brief correspondence to the New England Journal Medicine in February. At that time, 11 of 12 isolates cultured from 2011 and 2012 expressed the pertactin variants. Seven expressed stop codons that truncated the protein, and four expressed insertion sequences that disrupted the pertactin coding region. The investigators also noted that these mutations appeared to be unique and not related to those seen in other countries.
Since then, the team has expanded its search, attempting to pinpoint the time these variants first appeared. To do that, they randomly selected 70 samples taken from Philadelphia patients who had culture-proven pertussis from 2007 to 2012. Most (80%) of the samples were from hospitalized patients, the majority of whom (87%) were younger than 1 year. More than half of the patients were younger than 3 months old. So far, 30 of the isolates have been molecularly examined.
After pertussis immunization became widespread in the 1940s, the disease incidence dropped dramatically in the United States. But in the mid-1990s – shortly after the acellular vaccine was introduced in 1991 – a gradual resurgence began. The incidence really picked up in the early 2000s, when annual case reports jumped into the tens of thousands. There were 18,719 cases reported in 2011; in 2012, that number more than doubled, to 41,880 – the highest since 1955.
The rise in cases was temporally related to the initiation of the acellular vaccine, which carries the pertactin antigen. The acellular vaccine also confers a limited immunogenicity. This limited protection and increased surveillance and reporting – not the acellular pertactin-containing vaccine –have caused the rise in cases, according to the Centers for Disease Control and Prevention.
"It does not appear that these strains are the reason the United States has experienced a dramatic increase in the number of reported pertussis cases recently," the agency says on its pertussis pages. "But CDC will continue to closely monitor the situation before drawing any conclusions. There is also no suggestion that these new strains are causing more severe cases of pertussis," or that the mutated strains carry any antibiotic resistance.
The appearance of pertactin-negative strains does seem to parallel the recent jump in cases, but as yet there are no hard data linking these three occurrences, Dr. Vodzak said.
Right now, she added, there’s no way to know if – or when – similar pertactin-negative strains have developed elsewhere in the United States. She and her team are encouraging public health agencies to test their stored samples so a more complete picture can be drawn.
"It will be important to consider the pathogen’s adaptations as we consider both the decreased vaccine effectiveness and vaccine development," she said. "I think the next step is to look at the clinical picture of these variants."
Dr. Vodzak said she had no relevant financial disclosures. Her coauthor, Anne Marie Queenan, Ph.D., is an employee of Janssen Research and Development.
WASHINGTON – Vaccine-resistant isolates of Bordetella pertussis have appeared in Philadelphia – the first such strains to be seen in the United States.
Of 30 samples analyzed, 18 (60%) showed a variant that conferred resistance to the current vaccine formulation, Dr. Jennifer Vodzak said at the annual meeting of the Pediatric Academic Societies. The strains had developed two different mutations, each of which deleted their expression of pertactin, an outer membrane protein that helps the bacteria adhere to respiratory epithelium. Pertactin is used as an antigen in the acellular pertussis component of the Tdap vaccine.
"It seems that, responding to vaccine pressure, B. pertussis has acquired several adaptations to halt the production of pertactin," said Dr. Vodzak, an infectious disease specialist at St. Christopher’s Hospital for Children, Philadelphia.
For the past decade, pertactin-negative strains have been reported in Japan, France, and Finland. Although the bacteria lack pertactin, French studies have shown that they are just as virulent as the nonmutated strains. The bacteria have simply found a way to cause disease without that particular protein.
Dr. Vodzak and her colleagues first reported their findings in a brief correspondence to the New England Journal Medicine in February. At that time, 11 of 12 isolates cultured from 2011 and 2012 expressed the pertactin variants. Seven expressed stop codons that truncated the protein, and four expressed insertion sequences that disrupted the pertactin coding region. The investigators also noted that these mutations appeared to be unique and not related to those seen in other countries.
Since then, the team has expanded its search, attempting to pinpoint the time these variants first appeared. To do that, they randomly selected 70 samples taken from Philadelphia patients who had culture-proven pertussis from 2007 to 2012. Most (80%) of the samples were from hospitalized patients, the majority of whom (87%) were younger than 1 year. More than half of the patients were younger than 3 months old. So far, 30 of the isolates have been molecularly examined.
After pertussis immunization became widespread in the 1940s, the disease incidence dropped dramatically in the United States. But in the mid-1990s – shortly after the acellular vaccine was introduced in 1991 – a gradual resurgence began. The incidence really picked up in the early 2000s, when annual case reports jumped into the tens of thousands. There were 18,719 cases reported in 2011; in 2012, that number more than doubled, to 41,880 – the highest since 1955.
The rise in cases was temporally related to the initiation of the acellular vaccine, which carries the pertactin antigen. The acellular vaccine also confers a limited immunogenicity. This limited protection and increased surveillance and reporting – not the acellular pertactin-containing vaccine –have caused the rise in cases, according to the Centers for Disease Control and Prevention.
"It does not appear that these strains are the reason the United States has experienced a dramatic increase in the number of reported pertussis cases recently," the agency says on its pertussis pages. "But CDC will continue to closely monitor the situation before drawing any conclusions. There is also no suggestion that these new strains are causing more severe cases of pertussis," or that the mutated strains carry any antibiotic resistance.
The appearance of pertactin-negative strains does seem to parallel the recent jump in cases, but as yet there are no hard data linking these three occurrences, Dr. Vodzak said.
Right now, she added, there’s no way to know if – or when – similar pertactin-negative strains have developed elsewhere in the United States. She and her team are encouraging public health agencies to test their stored samples so a more complete picture can be drawn.
"It will be important to consider the pathogen’s adaptations as we consider both the decreased vaccine effectiveness and vaccine development," she said. "I think the next step is to look at the clinical picture of these variants."
Dr. Vodzak said she had no relevant financial disclosures. Her coauthor, Anne Marie Queenan, Ph.D., is an employee of Janssen Research and Development.
WASHINGTON – Vaccine-resistant isolates of Bordetella pertussis have appeared in Philadelphia – the first such strains to be seen in the United States.
Of 30 samples analyzed, 18 (60%) showed a variant that conferred resistance to the current vaccine formulation, Dr. Jennifer Vodzak said at the annual meeting of the Pediatric Academic Societies. The strains had developed two different mutations, each of which deleted their expression of pertactin, an outer membrane protein that helps the bacteria adhere to respiratory epithelium. Pertactin is used as an antigen in the acellular pertussis component of the Tdap vaccine.
"It seems that, responding to vaccine pressure, B. pertussis has acquired several adaptations to halt the production of pertactin," said Dr. Vodzak, an infectious disease specialist at St. Christopher’s Hospital for Children, Philadelphia.
For the past decade, pertactin-negative strains have been reported in Japan, France, and Finland. Although the bacteria lack pertactin, French studies have shown that they are just as virulent as the nonmutated strains. The bacteria have simply found a way to cause disease without that particular protein.
Dr. Vodzak and her colleagues first reported their findings in a brief correspondence to the New England Journal Medicine in February. At that time, 11 of 12 isolates cultured from 2011 and 2012 expressed the pertactin variants. Seven expressed stop codons that truncated the protein, and four expressed insertion sequences that disrupted the pertactin coding region. The investigators also noted that these mutations appeared to be unique and not related to those seen in other countries.
Since then, the team has expanded its search, attempting to pinpoint the time these variants first appeared. To do that, they randomly selected 70 samples taken from Philadelphia patients who had culture-proven pertussis from 2007 to 2012. Most (80%) of the samples were from hospitalized patients, the majority of whom (87%) were younger than 1 year. More than half of the patients were younger than 3 months old. So far, 30 of the isolates have been molecularly examined.
After pertussis immunization became widespread in the 1940s, the disease incidence dropped dramatically in the United States. But in the mid-1990s – shortly after the acellular vaccine was introduced in 1991 – a gradual resurgence began. The incidence really picked up in the early 2000s, when annual case reports jumped into the tens of thousands. There were 18,719 cases reported in 2011; in 2012, that number more than doubled, to 41,880 – the highest since 1955.
The rise in cases was temporally related to the initiation of the acellular vaccine, which carries the pertactin antigen. The acellular vaccine also confers a limited immunogenicity. This limited protection and increased surveillance and reporting – not the acellular pertactin-containing vaccine –have caused the rise in cases, according to the Centers for Disease Control and Prevention.
"It does not appear that these strains are the reason the United States has experienced a dramatic increase in the number of reported pertussis cases recently," the agency says on its pertussis pages. "But CDC will continue to closely monitor the situation before drawing any conclusions. There is also no suggestion that these new strains are causing more severe cases of pertussis," or that the mutated strains carry any antibiotic resistance.
The appearance of pertactin-negative strains does seem to parallel the recent jump in cases, but as yet there are no hard data linking these three occurrences, Dr. Vodzak said.
Right now, she added, there’s no way to know if – or when – similar pertactin-negative strains have developed elsewhere in the United States. She and her team are encouraging public health agencies to test their stored samples so a more complete picture can be drawn.
"It will be important to consider the pathogen’s adaptations as we consider both the decreased vaccine effectiveness and vaccine development," she said. "I think the next step is to look at the clinical picture of these variants."
Dr. Vodzak said she had no relevant financial disclosures. Her coauthor, Anne Marie Queenan, Ph.D., is an employee of Janssen Research and Development.
FROM THE PAS ANNUAL MEETING
Major finding: About 60% of 30 B. pertussis isolates from 2007 to 2012 in Philadelphia showed a mutation that deletes their pertactin expression – making them immune to the pertactin-containing acellular pertussis vaccine.
Data source: An ongoing analysis of 70 isolates taken from Philadelphia residents who had culture-proven pertussis from 2007 to 2012.
Disclosures: Dr. Vodzak said she had no relevant financial disclosures. Her coauthor, Anne Marie Queenan, Ph.D., is an employee of Janssen Research and Development.
Viral testing cut antibiotic use in children with respiratory illness
WASHINGTON – A rapid viral testing panel decreased the odds of inappropriate antibiotic use by 67% in children hospitalized with an acute respiratory illness, allowing about 6% of the children taking them to discontinue them.
Use of such a test could be part of a facility’s overall antibiotic control program, Dr. Russell McCulloh said at the annual meeting of the Pediatric Academic Societies.
"Now we need to talk about when a test like this can be used appropriately," said Dr. McCulloh, an infectious disease specialist at Rhode Island Hospital, Providence. "There is always a strong possibility for a bacterial coinfection in these patients, and that can be very hard to determine because we don’t have a gold standard test for that. Adjunctive diagnostic testing will be necessary if you’re really going to close the loop and implement this as part of an antibiotic stewardship program."
Dr. McCulloh conducted a retrospective chart review of 1,731 children admitted to the hospital for an acute respiratory illness from 2009 to 2011. He then compared the rates of antimicrobial use in children who had the rapid viral panel (809) and those who did not (922). About half of the group (860) had received antibiotics before having the test run, while 255 had received oseltamivir.
Most of the children who had a positive viral panel were prescribed oseltamivir (87%); the drug was used in about 18% of those who had a negative test. A multivariate analysis found that a positive rapid viral panel was the single biggest predictor of getting the antiviral drug, increasing the odds by more than 27 times, Dr. McCulloh said.
Younger age also had a significant association, but the odds ratio was only 1.7. Having a significant past medical history was predictive in an unadjusted analysis, but not in the final model. Abnormal chest x-ray, intensive care unit admission, and abnormal white cell counts had no significant predictive value.
The test also influenced the use of antibiotics, Dr. McCulloh said. Antibiotics were given to 11% of children who had the viral testing, but to 100% of those who did not have it. Antibiotics were used in 51% of those with a positive test, and 67% of those with a negative test. Antibiotics also were discontinued in 6% of children who had a positive viral test.
A multivariate analysis found several factors significantly associated with antibiotic use. A significant past medical history increased the odds by 7%. Stronger predictors included a codiagnosis of acute otitis media (OR 6.0), an abnormal chest x-ray (OR 2.57), and a positive blood culture (OR 3). However, a negative viral panel was associated with a 69% decreased chance of receiving an antibiotic.
The test was a big shaper of physician behavior, Dr. McCulloh said, allowing a more judicious and targeted use of antibiotics while increasing the use of antiviral medication. "Rapid viral panel testing seems to enhance physician decision-making in these patients."
Dr. McCulloh had no financial disclosures.
WASHINGTON – A rapid viral testing panel decreased the odds of inappropriate antibiotic use by 67% in children hospitalized with an acute respiratory illness, allowing about 6% of the children taking them to discontinue them.
Use of such a test could be part of a facility’s overall antibiotic control program, Dr. Russell McCulloh said at the annual meeting of the Pediatric Academic Societies.
"Now we need to talk about when a test like this can be used appropriately," said Dr. McCulloh, an infectious disease specialist at Rhode Island Hospital, Providence. "There is always a strong possibility for a bacterial coinfection in these patients, and that can be very hard to determine because we don’t have a gold standard test for that. Adjunctive diagnostic testing will be necessary if you’re really going to close the loop and implement this as part of an antibiotic stewardship program."
Dr. McCulloh conducted a retrospective chart review of 1,731 children admitted to the hospital for an acute respiratory illness from 2009 to 2011. He then compared the rates of antimicrobial use in children who had the rapid viral panel (809) and those who did not (922). About half of the group (860) had received antibiotics before having the test run, while 255 had received oseltamivir.
Most of the children who had a positive viral panel were prescribed oseltamivir (87%); the drug was used in about 18% of those who had a negative test. A multivariate analysis found that a positive rapid viral panel was the single biggest predictor of getting the antiviral drug, increasing the odds by more than 27 times, Dr. McCulloh said.
Younger age also had a significant association, but the odds ratio was only 1.7. Having a significant past medical history was predictive in an unadjusted analysis, but not in the final model. Abnormal chest x-ray, intensive care unit admission, and abnormal white cell counts had no significant predictive value.
The test also influenced the use of antibiotics, Dr. McCulloh said. Antibiotics were given to 11% of children who had the viral testing, but to 100% of those who did not have it. Antibiotics were used in 51% of those with a positive test, and 67% of those with a negative test. Antibiotics also were discontinued in 6% of children who had a positive viral test.
A multivariate analysis found several factors significantly associated with antibiotic use. A significant past medical history increased the odds by 7%. Stronger predictors included a codiagnosis of acute otitis media (OR 6.0), an abnormal chest x-ray (OR 2.57), and a positive blood culture (OR 3). However, a negative viral panel was associated with a 69% decreased chance of receiving an antibiotic.
The test was a big shaper of physician behavior, Dr. McCulloh said, allowing a more judicious and targeted use of antibiotics while increasing the use of antiviral medication. "Rapid viral panel testing seems to enhance physician decision-making in these patients."
Dr. McCulloh had no financial disclosures.
WASHINGTON – A rapid viral testing panel decreased the odds of inappropriate antibiotic use by 67% in children hospitalized with an acute respiratory illness, allowing about 6% of the children taking them to discontinue them.
Use of such a test could be part of a facility’s overall antibiotic control program, Dr. Russell McCulloh said at the annual meeting of the Pediatric Academic Societies.
"Now we need to talk about when a test like this can be used appropriately," said Dr. McCulloh, an infectious disease specialist at Rhode Island Hospital, Providence. "There is always a strong possibility for a bacterial coinfection in these patients, and that can be very hard to determine because we don’t have a gold standard test for that. Adjunctive diagnostic testing will be necessary if you’re really going to close the loop and implement this as part of an antibiotic stewardship program."
Dr. McCulloh conducted a retrospective chart review of 1,731 children admitted to the hospital for an acute respiratory illness from 2009 to 2011. He then compared the rates of antimicrobial use in children who had the rapid viral panel (809) and those who did not (922). About half of the group (860) had received antibiotics before having the test run, while 255 had received oseltamivir.
Most of the children who had a positive viral panel were prescribed oseltamivir (87%); the drug was used in about 18% of those who had a negative test. A multivariate analysis found that a positive rapid viral panel was the single biggest predictor of getting the antiviral drug, increasing the odds by more than 27 times, Dr. McCulloh said.
Younger age also had a significant association, but the odds ratio was only 1.7. Having a significant past medical history was predictive in an unadjusted analysis, but not in the final model. Abnormal chest x-ray, intensive care unit admission, and abnormal white cell counts had no significant predictive value.
The test also influenced the use of antibiotics, Dr. McCulloh said. Antibiotics were given to 11% of children who had the viral testing, but to 100% of those who did not have it. Antibiotics were used in 51% of those with a positive test, and 67% of those with a negative test. Antibiotics also were discontinued in 6% of children who had a positive viral test.
A multivariate analysis found several factors significantly associated with antibiotic use. A significant past medical history increased the odds by 7%. Stronger predictors included a codiagnosis of acute otitis media (OR 6.0), an abnormal chest x-ray (OR 2.57), and a positive blood culture (OR 3). However, a negative viral panel was associated with a 69% decreased chance of receiving an antibiotic.
The test was a big shaper of physician behavior, Dr. McCulloh said, allowing a more judicious and targeted use of antibiotics while increasing the use of antiviral medication. "Rapid viral panel testing seems to enhance physician decision-making in these patients."
Dr. McCulloh had no financial disclosures.
AT THE PAS ANNUAL MEETING
Major finding: In children hospitalized with an acute respiratory illness, a positive rapid viral panel increased the odds of receiving oseltamivir by more than 27 times, while decreasing the odds of antibiotic use by 69%.
Data source: A retrospective chart review of 1,731 children.
Disclosures: Dr. McCulloh had no financial disclosures.
AAP guidelines have changed bronchiolitis management
WASHINGTON – The use of radiographs, viral testing, steroids, and bronchodilators for young children with bronchiolitis has declined significantly since the introduction of the American Academy of Pediatrics’ diagnostic and management guidelines.
Before the guidelines were released in 2006 (Pediatrics 2006;118:1774-93), use of all these diagnostic and treatment modalities was on the rise, Dr. Kavita Parikh said at the annual meeting of the Pediatric Academic Societies.
Her retrospective study of more than 130,000 cases demonstrated that the document has had a positive impact on the way bronchiolitis is now managed.
"The AAP practice guideline advocates primarily supportive care," said Dr. Parikh, a pediatric hospitalist at Children’s National Medical Center, Washington. "And as many of us now know, less is more for this illness."
The cases for this study came from a large hospital administration database covering 43 facilities. Dr. Parikh compared diagnostic and treatment resource utilization in three periods: November 2004 to March 2005 (pre-guidelines), November 2007 to March 2008 (early post-guidelines), and November 2011 to March 2012 (late post-guidelines).
The study examined changes in four diagnostic measures (complete blood count [CBC], chest x-rays, respiratory syncytial virus testing, and influenza testing) and three treatment measures (steroids, bronchodilators, and antibiotics).
The study cohort comprised 130,262 children, with a mean age of 4 months. Most (59%) were covered by public insurance.
In the pre-guideline period, CBC was employed in 35% of cases, chest x-ray and RSV testing each in 61%, and influenza testing in 32%. These numbers were essentially unchanged in the early post-guidelines period, but by the late post-guidelines period the recommendations were taking root. All of the measures had decreased significantly: CBC use had gone down by 6%, chest x-rays by about 11%, RSV testing by 20%, and influenza testing by 12%.
Treatment measures changed as well, Dr. Parikh said.
In the pre-guidelines period, steroids were employed in 25% of cases, bronchodilators in 65%, and antibiotics in 34%. Again, the numbers were similar in the early post-guidelines period. By the late post-guidelines period, however, steroid and bronchodilator use had both dropped by 9%. Antibiotic use rose by 3% in the early post-guidelines period but decreased again later for a net change of about 2%. The difference was statistically significant but probably not clinically relevant, Dr. Parikh noted.
"The AAP guidelines have apparently had a positive effect on the way we deal with bronchiolitis, with the greatest impact on chest x-ray, steroid, and bronchodilator use," she said. "We want to continue to look at this and compare local practices to further evaluate implementation by region and hospital type."
Dr. Parikh said that she had no financial disclosures.
WASHINGTON – The use of radiographs, viral testing, steroids, and bronchodilators for young children with bronchiolitis has declined significantly since the introduction of the American Academy of Pediatrics’ diagnostic and management guidelines.
Before the guidelines were released in 2006 (Pediatrics 2006;118:1774-93), use of all these diagnostic and treatment modalities was on the rise, Dr. Kavita Parikh said at the annual meeting of the Pediatric Academic Societies.
Her retrospective study of more than 130,000 cases demonstrated that the document has had a positive impact on the way bronchiolitis is now managed.
"The AAP practice guideline advocates primarily supportive care," said Dr. Parikh, a pediatric hospitalist at Children’s National Medical Center, Washington. "And as many of us now know, less is more for this illness."
The cases for this study came from a large hospital administration database covering 43 facilities. Dr. Parikh compared diagnostic and treatment resource utilization in three periods: November 2004 to March 2005 (pre-guidelines), November 2007 to March 2008 (early post-guidelines), and November 2011 to March 2012 (late post-guidelines).
The study examined changes in four diagnostic measures (complete blood count [CBC], chest x-rays, respiratory syncytial virus testing, and influenza testing) and three treatment measures (steroids, bronchodilators, and antibiotics).
The study cohort comprised 130,262 children, with a mean age of 4 months. Most (59%) were covered by public insurance.
In the pre-guideline period, CBC was employed in 35% of cases, chest x-ray and RSV testing each in 61%, and influenza testing in 32%. These numbers were essentially unchanged in the early post-guidelines period, but by the late post-guidelines period the recommendations were taking root. All of the measures had decreased significantly: CBC use had gone down by 6%, chest x-rays by about 11%, RSV testing by 20%, and influenza testing by 12%.
Treatment measures changed as well, Dr. Parikh said.
In the pre-guidelines period, steroids were employed in 25% of cases, bronchodilators in 65%, and antibiotics in 34%. Again, the numbers were similar in the early post-guidelines period. By the late post-guidelines period, however, steroid and bronchodilator use had both dropped by 9%. Antibiotic use rose by 3% in the early post-guidelines period but decreased again later for a net change of about 2%. The difference was statistically significant but probably not clinically relevant, Dr. Parikh noted.
"The AAP guidelines have apparently had a positive effect on the way we deal with bronchiolitis, with the greatest impact on chest x-ray, steroid, and bronchodilator use," she said. "We want to continue to look at this and compare local practices to further evaluate implementation by region and hospital type."
Dr. Parikh said that she had no financial disclosures.
WASHINGTON – The use of radiographs, viral testing, steroids, and bronchodilators for young children with bronchiolitis has declined significantly since the introduction of the American Academy of Pediatrics’ diagnostic and management guidelines.
Before the guidelines were released in 2006 (Pediatrics 2006;118:1774-93), use of all these diagnostic and treatment modalities was on the rise, Dr. Kavita Parikh said at the annual meeting of the Pediatric Academic Societies.
Her retrospective study of more than 130,000 cases demonstrated that the document has had a positive impact on the way bronchiolitis is now managed.
"The AAP practice guideline advocates primarily supportive care," said Dr. Parikh, a pediatric hospitalist at Children’s National Medical Center, Washington. "And as many of us now know, less is more for this illness."
The cases for this study came from a large hospital administration database covering 43 facilities. Dr. Parikh compared diagnostic and treatment resource utilization in three periods: November 2004 to March 2005 (pre-guidelines), November 2007 to March 2008 (early post-guidelines), and November 2011 to March 2012 (late post-guidelines).
The study examined changes in four diagnostic measures (complete blood count [CBC], chest x-rays, respiratory syncytial virus testing, and influenza testing) and three treatment measures (steroids, bronchodilators, and antibiotics).
The study cohort comprised 130,262 children, with a mean age of 4 months. Most (59%) were covered by public insurance.
In the pre-guideline period, CBC was employed in 35% of cases, chest x-ray and RSV testing each in 61%, and influenza testing in 32%. These numbers were essentially unchanged in the early post-guidelines period, but by the late post-guidelines period the recommendations were taking root. All of the measures had decreased significantly: CBC use had gone down by 6%, chest x-rays by about 11%, RSV testing by 20%, and influenza testing by 12%.
Treatment measures changed as well, Dr. Parikh said.
In the pre-guidelines period, steroids were employed in 25% of cases, bronchodilators in 65%, and antibiotics in 34%. Again, the numbers were similar in the early post-guidelines period. By the late post-guidelines period, however, steroid and bronchodilator use had both dropped by 9%. Antibiotic use rose by 3% in the early post-guidelines period but decreased again later for a net change of about 2%. The difference was statistically significant but probably not clinically relevant, Dr. Parikh noted.
"The AAP guidelines have apparently had a positive effect on the way we deal with bronchiolitis, with the greatest impact on chest x-ray, steroid, and bronchodilator use," she said. "We want to continue to look at this and compare local practices to further evaluate implementation by region and hospital type."
Dr. Parikh said that she had no financial disclosures.
AT THE PAS ANNUAL MEETING
Major finding: Nonrecommended diagnostic and treatment method utilization in bronchiolitis cases decreased by up to 20% within 6 years of the release of disease management guidelines.
Data source: The records review included more than 130,000 cases over an 8-year period.
Disclosures: Dr. Parikh said that she had no financial disclosures.
Children with ulcerative colitis benefited from fecal transplants
Seven out of nine children with active ulcerative colitis experienced at least a temporary clinical response within 1 week of a series of fecal transplants – with four of the patients staying in complete remission 1 month later.
The procedures represent the first time fecal transplantation has been used to treat ulcerative colitis, Dr. Sachin Kunde and his colleagues reported online in the Journal of Pediatric Gastroenterology and Nutrition (2013 March 29 [doi: 10.1097/MPG.0b013e318292fa0d]).
"Utilization of fecal material transplantation in ulcerative colitis may not be as simple as its use in recurrent C. difficile infection," wrote Dr. Kunde of the Helen DeVos Children’s Hospital, Grand Rapids, Mich., and his coauthors. Still, they said, this early success in a devastating, hard-to-manage disease should be the launching point for larger trials.
The study group comprised 10 patients who ranged in age from 7 to 20 years. All had mild to moderate, active ulcerative colitis. Disease duration ranged from 1 to 8 years. Participants had stable disease and received medical treatment for at least 2 months before the procedure. Only one patient had used anti–tumor necrosis factor (anti-TNF)-alpha medications.
The intervention consisted of a 5-day series of daily enemas containing fresh stool from a donor. Each of the patients chose an adult donor; most were first-degree relatives. One patient chose a close family friend. The donors took daily over-the-counter stool softeners to produce the required amount – a mean of 90 g/day. This was blended with 250 mL of sterile normal saline, strained, and divided into four 60-mL portions. In each treatment, all four of the portions were infused, each over a 15-minute period.
The patients did not receive any bowel preparation before the procedures. They received the enemas while lying on the left side, and then rotating to the right side and back again to allow the solution to travel into the colon.
Ten patients entered treatment. However, one could not retain the enemas and so was not included in the final analysis. The remaining patients were able to tolerate an enema volume of 75-240 mL (average retention, 165 mL). Retention was not directly related to age, the investigators noted, since the subject who could not retain it was the oldest. Retention times ranged from 3 to 24 hours.
There were no serious adverse events during the study. Patients did report the expected discomfort of left-sided abdominal fullness. One experienced a moderate fever and chills 3 hours after the first two transplants, which spontaneously resolved over 6 hours. For the final three procedures, that patient took prophylactic acetaminophen and diphenhydramine.
Another patient had a low-grade fever after one transplant, which resolved without intervention. There were no cases of sepsis.
One patient experienced a disabling hematochezia 3 weeks after the transplant series. This was judged to be a flare unrelated to the transplant.
In the first week after the transplant series, seven of the nine patients in the analysis (78%) had a clinical response, defined as a decrease of more than 15 points in the Pediatric Ulcerative Colitis Activity Index. Six of the nine (67%) maintained that improvement at 1 month.
Three experienced clinical remission at 1 week, which lasted for 1 month. Two patients had a PUCAI score of 0 from week 3 until the end of the 7-week follow-up period.
The pilot study shows the feasibility of fecal transplants for ulcerative colitis, Dr. Kunde said. But while the technique is similar to that employed in C. difficile treatment, a more prolonged treatment seems necessary to elicit a response in ulcerative colitis.
"In order to better understand how fecal transplants can be used to treat ulcerative colitis, many unanswered questions need to be addressed. We must further investigate standardization of ... preparation, ideal donor selection, ideal route of administration, and optimal duration of scheduling [the transplants] to induce and maintain a clinical response. Most importantly, the effects of fecal material transplant on the colonic microbiome and mucosal inflammation in ulcerative colitis need to be explored."
The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
There has been much excitement about the use
of fecal material to treat recurrent Clostridium difficile infection.
Along the theory that the gut microbiome may be the “final frontier” of many
human diseases, so-called fecal microbiota transplantation (FMT) is of great
interest for other GI disorders.
Given the observation that patients with inflammatory
bowel disease (IBD) have an altered gut microbiome, clinicians and scientists
have wondered whether modifying the gut flora via FMT would provide symptom
improvement or disease control. It is much more complicated than treatment for C.
difficile, since IBD is a much more complex disorder, and as a single
organism or infectious etiology is not known. Clearly, our current
understanding is far from satisfying any of Koch’s postulates
of infectious disease. The observed dysbiosis may instead be a result of the underlying
inflammatory disorder or even a result of some of our treatments for IBD.
Nonetheless, providing FMT to patients with IBD is an interesting concept.
Dr. Kunde and his colleagues had promising results,
but they were careful in their selection of patients, the severity of disease,
and concomitant therapies. Safety appears acceptable, but there were some
short-term adverse events. We should await additional studies with mechanistic
and translational components and, importantly, safety follow-up to guide us
further.
Dr. David T. Rubin is a professor of medicine, the codirector
of the Inflammatory Bowel Disease Center, and the associate section chief for educational
programs at the University of Chicago. He had no relevant disclosures.
There has been much excitement about the use
of fecal material to treat recurrent Clostridium difficile infection.
Along the theory that the gut microbiome may be the “final frontier” of many
human diseases, so-called fecal microbiota transplantation (FMT) is of great
interest for other GI disorders.
Given the observation that patients with inflammatory
bowel disease (IBD) have an altered gut microbiome, clinicians and scientists
have wondered whether modifying the gut flora via FMT would provide symptom
improvement or disease control. It is much more complicated than treatment for C.
difficile, since IBD is a much more complex disorder, and as a single
organism or infectious etiology is not known. Clearly, our current
understanding is far from satisfying any of Koch’s postulates
of infectious disease. The observed dysbiosis may instead be a result of the underlying
inflammatory disorder or even a result of some of our treatments for IBD.
Nonetheless, providing FMT to patients with IBD is an interesting concept.
Dr. Kunde and his colleagues had promising results,
but they were careful in their selection of patients, the severity of disease,
and concomitant therapies. Safety appears acceptable, but there were some
short-term adverse events. We should await additional studies with mechanistic
and translational components and, importantly, safety follow-up to guide us
further.
Dr. David T. Rubin is a professor of medicine, the codirector
of the Inflammatory Bowel Disease Center, and the associate section chief for educational
programs at the University of Chicago. He had no relevant disclosures.
There has been much excitement about the use
of fecal material to treat recurrent Clostridium difficile infection.
Along the theory that the gut microbiome may be the “final frontier” of many
human diseases, so-called fecal microbiota transplantation (FMT) is of great
interest for other GI disorders.
Given the observation that patients with inflammatory
bowel disease (IBD) have an altered gut microbiome, clinicians and scientists
have wondered whether modifying the gut flora via FMT would provide symptom
improvement or disease control. It is much more complicated than treatment for C.
difficile, since IBD is a much more complex disorder, and as a single
organism or infectious etiology is not known. Clearly, our current
understanding is far from satisfying any of Koch’s postulates
of infectious disease. The observed dysbiosis may instead be a result of the underlying
inflammatory disorder or even a result of some of our treatments for IBD.
Nonetheless, providing FMT to patients with IBD is an interesting concept.
Dr. Kunde and his colleagues had promising results,
but they were careful in their selection of patients, the severity of disease,
and concomitant therapies. Safety appears acceptable, but there were some
short-term adverse events. We should await additional studies with mechanistic
and translational components and, importantly, safety follow-up to guide us
further.
Dr. David T. Rubin is a professor of medicine, the codirector
of the Inflammatory Bowel Disease Center, and the associate section chief for educational
programs at the University of Chicago. He had no relevant disclosures.
Seven out of nine children with active ulcerative colitis experienced at least a temporary clinical response within 1 week of a series of fecal transplants – with four of the patients staying in complete remission 1 month later.
The procedures represent the first time fecal transplantation has been used to treat ulcerative colitis, Dr. Sachin Kunde and his colleagues reported online in the Journal of Pediatric Gastroenterology and Nutrition (2013 March 29 [doi: 10.1097/MPG.0b013e318292fa0d]).
"Utilization of fecal material transplantation in ulcerative colitis may not be as simple as its use in recurrent C. difficile infection," wrote Dr. Kunde of the Helen DeVos Children’s Hospital, Grand Rapids, Mich., and his coauthors. Still, they said, this early success in a devastating, hard-to-manage disease should be the launching point for larger trials.
The study group comprised 10 patients who ranged in age from 7 to 20 years. All had mild to moderate, active ulcerative colitis. Disease duration ranged from 1 to 8 years. Participants had stable disease and received medical treatment for at least 2 months before the procedure. Only one patient had used anti–tumor necrosis factor (anti-TNF)-alpha medications.
The intervention consisted of a 5-day series of daily enemas containing fresh stool from a donor. Each of the patients chose an adult donor; most were first-degree relatives. One patient chose a close family friend. The donors took daily over-the-counter stool softeners to produce the required amount – a mean of 90 g/day. This was blended with 250 mL of sterile normal saline, strained, and divided into four 60-mL portions. In each treatment, all four of the portions were infused, each over a 15-minute period.
The patients did not receive any bowel preparation before the procedures. They received the enemas while lying on the left side, and then rotating to the right side and back again to allow the solution to travel into the colon.
Ten patients entered treatment. However, one could not retain the enemas and so was not included in the final analysis. The remaining patients were able to tolerate an enema volume of 75-240 mL (average retention, 165 mL). Retention was not directly related to age, the investigators noted, since the subject who could not retain it was the oldest. Retention times ranged from 3 to 24 hours.
There were no serious adverse events during the study. Patients did report the expected discomfort of left-sided abdominal fullness. One experienced a moderate fever and chills 3 hours after the first two transplants, which spontaneously resolved over 6 hours. For the final three procedures, that patient took prophylactic acetaminophen and diphenhydramine.
Another patient had a low-grade fever after one transplant, which resolved without intervention. There were no cases of sepsis.
One patient experienced a disabling hematochezia 3 weeks after the transplant series. This was judged to be a flare unrelated to the transplant.
In the first week after the transplant series, seven of the nine patients in the analysis (78%) had a clinical response, defined as a decrease of more than 15 points in the Pediatric Ulcerative Colitis Activity Index. Six of the nine (67%) maintained that improvement at 1 month.
Three experienced clinical remission at 1 week, which lasted for 1 month. Two patients had a PUCAI score of 0 from week 3 until the end of the 7-week follow-up period.
The pilot study shows the feasibility of fecal transplants for ulcerative colitis, Dr. Kunde said. But while the technique is similar to that employed in C. difficile treatment, a more prolonged treatment seems necessary to elicit a response in ulcerative colitis.
"In order to better understand how fecal transplants can be used to treat ulcerative colitis, many unanswered questions need to be addressed. We must further investigate standardization of ... preparation, ideal donor selection, ideal route of administration, and optimal duration of scheduling [the transplants] to induce and maintain a clinical response. Most importantly, the effects of fecal material transplant on the colonic microbiome and mucosal inflammation in ulcerative colitis need to be explored."
The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
Seven out of nine children with active ulcerative colitis experienced at least a temporary clinical response within 1 week of a series of fecal transplants – with four of the patients staying in complete remission 1 month later.
The procedures represent the first time fecal transplantation has been used to treat ulcerative colitis, Dr. Sachin Kunde and his colleagues reported online in the Journal of Pediatric Gastroenterology and Nutrition (2013 March 29 [doi: 10.1097/MPG.0b013e318292fa0d]).
"Utilization of fecal material transplantation in ulcerative colitis may not be as simple as its use in recurrent C. difficile infection," wrote Dr. Kunde of the Helen DeVos Children’s Hospital, Grand Rapids, Mich., and his coauthors. Still, they said, this early success in a devastating, hard-to-manage disease should be the launching point for larger trials.
The study group comprised 10 patients who ranged in age from 7 to 20 years. All had mild to moderate, active ulcerative colitis. Disease duration ranged from 1 to 8 years. Participants had stable disease and received medical treatment for at least 2 months before the procedure. Only one patient had used anti–tumor necrosis factor (anti-TNF)-alpha medications.
The intervention consisted of a 5-day series of daily enemas containing fresh stool from a donor. Each of the patients chose an adult donor; most were first-degree relatives. One patient chose a close family friend. The donors took daily over-the-counter stool softeners to produce the required amount – a mean of 90 g/day. This was blended with 250 mL of sterile normal saline, strained, and divided into four 60-mL portions. In each treatment, all four of the portions were infused, each over a 15-minute period.
The patients did not receive any bowel preparation before the procedures. They received the enemas while lying on the left side, and then rotating to the right side and back again to allow the solution to travel into the colon.
Ten patients entered treatment. However, one could not retain the enemas and so was not included in the final analysis. The remaining patients were able to tolerate an enema volume of 75-240 mL (average retention, 165 mL). Retention was not directly related to age, the investigators noted, since the subject who could not retain it was the oldest. Retention times ranged from 3 to 24 hours.
There were no serious adverse events during the study. Patients did report the expected discomfort of left-sided abdominal fullness. One experienced a moderate fever and chills 3 hours after the first two transplants, which spontaneously resolved over 6 hours. For the final three procedures, that patient took prophylactic acetaminophen and diphenhydramine.
Another patient had a low-grade fever after one transplant, which resolved without intervention. There were no cases of sepsis.
One patient experienced a disabling hematochezia 3 weeks after the transplant series. This was judged to be a flare unrelated to the transplant.
In the first week after the transplant series, seven of the nine patients in the analysis (78%) had a clinical response, defined as a decrease of more than 15 points in the Pediatric Ulcerative Colitis Activity Index. Six of the nine (67%) maintained that improvement at 1 month.
Three experienced clinical remission at 1 week, which lasted for 1 month. Two patients had a PUCAI score of 0 from week 3 until the end of the 7-week follow-up period.
The pilot study shows the feasibility of fecal transplants for ulcerative colitis, Dr. Kunde said. But while the technique is similar to that employed in C. difficile treatment, a more prolonged treatment seems necessary to elicit a response in ulcerative colitis.
"In order to better understand how fecal transplants can be used to treat ulcerative colitis, many unanswered questions need to be addressed. We must further investigate standardization of ... preparation, ideal donor selection, ideal route of administration, and optimal duration of scheduling [the transplants] to induce and maintain a clinical response. Most importantly, the effects of fecal material transplant on the colonic microbiome and mucosal inflammation in ulcerative colitis need to be explored."
The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
FROM PEDIATRIC GASTROENTEROLOGY AND NUTRITION
Major finding: Fecal transplants effected clinical improvement in 78% of children with ulcerative colitis.
Data source: Nine children were enrolled in a small prospective study.
Disclosures: The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
High blood pressure begins early in overweight children
WASHINGTON – Children as young as 3-5 years old appear to be at risk for developing hypertension if they become overweight or obese as they grow.
Prehypertension was 57% more likely to develop in children who went from being of normal weight to being overweight, and hypertension was almost twice as likely to develop, compared with children who maintained a normal weight, *Dr. Elyse Kharbanda, reported at the annual meeting of the Pediatric Academic Societies.
The picture was even grimmer for the 10% of children who remained obese during the entire 2.5-year study, said *Dr. Kharbanda of HealthPartners Institute for Education and Research, Bloomington, Minn. Those children were more than twice as likely to develop incident prehypertension and nearly four times as likely to develop incident hypertension.
Her study examined trends in weight and blood pressure among 59,638 children aged 3-17 years. The children were drawn from three large insurance data sets in northern California, Colorado, and Minnesota from the time period of 2007-2010. All of the children had visited a health care facility in their group at least four times during the study period, and all had normal blood pressure at the first visit.
About half (45%) of the children were white, 11% were black, 8% Asian, and 7% Hispanic; other ethnicities made up the remainder of the cohort. Age ranges were 3-5 years (27%), 6-8 years (17%), 9-11 years (21%), 12-14 years (22%), and 15-17 years (13%).
For the study, normal weight was defined as a body mass index in the 5th to less than 85th percentile, while overweight was defined as BMI in the 85th to less than 95th percentile. Obesity was defined as a BMI in the 95th percentile or greater.
At baseline, mean BMI was in the 64th percentile. The children’s mean baseline blood pressure was in the 39th percentile for systolic and 50th for diastolic.
Over the study period, 65% of the children maintained a normal weight, 8% remained overweight, and 10% remained obese. Nine percent of the group increased in weight, either from a healthy weight to overweight, or from overweight to obese. Eight percent of the children lost weight, going from overweight to normal weight or from obese to overweight.
During the study period, there were 16,102 new cases of prehypertension (27%) and 597 cases of incident hypertension (1%).
A multivariate analysis controlled for age, race, study site, and systolic blood pressure at baseline. In the fully adjusted model, compared with children who maintained a healthy weight, those who became overweight or obese were 57% more likely to develop prehypertension. Children who stayed overweight were 49% more likely to develop prehypertension, and those who remained obese were 2.3 times more likely to develop prehypertension. All of the differences were statistically significant.
Children who increased from one weight category to the next were 87% more likely to develop hypertension. The increased risk was 28% for those who stayed overweight and 3.6% for those who remained obese. Again, the changes were statistically significant.
The analysis also found significant differences in progression from prehypertension to hypertension. Children whose weight category increased were 27% more likely to progress, and those who stayed obese, 86% more likely. Children who stayed overweight were not significantly more likely to progress from prehypertension to hypertension, Dr. Kharbanda said.
She had no financial disclosures.
*Correction 5/10/13: The photo and reference to the presenter of the study that originally accompanied this article were incorrect. The presenter of the study was Dr. Elyse Kharbanda, of HealthPartners Institute for Education and Research, Bloomington, Minn.
Prehypertension, normal weight, Dr. Emily D. Parker, the Pediatric Academic Societies, HealthPartners Institute for Education and Research,
WASHINGTON – Children as young as 3-5 years old appear to be at risk for developing hypertension if they become overweight or obese as they grow.
Prehypertension was 57% more likely to develop in children who went from being of normal weight to being overweight, and hypertension was almost twice as likely to develop, compared with children who maintained a normal weight, *Dr. Elyse Kharbanda, reported at the annual meeting of the Pediatric Academic Societies.
The picture was even grimmer for the 10% of children who remained obese during the entire 2.5-year study, said *Dr. Kharbanda of HealthPartners Institute for Education and Research, Bloomington, Minn. Those children were more than twice as likely to develop incident prehypertension and nearly four times as likely to develop incident hypertension.
Her study examined trends in weight and blood pressure among 59,638 children aged 3-17 years. The children were drawn from three large insurance data sets in northern California, Colorado, and Minnesota from the time period of 2007-2010. All of the children had visited a health care facility in their group at least four times during the study period, and all had normal blood pressure at the first visit.
About half (45%) of the children were white, 11% were black, 8% Asian, and 7% Hispanic; other ethnicities made up the remainder of the cohort. Age ranges were 3-5 years (27%), 6-8 years (17%), 9-11 years (21%), 12-14 years (22%), and 15-17 years (13%).
For the study, normal weight was defined as a body mass index in the 5th to less than 85th percentile, while overweight was defined as BMI in the 85th to less than 95th percentile. Obesity was defined as a BMI in the 95th percentile or greater.
At baseline, mean BMI was in the 64th percentile. The children’s mean baseline blood pressure was in the 39th percentile for systolic and 50th for diastolic.
Over the study period, 65% of the children maintained a normal weight, 8% remained overweight, and 10% remained obese. Nine percent of the group increased in weight, either from a healthy weight to overweight, or from overweight to obese. Eight percent of the children lost weight, going from overweight to normal weight or from obese to overweight.
During the study period, there were 16,102 new cases of prehypertension (27%) and 597 cases of incident hypertension (1%).
A multivariate analysis controlled for age, race, study site, and systolic blood pressure at baseline. In the fully adjusted model, compared with children who maintained a healthy weight, those who became overweight or obese were 57% more likely to develop prehypertension. Children who stayed overweight were 49% more likely to develop prehypertension, and those who remained obese were 2.3 times more likely to develop prehypertension. All of the differences were statistically significant.
Children who increased from one weight category to the next were 87% more likely to develop hypertension. The increased risk was 28% for those who stayed overweight and 3.6% for those who remained obese. Again, the changes were statistically significant.
The analysis also found significant differences in progression from prehypertension to hypertension. Children whose weight category increased were 27% more likely to progress, and those who stayed obese, 86% more likely. Children who stayed overweight were not significantly more likely to progress from prehypertension to hypertension, Dr. Kharbanda said.
She had no financial disclosures.
*Correction 5/10/13: The photo and reference to the presenter of the study that originally accompanied this article were incorrect. The presenter of the study was Dr. Elyse Kharbanda, of HealthPartners Institute for Education and Research, Bloomington, Minn.
WASHINGTON – Children as young as 3-5 years old appear to be at risk for developing hypertension if they become overweight or obese as they grow.
Prehypertension was 57% more likely to develop in children who went from being of normal weight to being overweight, and hypertension was almost twice as likely to develop, compared with children who maintained a normal weight, *Dr. Elyse Kharbanda, reported at the annual meeting of the Pediatric Academic Societies.
The picture was even grimmer for the 10% of children who remained obese during the entire 2.5-year study, said *Dr. Kharbanda of HealthPartners Institute for Education and Research, Bloomington, Minn. Those children were more than twice as likely to develop incident prehypertension and nearly four times as likely to develop incident hypertension.
Her study examined trends in weight and blood pressure among 59,638 children aged 3-17 years. The children were drawn from three large insurance data sets in northern California, Colorado, and Minnesota from the time period of 2007-2010. All of the children had visited a health care facility in their group at least four times during the study period, and all had normal blood pressure at the first visit.
About half (45%) of the children were white, 11% were black, 8% Asian, and 7% Hispanic; other ethnicities made up the remainder of the cohort. Age ranges were 3-5 years (27%), 6-8 years (17%), 9-11 years (21%), 12-14 years (22%), and 15-17 years (13%).
For the study, normal weight was defined as a body mass index in the 5th to less than 85th percentile, while overweight was defined as BMI in the 85th to less than 95th percentile. Obesity was defined as a BMI in the 95th percentile or greater.
At baseline, mean BMI was in the 64th percentile. The children’s mean baseline blood pressure was in the 39th percentile for systolic and 50th for diastolic.
Over the study period, 65% of the children maintained a normal weight, 8% remained overweight, and 10% remained obese. Nine percent of the group increased in weight, either from a healthy weight to overweight, or from overweight to obese. Eight percent of the children lost weight, going from overweight to normal weight or from obese to overweight.
During the study period, there were 16,102 new cases of prehypertension (27%) and 597 cases of incident hypertension (1%).
A multivariate analysis controlled for age, race, study site, and systolic blood pressure at baseline. In the fully adjusted model, compared with children who maintained a healthy weight, those who became overweight or obese were 57% more likely to develop prehypertension. Children who stayed overweight were 49% more likely to develop prehypertension, and those who remained obese were 2.3 times more likely to develop prehypertension. All of the differences were statistically significant.
Children who increased from one weight category to the next were 87% more likely to develop hypertension. The increased risk was 28% for those who stayed overweight and 3.6% for those who remained obese. Again, the changes were statistically significant.
The analysis also found significant differences in progression from prehypertension to hypertension. Children whose weight category increased were 27% more likely to progress, and those who stayed obese, 86% more likely. Children who stayed overweight were not significantly more likely to progress from prehypertension to hypertension, Dr. Kharbanda said.
She had no financial disclosures.
*Correction 5/10/13: The photo and reference to the presenter of the study that originally accompanied this article were incorrect. The presenter of the study was Dr. Elyse Kharbanda, of HealthPartners Institute for Education and Research, Bloomington, Minn.
Prehypertension, normal weight, Dr. Emily D. Parker, the Pediatric Academic Societies, HealthPartners Institute for Education and Research,
Prehypertension, normal weight, Dr. Emily D. Parker, the Pediatric Academic Societies, HealthPartners Institute for Education and Research,
AT THE PAS ANNUAL MEETING
Major finding: Children who went from normal weight to overweight or obese over 2.5 years were 57% more likely to develop prehypertension and 87% more likely to develop hypertension, compared with children who maintained a normal weight.
Data source: The prospective database study examined weight and blood pressure trends in 59,638 children aged 3-17 years.
Disclosures: Dr. Kharbanda had no financial disclosures.
Marijuana habit not linked to lung cancer
WASHINGTON – Regular cannabis smokers are no more likely to develop lung cancer than are people who indulge occasionally.
The finding of no significant increased risk held true whether the smokers imbibed once or twice – or more – each day, and regardless of how many years they had smoked, Dr. Li Rita Zhang reported at the annual meeting of the American Association of Cancer Research.
The study included data from six case-control studies conducted from 1999 to 2012 in the United States, Canada, the United Kingdom, and New Zealand, with a subject pool of 2,159 lung cancer cases and 2,985 controls. All of the studies were part of the International Lung Cancer Consortium (ILCCO), an international group of lung cancer researchers with the aim of sharing comparable data from ongoing and recently completed lung cancer studies from different geographical areas and ethnicities.
Dr. Zhang of the University of California, Los Angeles, performed two analyses. One compared all lung cancer cases and all controls, regardless of concurrent or past tobacco use. Then, to reduce confounding by tobacco, she restricted the analysis to those who had never smoked tobacco. That group comprised 370 cancer cases and 1,358 controls. The models were also adjusted for age, sex, sociodemographic factors, and tobacco pack-years. Habitual use was defined as one joint per day per year.
When compared with cannabis smokers who also used tobacco, habitual pot smokers had no significant increase in cancer risk.
In an analysis of marijuana smokers that excluded tobacco smokers, there were no significant differences in any of the comparisons, including habitual vs. nonhabitual use; number of joints smoked per day; duration of up to 20 years or duration of more than 20 years.
Other literature has shown a link between cannabis smoking and lung cancer, pulmonologist Michael Alberts said in an interview. However, he said, "The conventional wisdom is that cannabis smoking is not as dangerous as cigarette smoking."
The difference in risk is likely related to chemical additives in commercial cigarettes that aren’t present in most methods of inhaling marijuana smoke.
As a general recommendation, smoking anything isn’t good for the respiratory system, said Dr. Alberts, chief medical officer of the Moffitt Cancer Center, Tampa. But for patients using medical marijuana, the benefit could outweigh the risks.
"You can think of it as similar to a CT scan. Radiation isn’t good, but if the scan is something beneficial and the risk is low, you take it. If cannabis is indicated, and if it’s legal, and if there’s literature backing up the indication for use, then you weigh the risk of smoking and the benefit it could bring, and make the decision."
Dr. Zhang declined to comment on the study. In her poster presentation she noted that, "Our results cannot preclude the possibility that cannabis may exhibit an association with lung cancer risk at extremely high dosage over long periods of continued exposure."
Dr. Zhang did not disclosure any financial relationships. Dr. Alberts said he had no disclosures.
WASHINGTON – Regular cannabis smokers are no more likely to develop lung cancer than are people who indulge occasionally.
The finding of no significant increased risk held true whether the smokers imbibed once or twice – or more – each day, and regardless of how many years they had smoked, Dr. Li Rita Zhang reported at the annual meeting of the American Association of Cancer Research.
The study included data from six case-control studies conducted from 1999 to 2012 in the United States, Canada, the United Kingdom, and New Zealand, with a subject pool of 2,159 lung cancer cases and 2,985 controls. All of the studies were part of the International Lung Cancer Consortium (ILCCO), an international group of lung cancer researchers with the aim of sharing comparable data from ongoing and recently completed lung cancer studies from different geographical areas and ethnicities.
Dr. Zhang of the University of California, Los Angeles, performed two analyses. One compared all lung cancer cases and all controls, regardless of concurrent or past tobacco use. Then, to reduce confounding by tobacco, she restricted the analysis to those who had never smoked tobacco. That group comprised 370 cancer cases and 1,358 controls. The models were also adjusted for age, sex, sociodemographic factors, and tobacco pack-years. Habitual use was defined as one joint per day per year.
When compared with cannabis smokers who also used tobacco, habitual pot smokers had no significant increase in cancer risk.
In an analysis of marijuana smokers that excluded tobacco smokers, there were no significant differences in any of the comparisons, including habitual vs. nonhabitual use; number of joints smoked per day; duration of up to 20 years or duration of more than 20 years.
Other literature has shown a link between cannabis smoking and lung cancer, pulmonologist Michael Alberts said in an interview. However, he said, "The conventional wisdom is that cannabis smoking is not as dangerous as cigarette smoking."
The difference in risk is likely related to chemical additives in commercial cigarettes that aren’t present in most methods of inhaling marijuana smoke.
As a general recommendation, smoking anything isn’t good for the respiratory system, said Dr. Alberts, chief medical officer of the Moffitt Cancer Center, Tampa. But for patients using medical marijuana, the benefit could outweigh the risks.
"You can think of it as similar to a CT scan. Radiation isn’t good, but if the scan is something beneficial and the risk is low, you take it. If cannabis is indicated, and if it’s legal, and if there’s literature backing up the indication for use, then you weigh the risk of smoking and the benefit it could bring, and make the decision."
Dr. Zhang declined to comment on the study. In her poster presentation she noted that, "Our results cannot preclude the possibility that cannabis may exhibit an association with lung cancer risk at extremely high dosage over long periods of continued exposure."
Dr. Zhang did not disclosure any financial relationships. Dr. Alberts said he had no disclosures.
WASHINGTON – Regular cannabis smokers are no more likely to develop lung cancer than are people who indulge occasionally.
The finding of no significant increased risk held true whether the smokers imbibed once or twice – or more – each day, and regardless of how many years they had smoked, Dr. Li Rita Zhang reported at the annual meeting of the American Association of Cancer Research.
The study included data from six case-control studies conducted from 1999 to 2012 in the United States, Canada, the United Kingdom, and New Zealand, with a subject pool of 2,159 lung cancer cases and 2,985 controls. All of the studies were part of the International Lung Cancer Consortium (ILCCO), an international group of lung cancer researchers with the aim of sharing comparable data from ongoing and recently completed lung cancer studies from different geographical areas and ethnicities.
Dr. Zhang of the University of California, Los Angeles, performed two analyses. One compared all lung cancer cases and all controls, regardless of concurrent or past tobacco use. Then, to reduce confounding by tobacco, she restricted the analysis to those who had never smoked tobacco. That group comprised 370 cancer cases and 1,358 controls. The models were also adjusted for age, sex, sociodemographic factors, and tobacco pack-years. Habitual use was defined as one joint per day per year.
When compared with cannabis smokers who also used tobacco, habitual pot smokers had no significant increase in cancer risk.
In an analysis of marijuana smokers that excluded tobacco smokers, there were no significant differences in any of the comparisons, including habitual vs. nonhabitual use; number of joints smoked per day; duration of up to 20 years or duration of more than 20 years.
Other literature has shown a link between cannabis smoking and lung cancer, pulmonologist Michael Alberts said in an interview. However, he said, "The conventional wisdom is that cannabis smoking is not as dangerous as cigarette smoking."
The difference in risk is likely related to chemical additives in commercial cigarettes that aren’t present in most methods of inhaling marijuana smoke.
As a general recommendation, smoking anything isn’t good for the respiratory system, said Dr. Alberts, chief medical officer of the Moffitt Cancer Center, Tampa. But for patients using medical marijuana, the benefit could outweigh the risks.
"You can think of it as similar to a CT scan. Radiation isn’t good, but if the scan is something beneficial and the risk is low, you take it. If cannabis is indicated, and if it’s legal, and if there’s literature backing up the indication for use, then you weigh the risk of smoking and the benefit it could bring, and make the decision."
Dr. Zhang declined to comment on the study. In her poster presentation she noted that, "Our results cannot preclude the possibility that cannabis may exhibit an association with lung cancer risk at extremely high dosage over long periods of continued exposure."
Dr. Zhang did not disclosure any financial relationships. Dr. Alberts said he had no disclosures.
AT THE AACR ANNUAL MEETING
Major finding: People who habitually smoked marijuana were no more likely to develop lung cancer than those who didn’t, whether or not they also smoked cigarettes.
Data source: The metaanalysis included 2,159 lung cancer cases and 2,985 controls extracted from six studies.
Disclosures: Neither Dr. Zhang nor Dr. Alberts reported any financial disclosures.
In children with hypertension, weight plus race don't add up equally
WASHINGTON – Race and weight seem to work in concert to drive up blood pressure in Hispanic and white children, a study has shown.
"The interaction between race, obesity, and hypertension within any group is simple," Dr. Joshua Samuels said at the annual meeting of the Pediatric Academic Societies. "As kids become fatter, their rates of hypertension rise. But among Caucasian and Hispanic children, there’s a much more pronounced rise at a lower body mass index, with hypertension starting when the BMI reaches the 60th percentile."
Dr. Samuels of the University of Texas Medical School at Houston* presented 12 years of data from his ongoing study of hypertension in public school students. So far, he and his colleagues have performed serial blood pressure screening on more than 20,000 children. Each child had blood pressure measurements on four separate occasions, with height and weight recorded each time.
After three measurements, each child was categorized as normotensive (three normal readings), prehypertensive (one hypertensive reading), or sustained hypertensive (three hypertensive readings).
The study population consisted of 20,729 racially and ethnically diverse students aged 10-18 years, with a mean age of 14.
A majority (64%) were normal weight, 18% were overweight, and 18% were obese.
"Obesity was prominent. All of these children were shifted toward the heavier range, and less than 2/3 was at a normal, healthy weight," Dr. Samuels said.
Hispanic and black youths were disproportionately overweight and obese, he said. Hispanic youths made up 34% of the study population but 44% of the obese group. Black youths made up 25% of the population but 30% of the obese group. Conversely, 34% of the population was white, but 22% of the obese group was white. Asian youths made up 7% of the population but 4% of the obese group.
Obesity was strongly associated with hypertension, with hypertension present in 1.6% of normal-weight youths, 2.6% of overweight youths, and 6.6% of obese youths.
While race alone was not significantly associated with hypertension, the interaction of race, weight, and hypertension was.
Among normal-weight youths when categorized by racial groups, hypertension clustered at 1.2%-2% for all groups. Among the overweight youths, hypertension was diagnosed in 1.8% of Asians, 2.4% of whites, 2.6% of Hispanics, and 2.9% of blacks.
Among obese children, however, more Hispanics (8%) and whites (7.5%) were hypertensive, compared with 4.5% of both Asians and blacks.
Furthermore, Dr. Samuels said, in whites and Hispanics, hypertension began at a much lower BMI. At the 50th percentile, hypertension clustered around 1.5%-2% for all racial groups. The groups began to separate around the 60th percentile, with blacks and whites having about a 1% higher rate of hypertension than Hispanics and Asians. By the 70th percentile, hypertension in Hispanics, blacks, and whites all clustered around 3%, with Asians below 2%. By the 90th percentile, hypertension in Asians was still less than 3%. It was around 3% in blacks, but was about 4% in Hispanics and whites.
The study wasn’t designed to investigate the reasons behind these differences, although Dr. Samuels said some of his colleagues are launching such a study. "My feeling is that there is some genetic component to it."
Whatever the reason, he said, the growing obesity problem among children portends ill for the next generation of adults.
"What we see now is a group of children who are obese, but what’s coming down the pike, if we’re not careful, is a huge undercurrent of adults with diabetes, stroke, blindness, cancer, kidney failure, and cardiovascular disease," he said.
Dr. Samuels said he had no relevant financial disclosures.
*This story was updated 5/6/13.
WASHINGTON – Race and weight seem to work in concert to drive up blood pressure in Hispanic and white children, a study has shown.
"The interaction between race, obesity, and hypertension within any group is simple," Dr. Joshua Samuels said at the annual meeting of the Pediatric Academic Societies. "As kids become fatter, their rates of hypertension rise. But among Caucasian and Hispanic children, there’s a much more pronounced rise at a lower body mass index, with hypertension starting when the BMI reaches the 60th percentile."
Dr. Samuels of the University of Texas Medical School at Houston* presented 12 years of data from his ongoing study of hypertension in public school students. So far, he and his colleagues have performed serial blood pressure screening on more than 20,000 children. Each child had blood pressure measurements on four separate occasions, with height and weight recorded each time.
After three measurements, each child was categorized as normotensive (three normal readings), prehypertensive (one hypertensive reading), or sustained hypertensive (three hypertensive readings).
The study population consisted of 20,729 racially and ethnically diverse students aged 10-18 years, with a mean age of 14.
A majority (64%) were normal weight, 18% were overweight, and 18% were obese.
"Obesity was prominent. All of these children were shifted toward the heavier range, and less than 2/3 was at a normal, healthy weight," Dr. Samuels said.
Hispanic and black youths were disproportionately overweight and obese, he said. Hispanic youths made up 34% of the study population but 44% of the obese group. Black youths made up 25% of the population but 30% of the obese group. Conversely, 34% of the population was white, but 22% of the obese group was white. Asian youths made up 7% of the population but 4% of the obese group.
Obesity was strongly associated with hypertension, with hypertension present in 1.6% of normal-weight youths, 2.6% of overweight youths, and 6.6% of obese youths.
While race alone was not significantly associated with hypertension, the interaction of race, weight, and hypertension was.
Among normal-weight youths when categorized by racial groups, hypertension clustered at 1.2%-2% for all groups. Among the overweight youths, hypertension was diagnosed in 1.8% of Asians, 2.4% of whites, 2.6% of Hispanics, and 2.9% of blacks.
Among obese children, however, more Hispanics (8%) and whites (7.5%) were hypertensive, compared with 4.5% of both Asians and blacks.
Furthermore, Dr. Samuels said, in whites and Hispanics, hypertension began at a much lower BMI. At the 50th percentile, hypertension clustered around 1.5%-2% for all racial groups. The groups began to separate around the 60th percentile, with blacks and whites having about a 1% higher rate of hypertension than Hispanics and Asians. By the 70th percentile, hypertension in Hispanics, blacks, and whites all clustered around 3%, with Asians below 2%. By the 90th percentile, hypertension in Asians was still less than 3%. It was around 3% in blacks, but was about 4% in Hispanics and whites.
The study wasn’t designed to investigate the reasons behind these differences, although Dr. Samuels said some of his colleagues are launching such a study. "My feeling is that there is some genetic component to it."
Whatever the reason, he said, the growing obesity problem among children portends ill for the next generation of adults.
"What we see now is a group of children who are obese, but what’s coming down the pike, if we’re not careful, is a huge undercurrent of adults with diabetes, stroke, blindness, cancer, kidney failure, and cardiovascular disease," he said.
Dr. Samuels said he had no relevant financial disclosures.
*This story was updated 5/6/13.
WASHINGTON – Race and weight seem to work in concert to drive up blood pressure in Hispanic and white children, a study has shown.
"The interaction between race, obesity, and hypertension within any group is simple," Dr. Joshua Samuels said at the annual meeting of the Pediatric Academic Societies. "As kids become fatter, their rates of hypertension rise. But among Caucasian and Hispanic children, there’s a much more pronounced rise at a lower body mass index, with hypertension starting when the BMI reaches the 60th percentile."
Dr. Samuels of the University of Texas Medical School at Houston* presented 12 years of data from his ongoing study of hypertension in public school students. So far, he and his colleagues have performed serial blood pressure screening on more than 20,000 children. Each child had blood pressure measurements on four separate occasions, with height and weight recorded each time.
After three measurements, each child was categorized as normotensive (three normal readings), prehypertensive (one hypertensive reading), or sustained hypertensive (three hypertensive readings).
The study population consisted of 20,729 racially and ethnically diverse students aged 10-18 years, with a mean age of 14.
A majority (64%) were normal weight, 18% were overweight, and 18% were obese.
"Obesity was prominent. All of these children were shifted toward the heavier range, and less than 2/3 was at a normal, healthy weight," Dr. Samuels said.
Hispanic and black youths were disproportionately overweight and obese, he said. Hispanic youths made up 34% of the study population but 44% of the obese group. Black youths made up 25% of the population but 30% of the obese group. Conversely, 34% of the population was white, but 22% of the obese group was white. Asian youths made up 7% of the population but 4% of the obese group.
Obesity was strongly associated with hypertension, with hypertension present in 1.6% of normal-weight youths, 2.6% of overweight youths, and 6.6% of obese youths.
While race alone was not significantly associated with hypertension, the interaction of race, weight, and hypertension was.
Among normal-weight youths when categorized by racial groups, hypertension clustered at 1.2%-2% for all groups. Among the overweight youths, hypertension was diagnosed in 1.8% of Asians, 2.4% of whites, 2.6% of Hispanics, and 2.9% of blacks.
Among obese children, however, more Hispanics (8%) and whites (7.5%) were hypertensive, compared with 4.5% of both Asians and blacks.
Furthermore, Dr. Samuels said, in whites and Hispanics, hypertension began at a much lower BMI. At the 50th percentile, hypertension clustered around 1.5%-2% for all racial groups. The groups began to separate around the 60th percentile, with blacks and whites having about a 1% higher rate of hypertension than Hispanics and Asians. By the 70th percentile, hypertension in Hispanics, blacks, and whites all clustered around 3%, with Asians below 2%. By the 90th percentile, hypertension in Asians was still less than 3%. It was around 3% in blacks, but was about 4% in Hispanics and whites.
The study wasn’t designed to investigate the reasons behind these differences, although Dr. Samuels said some of his colleagues are launching such a study. "My feeling is that there is some genetic component to it."
Whatever the reason, he said, the growing obesity problem among children portends ill for the next generation of adults.
"What we see now is a group of children who are obese, but what’s coming down the pike, if we’re not careful, is a huge undercurrent of adults with diabetes, stroke, blindness, cancer, kidney failure, and cardiovascular disease," he said.
Dr. Samuels said he had no relevant financial disclosures.
*This story was updated 5/6/13.
AT THE PAS ANNUAL MEETING
Major finding: Race and weight interact to drive up hypertension rates in white and Hispanic children to nearly twice those seen in black and Asian children.
Data source: A prospective study with data on more than 20,000 children aged 10-18 years.
Disclosures: Dr. Samuels said he had no relevant financial disclosures.
Small vitamin D dose hits the plasma target
A daily vitamin D dose of 400 IU was enough for breast-fed infants to reach the plasma concentration recommended by several clinical associations.
Very nearly 100% of the infants in a randomized trial who took 400 IU attained the 50-nmol/L target for 25-hydroxyvitamin D (25(OH)D). All infants who took a daily dose of 800 IU or 1,200 IU also met that goal, although those babies didn’t gain any additional bone health benefits over the 400-IU group, Hope Weiler, Ph.D., and her colleagues wrote in the May 1 issue of JAMA (JAMA 2013;309:1785-92).
In a press briefing, Dr. Weiler, of the McGill University School of Dietetics and Human Nutrition, Montreal, said she and her coinvestigators undertook the study for two reasons: Six different clinical associations each recommend a different daily dose of the vitamin, and there are no clear data on what plasma level confers maximum health benefits while posing the smallest risk to infants.
"What we were lacking is an understanding of that relationship between how much is consumed and how much is in the blood, and whether that is enough to help them grow in a healthy manner," she said. "We know that very low levels [of 25(OH)D] are associated with rickets, and we have good evidence that you don’t want levels to go below 30 nmol/L."
Some studies, however, had found rickets associated with 25(OH)D levels as high as 50 nmol/L. This evidence spread has led to the divergent dosing recommendations, calling for as little as 200 IU/day to as much as 1,600 IU/day.
The American Academy of Pediatrics recommends a level of 200 IU/day. Health Canada recommends 400 IU/day, and the Canadian Paediatric Society recommends 400-800 IU/day. The AAP and CPS also recommend aiming for a plasma concentration of 75 nmol/L, "but this is based on findings in adults and older children," Dr. Weiler said. "We wanted to find out if this was a good fit for infants, too."
The study’s primary goal was to find the vitamin D dosage that would achieve a 75-nmol/L level in more than 97% of infants. A secondary goal was to find a dosage that would result in a level of at least 50 nmol/L.
The trial randomized 132 breast-fed, 1-month-old infants to a vitamin D supplement of 400, 800, 1,200 or 1,600 IU/day. The babies were assessed at 2, 3, 6, 9, and 12 months.
The mothers were an average of 33 years; 85% were white. Most of the babies (58%) were born between October and April, months when sunlight is limited in Canada.
At 3 and 6 months, nearly 100% of infants taking the 1,600-IU dose fulfilled the primary endpoint of a 97% response rate for 75 nmol/L. By 6 and 12 months, however, the response rates were about 90%. In fact, all of the response rates declined over the study period.
There was a clear dose-dependent response in the other groups. At 3 months, compared with infants taking 400 IU/day, those taking 800 IU were 3.5 times as likely to hit the target of 75 nmol/L, and those taking 1,200 IU were almost 10 times as likely to hit the target.
Nearly 100% of all groups, however, hit the 50-nmol/L target, and the response was sustained at each assessment throughout the study.
The 25(OH)D concentrations peaked at 3 months in every group. At that time, the mean concentrations were 78 nmol/L in the 400-IU group, 102 nmol/L in the 800-IU group, 134 nmol/L in the 1,200-IU group, and 180 nmol/L in the 1,600-IU group. Several infants had levels of more than 200 nmol/L – a level generally considered to increase the risk of hypercalcemia.
The 1,600-IU dosage "was discontinued because most infants in that group developed elevated plasma 25(OH)D concentrations that have been associated with hypercalcemia," Dr. Weiler and her coauthors noted in the paper. However, additional safety testing on these infants showed no signs of the disorder, she added. Dual-energy x-ray absorptiometry scans at each assessment showed that infants in each group were growing well, with no significant between-group differences in bone mineral content or bone density.
"The 400-IU dose was quite satisfactory to meet the plasma concentration recommended by the Institute of Medicine, Canadian Paediatric Association, and the American Academy of Pediatrics," Dr. Weiler said during the briefing. But there are still unanswered questions, she added.
"We’ve been able to link up how much vitamin D gets us the response we want in vitamin D stores in the body, but how high should those stores be, not only for bone health, but for other processes, like immune regulation? We also had a mostly white, well-educated group, so we need to focus now on mothers and infants with darker skin who are at a higher risk of deficiency."
The Canadian Institutes of Health Research funded the study. Dr. Weiler declared no financial relationships.
For now, clinicians can feel comfortable in recommending a daily vitamin D dose of 400 IU for infants.
But some questions still remain.
While there are no studies suggesting that 50 nmol/L is an inadequate plasma concentration of 25(OH)D, there are also none that examine whether 75 nmol/L could be a useful goal for infants who have some special needs, Dr. Abrams noted.
"Another question that needs to be answered is whether there are non–bone health reasons to target a plasma 25(OH)D concentration greater than 75 nmol/L," he said. "Although such outcomes of vitamin D supplementation in infants might include respiratory or infectious end points in infancy, it is likely that the real potential major benefits would be long-term outcomes, such as the risk of asthma or autoimmune disorders such as type 1 diabetes mellitus."
According to the U.S. Institute of Medicine, there are not enough data for any childhood age group to recommend certain dosages of vitamin D based on bone health outcome.
"It is not likely that substantial data based on such trials will be available in the near future, but this research should be advocated and supported as key to providing true answers to these critical questions."
Dr. Steven A. Abrams is a professor of pediatrics at the Baylor College University of Medicine, and a neonatologist at Texas Children’s Hospital, both in Houston. He has financial relationships with Abbott Nutrition and Mead-Johnson Nutrition. He made these comments in an editorial accompanying Dr. Weiler’s study (JAMA 2013;309:1830-31).
For now, clinicians can feel comfortable in recommending a daily vitamin D dose of 400 IU for infants.
But some questions still remain.
While there are no studies suggesting that 50 nmol/L is an inadequate plasma concentration of 25(OH)D, there are also none that examine whether 75 nmol/L could be a useful goal for infants who have some special needs, Dr. Abrams noted.
"Another question that needs to be answered is whether there are non–bone health reasons to target a plasma 25(OH)D concentration greater than 75 nmol/L," he said. "Although such outcomes of vitamin D supplementation in infants might include respiratory or infectious end points in infancy, it is likely that the real potential major benefits would be long-term outcomes, such as the risk of asthma or autoimmune disorders such as type 1 diabetes mellitus."
According to the U.S. Institute of Medicine, there are not enough data for any childhood age group to recommend certain dosages of vitamin D based on bone health outcome.
"It is not likely that substantial data based on such trials will be available in the near future, but this research should be advocated and supported as key to providing true answers to these critical questions."
Dr. Steven A. Abrams is a professor of pediatrics at the Baylor College University of Medicine, and a neonatologist at Texas Children’s Hospital, both in Houston. He has financial relationships with Abbott Nutrition and Mead-Johnson Nutrition. He made these comments in an editorial accompanying Dr. Weiler’s study (JAMA 2013;309:1830-31).
For now, clinicians can feel comfortable in recommending a daily vitamin D dose of 400 IU for infants.
But some questions still remain.
While there are no studies suggesting that 50 nmol/L is an inadequate plasma concentration of 25(OH)D, there are also none that examine whether 75 nmol/L could be a useful goal for infants who have some special needs, Dr. Abrams noted.
"Another question that needs to be answered is whether there are non–bone health reasons to target a plasma 25(OH)D concentration greater than 75 nmol/L," he said. "Although such outcomes of vitamin D supplementation in infants might include respiratory or infectious end points in infancy, it is likely that the real potential major benefits would be long-term outcomes, such as the risk of asthma or autoimmune disorders such as type 1 diabetes mellitus."
According to the U.S. Institute of Medicine, there are not enough data for any childhood age group to recommend certain dosages of vitamin D based on bone health outcome.
"It is not likely that substantial data based on such trials will be available in the near future, but this research should be advocated and supported as key to providing true answers to these critical questions."
Dr. Steven A. Abrams is a professor of pediatrics at the Baylor College University of Medicine, and a neonatologist at Texas Children’s Hospital, both in Houston. He has financial relationships with Abbott Nutrition and Mead-Johnson Nutrition. He made these comments in an editorial accompanying Dr. Weiler’s study (JAMA 2013;309:1830-31).
A daily vitamin D dose of 400 IU was enough for breast-fed infants to reach the plasma concentration recommended by several clinical associations.
Very nearly 100% of the infants in a randomized trial who took 400 IU attained the 50-nmol/L target for 25-hydroxyvitamin D (25(OH)D). All infants who took a daily dose of 800 IU or 1,200 IU also met that goal, although those babies didn’t gain any additional bone health benefits over the 400-IU group, Hope Weiler, Ph.D., and her colleagues wrote in the May 1 issue of JAMA (JAMA 2013;309:1785-92).
In a press briefing, Dr. Weiler, of the McGill University School of Dietetics and Human Nutrition, Montreal, said she and her coinvestigators undertook the study for two reasons: Six different clinical associations each recommend a different daily dose of the vitamin, and there are no clear data on what plasma level confers maximum health benefits while posing the smallest risk to infants.
"What we were lacking is an understanding of that relationship between how much is consumed and how much is in the blood, and whether that is enough to help them grow in a healthy manner," she said. "We know that very low levels [of 25(OH)D] are associated with rickets, and we have good evidence that you don’t want levels to go below 30 nmol/L."
Some studies, however, had found rickets associated with 25(OH)D levels as high as 50 nmol/L. This evidence spread has led to the divergent dosing recommendations, calling for as little as 200 IU/day to as much as 1,600 IU/day.
The American Academy of Pediatrics recommends a level of 200 IU/day. Health Canada recommends 400 IU/day, and the Canadian Paediatric Society recommends 400-800 IU/day. The AAP and CPS also recommend aiming for a plasma concentration of 75 nmol/L, "but this is based on findings in adults and older children," Dr. Weiler said. "We wanted to find out if this was a good fit for infants, too."
The study’s primary goal was to find the vitamin D dosage that would achieve a 75-nmol/L level in more than 97% of infants. A secondary goal was to find a dosage that would result in a level of at least 50 nmol/L.
The trial randomized 132 breast-fed, 1-month-old infants to a vitamin D supplement of 400, 800, 1,200 or 1,600 IU/day. The babies were assessed at 2, 3, 6, 9, and 12 months.
The mothers were an average of 33 years; 85% were white. Most of the babies (58%) were born between October and April, months when sunlight is limited in Canada.
At 3 and 6 months, nearly 100% of infants taking the 1,600-IU dose fulfilled the primary endpoint of a 97% response rate for 75 nmol/L. By 6 and 12 months, however, the response rates were about 90%. In fact, all of the response rates declined over the study period.
There was a clear dose-dependent response in the other groups. At 3 months, compared with infants taking 400 IU/day, those taking 800 IU were 3.5 times as likely to hit the target of 75 nmol/L, and those taking 1,200 IU were almost 10 times as likely to hit the target.
Nearly 100% of all groups, however, hit the 50-nmol/L target, and the response was sustained at each assessment throughout the study.
The 25(OH)D concentrations peaked at 3 months in every group. At that time, the mean concentrations were 78 nmol/L in the 400-IU group, 102 nmol/L in the 800-IU group, 134 nmol/L in the 1,200-IU group, and 180 nmol/L in the 1,600-IU group. Several infants had levels of more than 200 nmol/L – a level generally considered to increase the risk of hypercalcemia.
The 1,600-IU dosage "was discontinued because most infants in that group developed elevated plasma 25(OH)D concentrations that have been associated with hypercalcemia," Dr. Weiler and her coauthors noted in the paper. However, additional safety testing on these infants showed no signs of the disorder, she added. Dual-energy x-ray absorptiometry scans at each assessment showed that infants in each group were growing well, with no significant between-group differences in bone mineral content or bone density.
"The 400-IU dose was quite satisfactory to meet the plasma concentration recommended by the Institute of Medicine, Canadian Paediatric Association, and the American Academy of Pediatrics," Dr. Weiler said during the briefing. But there are still unanswered questions, she added.
"We’ve been able to link up how much vitamin D gets us the response we want in vitamin D stores in the body, but how high should those stores be, not only for bone health, but for other processes, like immune regulation? We also had a mostly white, well-educated group, so we need to focus now on mothers and infants with darker skin who are at a higher risk of deficiency."
The Canadian Institutes of Health Research funded the study. Dr. Weiler declared no financial relationships.
A daily vitamin D dose of 400 IU was enough for breast-fed infants to reach the plasma concentration recommended by several clinical associations.
Very nearly 100% of the infants in a randomized trial who took 400 IU attained the 50-nmol/L target for 25-hydroxyvitamin D (25(OH)D). All infants who took a daily dose of 800 IU or 1,200 IU also met that goal, although those babies didn’t gain any additional bone health benefits over the 400-IU group, Hope Weiler, Ph.D., and her colleagues wrote in the May 1 issue of JAMA (JAMA 2013;309:1785-92).
In a press briefing, Dr. Weiler, of the McGill University School of Dietetics and Human Nutrition, Montreal, said she and her coinvestigators undertook the study for two reasons: Six different clinical associations each recommend a different daily dose of the vitamin, and there are no clear data on what plasma level confers maximum health benefits while posing the smallest risk to infants.
"What we were lacking is an understanding of that relationship between how much is consumed and how much is in the blood, and whether that is enough to help them grow in a healthy manner," she said. "We know that very low levels [of 25(OH)D] are associated with rickets, and we have good evidence that you don’t want levels to go below 30 nmol/L."
Some studies, however, had found rickets associated with 25(OH)D levels as high as 50 nmol/L. This evidence spread has led to the divergent dosing recommendations, calling for as little as 200 IU/day to as much as 1,600 IU/day.
The American Academy of Pediatrics recommends a level of 200 IU/day. Health Canada recommends 400 IU/day, and the Canadian Paediatric Society recommends 400-800 IU/day. The AAP and CPS also recommend aiming for a plasma concentration of 75 nmol/L, "but this is based on findings in adults and older children," Dr. Weiler said. "We wanted to find out if this was a good fit for infants, too."
The study’s primary goal was to find the vitamin D dosage that would achieve a 75-nmol/L level in more than 97% of infants. A secondary goal was to find a dosage that would result in a level of at least 50 nmol/L.
The trial randomized 132 breast-fed, 1-month-old infants to a vitamin D supplement of 400, 800, 1,200 or 1,600 IU/day. The babies were assessed at 2, 3, 6, 9, and 12 months.
The mothers were an average of 33 years; 85% were white. Most of the babies (58%) were born between October and April, months when sunlight is limited in Canada.
At 3 and 6 months, nearly 100% of infants taking the 1,600-IU dose fulfilled the primary endpoint of a 97% response rate for 75 nmol/L. By 6 and 12 months, however, the response rates were about 90%. In fact, all of the response rates declined over the study period.
There was a clear dose-dependent response in the other groups. At 3 months, compared with infants taking 400 IU/day, those taking 800 IU were 3.5 times as likely to hit the target of 75 nmol/L, and those taking 1,200 IU were almost 10 times as likely to hit the target.
Nearly 100% of all groups, however, hit the 50-nmol/L target, and the response was sustained at each assessment throughout the study.
The 25(OH)D concentrations peaked at 3 months in every group. At that time, the mean concentrations were 78 nmol/L in the 400-IU group, 102 nmol/L in the 800-IU group, 134 nmol/L in the 1,200-IU group, and 180 nmol/L in the 1,600-IU group. Several infants had levels of more than 200 nmol/L – a level generally considered to increase the risk of hypercalcemia.
The 1,600-IU dosage "was discontinued because most infants in that group developed elevated plasma 25(OH)D concentrations that have been associated with hypercalcemia," Dr. Weiler and her coauthors noted in the paper. However, additional safety testing on these infants showed no signs of the disorder, she added. Dual-energy x-ray absorptiometry scans at each assessment showed that infants in each group were growing well, with no significant between-group differences in bone mineral content or bone density.
"The 400-IU dose was quite satisfactory to meet the plasma concentration recommended by the Institute of Medicine, Canadian Paediatric Association, and the American Academy of Pediatrics," Dr. Weiler said during the briefing. But there are still unanswered questions, she added.
"We’ve been able to link up how much vitamin D gets us the response we want in vitamin D stores in the body, but how high should those stores be, not only for bone health, but for other processes, like immune regulation? We also had a mostly white, well-educated group, so we need to focus now on mothers and infants with darker skin who are at a higher risk of deficiency."
The Canadian Institutes of Health Research funded the study. Dr. Weiler declared no financial relationships.
FROM JAMA
Major finding: For breast-fed infants, a daily dose of 400 IU of vitamin D boosted plasma concentrations of 25(OH)D to the 400-nmol/L level recommended by the American Academy of Pediatrics.
Data source: The randomized trial comprised 132 infants.
Disclosures: The Canadian Institutes of Health Research funded the study. Dr. Weiler declared no financial relationships.
Infant UTI: Spinal tap for meningitis before ED discharge
LAKE BUENA VISTA, FLA. – Does every baby who presents to the emergency department with a urinary tract infection need a lumbar puncture to rule out meningitis?
Maybe not, Dr. James Callahan said at the Advanced Pediatric Emergency Medicine Assembly. Age, past medical history, and the child’s overall demeanor are the best clues as to whether to proceed with a spinal tap in babies with a confirmed source of infection.
The topic is worth reviewing because childhood meningitis cases are on the decline, said Dr. Callahan of Children’s Hospital of Pennsylvania, Philadelphia.
When a disease begins to fade from a patient population, it also can fade from the collective consciousness of clinicians. "There are residents and fellows in emergency medicine and pediatrics now who have never seen a case of [Haemophilus] influenzae meningitis," he said at the meeting, which was sponsored by the American College of Emergency Physicians and the American Academy of Pediatrics.
That can mean tragedy for patients and families, and disaster for doctors. "Missed meningitis remains the number-one cause of settled lawsuits in pediatric emergency medicine, and carries the highest settlement and indemnity costs," he said.
A number of signs can help rule in the disease, but few can completely rule it out. "Although several clinical features are useful in diagnosing meningitis, no one isolated clinical feature is diagnostic. Nor can any isolated clinical feature completely exclude meningitis as a diagnostic possibility, and it’s not clear what the most accurate combination of clinical features is – or if there even is such a combination," Dr. Callahan explained.
That leaves clinicians with what seems to be the only concrete option – the lumbar puncture. "I personally think an LP is a relatively simple procedure, but there is a lot of parental resistance to it," he noted.
Dr. Callahan examined the question in light of infants’ most common bacterial infection – the urinary tract infection (UTI). Studies from the last 15 years agree that, while the risk of meningitis in conjunction with UTI is very low, it is there.
The largest of these included nearly 2,000 infants with culture-proven UTI. Most (1,609) underwent an LP. Of those patients, 3% had bacterial meningitis. A combination of clinical findings – not clinically ill on exam, no dehydration or acute respiratory distress, no concomitant acute disease or high-risk medical history – ruled out meningitis with a 98% sensitivity and 99.9% negative predictive value (Pediatrics 2010;126:1074-83).
A 2011 study found a 1% rate of meningitis associated with UTI in infants younger than 28 days, but there were no cases at all in the older babies. All of those with meningitis were symptomatic on admission, with fever, irritability, and lethargy (PLoS One 2011;6:e26576).
"Meningitis appears exceedingly rare in children older than 28 days," Dr. Callahan said. "All neonates who present with a culture-proven UTI should have an LP. But those who are older, and who look well, without a negative past history – you might consider not doing one."
Whether or not the child will be admitted to the hospital plays a part in Dr. Callahan’s decision.
"If they have a UTI and they’re getting admitted, but look well and have a negative past medical history, I don’t tap. I really think the data say if they look like they are well, they will not get meningitis."
If, on the other hand, the baby will be going home from the emergency visit, he does the procedure. "And make sure you have someone who’s going to follow that child very closely," he advised.
Dr. Callahan had no financial disclosures.
LAKE BUENA VISTA, FLA. – Does every baby who presents to the emergency department with a urinary tract infection need a lumbar puncture to rule out meningitis?
Maybe not, Dr. James Callahan said at the Advanced Pediatric Emergency Medicine Assembly. Age, past medical history, and the child’s overall demeanor are the best clues as to whether to proceed with a spinal tap in babies with a confirmed source of infection.
The topic is worth reviewing because childhood meningitis cases are on the decline, said Dr. Callahan of Children’s Hospital of Pennsylvania, Philadelphia.
When a disease begins to fade from a patient population, it also can fade from the collective consciousness of clinicians. "There are residents and fellows in emergency medicine and pediatrics now who have never seen a case of [Haemophilus] influenzae meningitis," he said at the meeting, which was sponsored by the American College of Emergency Physicians and the American Academy of Pediatrics.
That can mean tragedy for patients and families, and disaster for doctors. "Missed meningitis remains the number-one cause of settled lawsuits in pediatric emergency medicine, and carries the highest settlement and indemnity costs," he said.
A number of signs can help rule in the disease, but few can completely rule it out. "Although several clinical features are useful in diagnosing meningitis, no one isolated clinical feature is diagnostic. Nor can any isolated clinical feature completely exclude meningitis as a diagnostic possibility, and it’s not clear what the most accurate combination of clinical features is – or if there even is such a combination," Dr. Callahan explained.
That leaves clinicians with what seems to be the only concrete option – the lumbar puncture. "I personally think an LP is a relatively simple procedure, but there is a lot of parental resistance to it," he noted.
Dr. Callahan examined the question in light of infants’ most common bacterial infection – the urinary tract infection (UTI). Studies from the last 15 years agree that, while the risk of meningitis in conjunction with UTI is very low, it is there.
The largest of these included nearly 2,000 infants with culture-proven UTI. Most (1,609) underwent an LP. Of those patients, 3% had bacterial meningitis. A combination of clinical findings – not clinically ill on exam, no dehydration or acute respiratory distress, no concomitant acute disease or high-risk medical history – ruled out meningitis with a 98% sensitivity and 99.9% negative predictive value (Pediatrics 2010;126:1074-83).
A 2011 study found a 1% rate of meningitis associated with UTI in infants younger than 28 days, but there were no cases at all in the older babies. All of those with meningitis were symptomatic on admission, with fever, irritability, and lethargy (PLoS One 2011;6:e26576).
"Meningitis appears exceedingly rare in children older than 28 days," Dr. Callahan said. "All neonates who present with a culture-proven UTI should have an LP. But those who are older, and who look well, without a negative past history – you might consider not doing one."
Whether or not the child will be admitted to the hospital plays a part in Dr. Callahan’s decision.
"If they have a UTI and they’re getting admitted, but look well and have a negative past medical history, I don’t tap. I really think the data say if they look like they are well, they will not get meningitis."
If, on the other hand, the baby will be going home from the emergency visit, he does the procedure. "And make sure you have someone who’s going to follow that child very closely," he advised.
Dr. Callahan had no financial disclosures.
LAKE BUENA VISTA, FLA. – Does every baby who presents to the emergency department with a urinary tract infection need a lumbar puncture to rule out meningitis?
Maybe not, Dr. James Callahan said at the Advanced Pediatric Emergency Medicine Assembly. Age, past medical history, and the child’s overall demeanor are the best clues as to whether to proceed with a spinal tap in babies with a confirmed source of infection.
The topic is worth reviewing because childhood meningitis cases are on the decline, said Dr. Callahan of Children’s Hospital of Pennsylvania, Philadelphia.
When a disease begins to fade from a patient population, it also can fade from the collective consciousness of clinicians. "There are residents and fellows in emergency medicine and pediatrics now who have never seen a case of [Haemophilus] influenzae meningitis," he said at the meeting, which was sponsored by the American College of Emergency Physicians and the American Academy of Pediatrics.
That can mean tragedy for patients and families, and disaster for doctors. "Missed meningitis remains the number-one cause of settled lawsuits in pediatric emergency medicine, and carries the highest settlement and indemnity costs," he said.
A number of signs can help rule in the disease, but few can completely rule it out. "Although several clinical features are useful in diagnosing meningitis, no one isolated clinical feature is diagnostic. Nor can any isolated clinical feature completely exclude meningitis as a diagnostic possibility, and it’s not clear what the most accurate combination of clinical features is – or if there even is such a combination," Dr. Callahan explained.
That leaves clinicians with what seems to be the only concrete option – the lumbar puncture. "I personally think an LP is a relatively simple procedure, but there is a lot of parental resistance to it," he noted.
Dr. Callahan examined the question in light of infants’ most common bacterial infection – the urinary tract infection (UTI). Studies from the last 15 years agree that, while the risk of meningitis in conjunction with UTI is very low, it is there.
The largest of these included nearly 2,000 infants with culture-proven UTI. Most (1,609) underwent an LP. Of those patients, 3% had bacterial meningitis. A combination of clinical findings – not clinically ill on exam, no dehydration or acute respiratory distress, no concomitant acute disease or high-risk medical history – ruled out meningitis with a 98% sensitivity and 99.9% negative predictive value (Pediatrics 2010;126:1074-83).
A 2011 study found a 1% rate of meningitis associated with UTI in infants younger than 28 days, but there were no cases at all in the older babies. All of those with meningitis were symptomatic on admission, with fever, irritability, and lethargy (PLoS One 2011;6:e26576).
"Meningitis appears exceedingly rare in children older than 28 days," Dr. Callahan said. "All neonates who present with a culture-proven UTI should have an LP. But those who are older, and who look well, without a negative past history – you might consider not doing one."
Whether or not the child will be admitted to the hospital plays a part in Dr. Callahan’s decision.
"If they have a UTI and they’re getting admitted, but look well and have a negative past medical history, I don’t tap. I really think the data say if they look like they are well, they will not get meningitis."
If, on the other hand, the baby will be going home from the emergency visit, he does the procedure. "And make sure you have someone who’s going to follow that child very closely," he advised.
Dr. Callahan had no financial disclosures.
EXPERT ANALYSIS FROM THE ADVANCED PEDIATRIC EMERGENCY MEDICINE ASSEMBLY
